Datasets:

TomTBT
/

pmc_open_access_xml

Dataset card Data Studio Files Files and versions Community

Subset (3)

commercial · ~3.84M rows (showing the first 120k)

Split (1)

train · ~3.84M rows (showing the first 120k)

accession_id stringlengths 9 11	pmid stringlengths 1 8	introduction listlengths 0 213	methods listlengths 0 389	results listlengths 0 2.61k	discussion listlengths 0 371	conclusion listlengths 0 229	front listlengths 0 66	body listlengths 0 2.64k	back listlengths 0 550	figure listlengths 0 370	table listlengths 0 999	formula listlengths 0 2.66k	box listlengths 0 58	code listlengths 0 10	quote listlengths 0 105	chemical listlengths 0 0	supplementary listlengths 0 74	footnote listlengths 0 37	graphic listlengths 0 2.41k	media listlengths 0 74	unknown_pub stringlengths 2 363k	glossary dict	n_references int32 0 1.35k	license stringclasses 4 values	retracted stringclasses 2 values	last_updated stringlengths 19 19	citation stringlengths 14 89	package_file stringlengths 0 35
PMC10590219	0	[]	[]	[]	[]	[]	[ "<p>District level access to surgical care has been identified as the rate limiting step to increasing access to the bottom billion and relies on a complex interplay of patient-related and system-based factors that underlie the provision of quality surgical care at point of care. Surgical mentoring via visiting teams, use of current proprietary technologies to enhance communication, establishment of a national surgical coordinator and multi-stakeholder engagement with creative cost-sharing have all demonstrated promising results. Regardless of strategic implementation frameworks, system-based thinking coupled with implementation science with practical solutions will be necessary to inform stakeholders on the best way forward in their respective geographic field of work charting a path towards surgical equity in universal health coverage (UHC).</p>", "<p>\n<bold>Citation:</bold> Henry JA. Beyond policy: strengthening district level access to surgery is critical to achieving surgical equity in universal health coverage: Comment on \"Improving access to surgery through surgical team mentoring – policy lessons from group model building with local stakeholders in Malawi.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7594. doi:10.34172/ijhpm.2023.7594</p>" ]	[ "<p> The accompanying article by Broekhuizen et al,<sup>##REF##34380202##1##</sup> is an interesting application of implementation science using a mixed methods approach that codifies the complex web of factors affecting district level surgical care access. The result is a hybrid model on the optimal frequency of surgical mentoring occurrences as well as various recommendations on increasing the effectiveness of the model in low- and middle-income countries. The goal is adoption, ownership, sustainability, and finally, institutionalization of district-level surgical team mentoring within national policy frameworks.</p>", "<p> The issue, strengthening district level access to surgical care, has long been identified as a key strategy to improve equity in surgical service provision<sup>##REF##26553824##2##,##UREF##0##3##</sup> and the absence of an accepted proven model has rendered most recommendations, at best, theoretical frameworks. The challenges are understandable, as no ‘one-size-fits-all’ strategy has come to the fore in the last few decades of work, and we are now faced with coming down to discerning nuances and identifying important principles of change. The authors are to be commended, therefore, for their continued focus on this area as well as in the application of scientific rigor to the project. The goal, ultimately, is sustainability and country-level ownership through policy-level actions. The conclusions from the paper can also provide guidance in terms of increasing the efficiency of the mentoring model, providing cost data as well as data on the efficiencies of particular design choices in the rollout of the intervention. Translated properly, this kind of information would be of interest to offices with very strict to almost no budgetary allotment to foster these kinds of activities. Taken in isolation, however, it runs the risk of overshadowing other equally important strategic elements of what it means to build capacity, as training without equipping someone with the means to deliver effective surgical care is akin to teaching someone to fish without supplying them with a boat and a fishing rod. Nevertheless, the overarching recommendations are sound, and perhaps can be expounded and clarified. For example, the authors emphasize the need to “create a focal point with a dedicated national coordinator.” This strategy has been employed in Mongolia<sup>##REF##22674091##4##</sup> and has served to help increase national surgical capacity by strengthening the <italic toggle=\"yes\">Soum</italic> (the equivalent of districts). Prior to the appointment of a national coordinator, various international organizations were operating independently of each other. In 2006, the Mongolian Ministry of Health launched a national program in partnership with the World Health Organization (WHO) to strengthen emergency and essential surgical care. The coordinator was able to bring together various organizations such as the Swiss Surgical Team, a branch of the International College of Surgeons, the Swiss Government Agency for Development and Cooperation, the Swanson Foundation, and various other organizations, to name a few, to enhance surgical education alongside infrastructure development, resulting in inclusion of 67% of the <italic toggle=\"yes\">aimags </italic>(provinces) and 52.66% of the <italic toggle=\"yes\">soum </italic>(district) hospitals. Post-training and infrastructure development assessments included increase in the fund of knowledge of participants from 47.72% (95% confidence interval 40.7–54.7) to 77.9% (95% confidence interval 70.1–85.7, <italic toggle=\"yes\">P</italic> = .0001) after the training program. There was also a 57.1% increase in the availability of emergency rooms, 59.1% increase in the supply of emergency kits, a 73.64% increase in the recording of emergency care cases, and a 46.66% increase in the provision of facility and instrument usage instructions at the included sites.<sup>##REF##22674091##4##</sup> It would be useful to clarify if this individual is an employee of the Ministry of Health and is charged with other matters pertaining to surgical capacity building (ie, organizing training programs, camps, interfacing with visiting surgical teams, procurement or supplies, equipment, quality improvement, etc) or is mainly focused on coordinating field visits. This coordinator, as the authors state, can now be the ‘glue’ that binds the districts and the central hospital, creating the hub and spoke model that was mentioned.<sup>##REF##35184510##6##</sup></p>", "<p> The authors also note field visits of up to four times per year with a corresponding 5% cancellation rate compared with six (25% cancellation rate). This roughly translates to one field visit every three months, with variable patient load available. With the rise of Zoom and WhatsApp technology as ubiquitous and freely available, virtual meetings should be held at least weekly or bi-weekly with conference, morbidity and mortality, and quality improvement meetings. This will allow regular reporting of District Hospital performance as well as provide an opportunity for the mentees to raise concerns and not have to wait for three months before being able to rectify any identified problems. This model is currently being studied in three African countries.<sup>##REF##30820336##7##</sup> The field visits should be used wisely and have strict parameters, eg, may stack elective complicated cases that could not be referred to the central hospital but need to address urgent or semi-urgent conditions with a specialist available by WhatsApp or Zoom. Moreover, the field visits, scheduled in advance, represents an opportunity for the communities serviced to conduct surgical outreach (eg, door to door campaigns searching for patients living with neglected surgical conditions)<sup>##REF##32801221##8##</sup> to reduce the backlog and address these conditions before they advance beyond functional repair.</p>", "<p> Several strategies that have been brought up reflect current global recommendations – district level packages of care, hub and spoke referral networks, monitoring and evaluation,<sup>##REF##35184510##6##</sup> and in the current article, introducing a financing mechanism through which district hospitals are rewarded for more surgical procedures done.<sup>##REF##34380202##1##</sup> While suggestions on increasing financial incentives for surgical care at the district level may increase the number of surgical care provision, for countries in the low-income bracket who have serious non-surgical competing priorities for resources, this may be not be feasible. The next statements confirm this fact as the authors point out that the source of financing in the districts as mainly donor-driven. Moreover, lessons learned from high-income countries and other low- and middle-income countries have shown that introducing a financing mechanism to reward either hospitals or providers for more surgery (eg, fee-for-service) does not necessarily translate to increased access to quality or safe surgical care, and may in fact, lead to unnecessary procedures designed to maximize income.<sup>##REF##25674568##9##</sup></p>", "<p> Thus, for countries at this economic stage, creative cost-sharing may fare better than suggesting fee-for-service incentives for providers. As an example, the Neglected Surgical Diseases (NSDs)<sup>##REF##32801221##8##</sup> project in Meru, Kenya partnered with the Kenya Ministry of Health, the Meru County Government and major non-governmental organizations in addressing the backlog of neglected surgical conditions such as neglected clefts, cataracts, clubfoot, injuries, obstetric fistulas, and hernias and hydroceles. The project involved a multi-stakeholder engagement strategy involving government, academia, non-governmental organizations, and private entities partnering with an established institution such as the College of Surgeons of East, Central, and Southern Africa (COSECSA) in identifying gaps in infrastructure, workforce, and processes required to deliver surgical care safely. In February 2019, 694 community health volunteers undertook door to door screening in five sub-counties of Meru covering 12 189 Meru citizens. An overall prevalence of 30.7% (n = 3748 NSDs) was reported, all with photo identifiers. Prevalence of index NSDs include hernia (7.63%), neglected injury (17.2%), cataract (10.2%), clubfoot (5.56%), fistula (0.6%), cleft (1.3%), and others (8.1%). The elimination of NSDs commenced in June 2019 with a second layer of screening undertaken by the County Health Management Team and Ophthalmic team (n = 1063 clients screened). 232 surgeries were done at the county level while training local ophthalmologic surgeons (n = 214 cataracts, 18 other eye conditions). The follow-up rate post-operatively was 60% with 90% reporting improved vision. The Meru county government equipped eight level four hospitals with a major operating room, onboarded 10 medical doctors and 50 nurses, and has installed 2 surgical residents in the Meru County Level 5 hospital in collaboration with the COSECSA. This model has proved to be an example of utilizing available resources to enhance local surgical capacity building marrying stakeholder engagement with creative cost sharing, building trust with the local government and engendering local ownership of the project.<sup>##UREF##2##10##</sup></p>", "<p> In conclusion, accelerated efforts to strengthen district level surgical care whether through local mentoring or other dedicated strategies is critical to achieving surgical equity within universal health coverage (UHC) and in pursuit of several goals and targets set within the WHO’s Thirteenth General Programme of Work 2019–2023 which calls for a global commitment to reach one billion more people with UHC<sup>##UREF##3##11##</sup> as well as to renew commitment to the landmark WHO Surgical Resolution 68.15, Strengthening Emergency and Essential Surgical Care as a Component of UHC.<sup>##UREF##4##12##</sup> Several proposed strategies are all commendable but will need system-based thinking coupled with implementation science to prove its efficacy according to corresponding environments in which it is applied as well as to institutionalize it within governmental frameworks. We need to move beyond proposing strategies to demonstrating effectiveness and scalability in order to move the needle towards safe, equitable, quality surgical care for all, especially for the bottom billion.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that she has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["3"], "person-group": ["\n"], "surname": ["Madhuri", "Stewart", "Lakhoo"], "given-names": ["V", "RJ", "K"], "article-title": ["Training of children\u2019s surgical teams at district level in low- and middle-income countries (LMIC): from concept to reality\u2014a south to south initiative"], "source": ["Int J Surg Glob Health"], "year": ["2019"], "volume": ["2"], "issue": ["3"], "fpage": ["e08"], "pub-id": ["10.1097/gh9.0000000000000008"]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Henry"], "given-names": ["JA"], "source": ["World Health Assembly Side event on Achieving Surgical Excellence through Evidence-Based Quality Improvement Initiatives in LMICs: Strategies for Scaling Up Access, Quality, and Safety in Surgical, Obstetric, Trauma, and Anesthesia Care"], "year": ["2022"], "publisher-loc": ["Geneva"], "publisher-name": ["G4 Alliance"], "size": ["2"]}, {"label": ["10"], "mixed-citation": [" Henry JA. The Right to Heal:Eradicating Neglected Surgical Diseases-Sharing the Progress in Meru County, Kenya. Paper presented at: Orlando, Florida: Academic Surgical Congress; 2020. "]}, {"label": ["11"], "mixed-citation": [" World Health Organization (WHO). Thirteenth General Programme of Work 2019-2023. WHO; 2019. "], "uri": ["https://apps.who.int/iris/bitstream/handle/10665/324775/WHO-PRP-18.1-eng.pdf"]}, {"label": ["12"], "mixed-citation": [" World Health Organization (WHO). Strengthening Emergency and Essential Surgical Care and Anaesthesia as a Component of Universal Health Coverage. WHO; 2015. "]}]	{ "acronym": [], "definition": [] }	12	CC BY	no	2024-01-13 00:00:40	Int J Health Policy Manag. 2023 Sep 17; 12:7594	oa_package/83/2c/PMC10590219.tar.gz
PMC10590220	0	[ "<title>Background</title>", "<p> The challenge of effectively scaling up promising innovations beyond pilot projects often hinders efforts to improve healthcare.<sup>##REF##29166911##1##, ####REF##11585159##2##, ##UREF##0##3##, ##REF##26264351##4####26264351##4##</sup> A healthcare innovation is a new product, intervention, care pathway, or service that significantly benefits patients and health systems.<sup>##REF##31098448##5##, ####REF##15595944##6##, ##REF##16407603##7##, ##REF##31076440##8####31076440##8##</sup> Scaling up innovations involves iterative decisions, events, and actions to tackle infrastructure issues that arise across health system levels while expanding innovations to full scale to benefit targeted populations.<sup>##REF##29166911##1##,##REF##26264351##4##,##REF##27993138##9##</sup></p>", "<p> Canada faces persistent difficulties in scaling-up healthcare innovations,<sup>##REF##29166911##1##,##REF##11585159##2##,##REF##31519185##10##, ####REF##19506272##11##, ##REF##26742111##12##, ##UREF##1##13##, ##REF##28202565##14####28202565##14##</sup> leading to its reputation as the “country of perpetual pilot projects.”<sup>##REF##19506272##11##</sup> Scaling up healthcare innovations in Canada presents a complex and multifaceted challenge that remains poorly understood. Health system leaders and experts have identified several potential barriers, including resources allocated primarily towards pilot projects rather than expansion, inadequate support for clinician-innovators, limited engagement of diverse actors including patients, a risk-averse culture, opaque decision-making processes, insufficient data infrastructure and access, fragmented health systems, ineffective change management, and a general lack of knowledge regarding the most effective strategies for scaling up innovations.<sup>##REF##19506272##11##,##UREF##1##13##,##REF##28202565##14##</sup></p>", "<p> A growing body of evidence on the science of scaling up healthcare innovations has identified several enabling factors.<sup>##REF##29166911##1##,##REF##26264351##4##,##REF##27993138##9##,##REF##31519185##10##,##REF##32493357##15##, ####REF##21738450##16##, ##UREF##2##17####2##17##</sup> These factors include (1) identifying population needs and system problems; (2) dedicating human, financial, and technical resources; (3) creating relational and political connections and actively involving key actors; (4) strong health professional leadership; (5) adapting to the political context and integrating with existing services; and (6) measuring and disseminating innovation and scale-up outcomes.</p>", "<p> However, two significant gaps persist in the current literature on scaling up healthcare innovations. Firstly, most studies focus on low- and middle-income countries, which provide valuable information but may differ in terms of resources, policies, governance, and infrastructure compared to high-income contexts.<sup>##REF##29166911##1##,##REF##26264351##4##,##UREF##2##17##, ####REF##33434141##18##, ##REF##27364384##19####27364384##19##</sup> Secondly, there is a notable dearth of evidence on the operationalization of scale-up and strategies that key actors can adopt to address enabling factors.<sup>##REF##37329836##20##</sup> Thus, there is a need to study empirical scale-up processes and strategies within the context of high-income countries. Such evidence may provide much-needed guidance on expanding proven healthcare innovations to improve equitable health outcomes in universal health systems.</p>", "<p> eConsult is one of the most promising health innovations piloted in Canada to improve access to specialist care.<sup>##REF##29743227##21##, ####REF##31637228##22##, ##UREF##3##23##, ##REF##24073898##24####24073898##24##</sup> eConsult is an asynchronous electronic communication platform used to transmit medical advice between a primary care professional and specialists in fields such as dermatology, cardiology, pediatrics, oncology, psychiatry, and geriatrics.<sup>##REF##29743227##21##, ####REF##31637228##22##, ##UREF##3##23##, ##REF##24073898##24####24073898##24##</sup> Studies have demonstrated that eConsult reduces wait times, avoids face-to-face referrals, is associated with positive patient and professional experiences, reduces health system costs, and improves equity.<sup>##REF##29743227##21##, ####REF##31637228##22##, ##UREF##3##23####3##23##</sup></p>", "<p> The Building Access to Specialists through eConsultation (BASE<sup>TM</sup>) eConsult model was developed and piloted in one region of the Canadian province of Ontario in 2009,<sup>##REF##24073898##24##</sup> then spread throughout Ontario and further expanded to other Canadian provinces. This evidence-based innovation began as a small proof-of-concept pilot project that was spread and is being scaled up in other Canadian provinces. eConsult is trademarked by the founders of BASE<sup>TM</sup> eConsult, who charge minimal fees for service maintenance but do not charge for its use by other provinces. eConsult is free-of-charge for physicians and professionals. Specialists received a pro-rated fee for each eConsultation as part of a research project. ##FIG##0##Figure 1## illustrates the eConsult innovation implemented in the four provinces under study. The fact that the four provinces are at different stages of the scale-up process offers a unique learning opportunity.<sup>##REF##31511008##25##</sup></p>", "<p> Our study aims to identify the key factors that enabled the scale-up of eConsult and the strategies used to address them in four provinces in Canada. As part of this study, we define the <italic toggle=\"yes\">factors</italic> enabling scale-up as the key areas identified to facilitate scale-up, whereas the <italic toggle=\"yes\">strategies</italic> for scale-up are the actions taken by actors to address these factors.</p>" ]	[ "<title>Methods</title>", "<title> Design </title>", "<p> The research used a narrative case study design.<sup>##UREF##4##26##</sup> This design involved an in-depth examination of eConsult implementation by triangulating data from multiple sources and contexts and reconstructing each studied case in narrative form.<sup>##UREF##5##27##</sup> The study included four Canadian provinces where eConsult scale-up was underway<sup>##UREF##6##28##</sup>: Quebec, Ontario, Manitoba, and Newfoundland & Labrador. In Canada, the health care system is publicly funded, but provinces are responsible for planning, administering, and delivering health care services, resulting in provincial differences in laws, regulations, and structures. The provinces under study had participated in a national Partnership for Health System Improvement grant and in the Canadian Foundation for Health Improvement’s (CFHI’s) Connected Medicine Initiative (2017–2018).<sup>##UREF##6##28##,##UREF##7##29##</sup> Each province was at a different stage of the scale-up process, providing a richer understanding of the various stages of implementation.<sup>##UREF##4##26##,##UREF##6##28##</sup></p>", "<title> Data Collection </title>", "<p> Between August 2018 and April 2021, we collected data for each jurisdiction as well as data from national organizations (across provinces). Our data sources included non-participant observations, reviews of internal documents, and interviews (see ##TAB##0##Table 1##). We continued data collection until we reached empirical data saturation within each jurisdiction.</p>", "<title> Non-participant Observations</title>", "<p> We observed provincial eConsult steering committee meetings (n = 65) selected based on agenda items. Participants of the steering committee meetings included primary care professionals, specialists, policy-makers, researchers, information technology (IT) experts, and patients. These meetings focused on the spread and provincial scale-up of eConsult and helped us to better understand the contexts and gather monthly data on what was happening in each province. We collected data using an observation form we developed based on the key enabling factors for scale-up identified in the literature<sup>##REF##29166911##1##,##REF##26264351##4##,##REF##32493357##15##,##UREF##8##30##</sup> as well as elements deemed essential by knowledge users for the implementation of eConsult at a provincial scale. We completed the observation form, which has been previously published elsewhere,<sup>##REF##31511008##25##</sup> live during the meetings. Two PhD-trained research professionals (MAS and CLL) conducted initial observations to test the form and achieve consensus on its use. CLL conducted the remaining observations. In addition, we used the same form to observe three National eConsult Forums (2018 – in person, 2019 – in person, 2020 – virtual) where 75 to 150 provincial and national actors (eg, policy-makers, patient partners, family physicians, specialists, researchers, partner organizations) discussed scale-up strategies.</p>", "<title> Internal document review</title>", "<p> We collected internal documents (n = 93), such as meeting minutes, PowerPoint presentation slide decks, working documents, policy documents, and scale-up plans, either directly from key actors or by observing committees.</p>", "<title> Semi-structured interviews</title>", "<p> We conducted semi-structured interviews (n = 40) with key actors in each province (eg, researchers, primary care professionals, specialists, policy-makers, patient partners). To capture a variety of perspectives, we recruited participants with varied roles in the scale-up process and experience with and knowledge of eConsult. We recruited all key actors participating in provincial eConsult committees and those involved in eConsult implementation at the regional, provincial, and national levels. The researchers and knowledge users on our team helped us identify key actors to approach for participation. We adapted the interview guide from a previously published guide<sup>##REF##31511008##25##</sup> and tailored it according to each participant’s role and province. Two researchers with expertise in qualitative interviewing (MAS and CLL) who had not played a role in the scale-up of eConsult conducted the interviews to ensure confidentiality and minimize the influence of the interviewers on the answers provided. We digitally recorded and transcribed all interviews verbatim.</p>", "<title> Data Analysis </title>", "<p> We based our analysis on the main factors identified in the literature that enable the scale-up of health innovations. Our initial thematic analysis<sup>##UREF##9##31##</sup> drew inspiration from Roger’s foundational work on the diffusion of innovations,<sup>##UREF##8##30##</sup> the 20 scale-up success factors identified by Milat et al,<sup>##REF##26264351##4##</sup> factors identified in a literature review published by Ben Charif and al,<sup>##REF##29166911##1##</sup> and factors identified in a study on factors influencing the scale-up of eConsult published by Moroz and al.<sup>##REF##32493357##15##</sup> We imported transcripts of the 40 interviews (lasting 60 minutes on average) into NVivo 12. Observation notes informed our analysis. First, CLL and MAS coded four transcripts, discussing divergences in their codes after each one. Once they reached coding agreement, CLL coded the remaining transcripts. Second, based on the codebook, CLL wrote case narratives for each province detailing context, strategies (eg, events, decisions, and actions), and enabling factors and their influence on the scale-up process. Two other team members (MB and MAS) reviewed these narratives for clarity and completeness. Three researchers on the team (MB, MAS, and CLL) then analyzed strategies across cases, grouping similar strategies and categorizing them within the key enabling factors identified in the literature review. Finally, in May 2021, we held two 60-minute virtual meetings to share, discuss, and validate the key enabling factors and related strategies with team members from the four provinces who were either involved in scaling up eConsult or had expertise in scaling up innovations. We organized two meetings based on the same content to reach as many participants as possible. At these meetings, we used interactive methods (eg, chat box, virtual sticky notes, and live discussions) to facilitate a structured discussion around the trustworthiness and confirmability of the preliminary findings.</p>" ]	[ "<title>Results</title>", "<p> We studied the process of scaling up eConsult in four provinces. ##TAB##1##Table 2## lists the characteristics of each of the jurisdictions.</p>", "<p> Based on case narratives and team discussions, we identified six common enabling factors across the four provinces, which we refer to as key factors enabling eConsult scale-up: (1) multi-actor engagement; (2) relative advantage; (3) knowledge transfer; (4) strong evidence base; (5) physician leadership; and (6) resource acquisition. Below, we present each factor in turn, explaining why it is key to the scale-up of eConsult and describing the strategies used to address it. ##FIG##1##Figure 2## summarizes the factors and strategies.</p>", "<title> Multi-actor Engagement </title>", "<title> Why Is This Enabling Factor Key to the Scale-Up of eConsult? </title>", "<p> Ongoing engagement of multiple key actors — including patient partners, policy-makers, primary care professionals, specialists, IT experts, and researchers — helped to strategically align the implementation of eConsult with provincial health system priorities and adapt to changing policy contexts. Additionally, engaging various actors from a broad range of organizations and with varied perspectives allowed for early identification of potential policy and infrastructure issues that needed to be addressed and helped to navigate complex policy processes.</p>", "<title> What Strategies Were Used? </title>", "<p> In each province, the engagement of key actors began with the physician leaders who first piloted the innovation. They recruited a team of knowledge users and patient partners through their personal and professional networks to prepare and apply for one or more research grants. Research funds facilitated the assembly of these teams, and collaborating on a concrete project in this way helped to build their interest and commitment. Motivated and action-oriented strategic actors received invitations to participate in research grants. As eConsult was spread and scaled up, steering committees enlisted additional members to provide insights into emerging issues and recruited specific high-level policy-makers to participate on the committee and act as representatives of their organizations (eg, ministries of health, medical associations). Provincial eConsult physician leaders chaired these meetings. Throughout the scale-up process, provincial eConsult steering committees that met once or twice per month maintained actor engagement for the most part. At these meetings, physician leaders and researchers provided updates on evaluation results (eg, eConsult volumes, wait times), members whose organizations were directly involved in the scale-up process updated the committee on their progress, and committee members discussed emerging challenges, brainstormed solutions, and advised high-level actors on strategic orientations. Beyond these meetings, the research team ensured ongoing engagement of key actors by providing communication tools they could use to advocate for eConsult (eg, presentation slide decks, policy briefs, and letter drafts). Moreover, they celebrated eConsult milestones and successes with all those involved to help build a sense of ownership among them. Furthermore, the Ontario team invited actors from around the country to participate in National eConsult Forums held in collaboration with the Royal College of Physicians and Surgeons of Canada. Participants perceived these forums as fostering further engagement, particularly in provinces that were at the earlier stages of scaling up eConsult. At these forums, 75–150 individuals discussed the potential value of scaling up eConsult. Inviting national-level policy-makers (eg, College of Family Physicians of Canada, Royal College of Physicians and Surgeons) to these forums provided them with an opportunity to discuss national issues, such as interjurisdictional licensing and inclusion of eConsult in medical curricula, to brainstorm solutions, and to stay up-to-date on the progress of scale-up in each province.</p>", "<p> Various actors played different complementary roles in the scale-up of eConsult. High-level actors (eg, policy-makers, representatives of medical associations, and physician leaders) participated as spokespeople who endorsed eConsult and advocated for its scale-up among influential actors. Patient partners encouraged the use of several strategies, such as evaluating eConsult from the patient perspective, acting as strong advocates for eConsult, drafting jargon-free promotional materials, and including rich patient stories to promote eConsult.</p>", "<p> “<italic toggle=\"yes\">I just think that the patient reps and the stories that they bring are the most important part of the development project because we need to be listening to them. We need to be learning from them</italic>” (Newfoundland & Labrador).</p>", "<p> Multiple types of actors spread a similar message about the need to scale up eConsult through their respective communication channels, generating momentum and excitement across the country.</p>", "<p>\n##TAB##2##Table 3## presents a summary of the strategies used in each province to address multi-actor engagement.</p>", "<title> Relative Advantage </title>", "<title> Why Is This Enabling Factor Key to the Scale-Up of eConsult? </title>", "<p> Our results suggest that, in all provinces, a variety of key actors perceived eConsult to be highly useful and to have a strong relative advantage over the status quo or other innovations. This positive perception facilitated its widespread adoption by health service professionals and, hence, its scale-up.</p>", "<title> What Strategies Were Used? </title>", "<p> eConsult was designed to be as simple as possible for professionals to use. Several respondents highlighted the importance of developing a simple intervention that facilitated its implementation and use. Participants perceived eConsult as being easy for potential adopters and policy-makers to understand and for professionals to use in everyday practice. Furthermore, it was seen as being easy for organizations to manage changes required for its implementation. In particular, participants noted that being a simple, streamlined innovation that integrates well into professionals’ workflows set eConsult apart from other innovations.</p>", "<p> “<italic toggle=\"yes\">What makes it different is how it is embedded in the workflow. So, it’s convenient…” </italic>(Manitoba).</p>", "<p> For example, respondents felt that the use of a standardized form with only four mandatory questions facilitated its integration into the workflows of primary care professionals. Although many specialists requested that the form be tailored to their specific needs, the Ontario team decided, based on their experience and user feedback, to use one standardized form with only four fields applicable to any medical specialty. They felt that this would be less burdensome for primary care professionals and, therefore, increase the likelihood of them using it. Our results show that this simplicity helped to avoid delays in scale-up because the design focused on core elements and limited “scope creep,” particularly in terms of IT developments and integration with electronic medical records. This idea of simplicity achieved consensus among the interviewees.</p>", "<p> “<italic toggle=\"yes\">…developing and scaling integrated things is much harder than developing and scaling dead simple things. So, the trade off, I think it’s easier to scale something dead simple</italic>…” (Ontario).</p>", "<p> “<italic toggle=\"yes\">…The conclusion that I have made is that, even if it’s not advanced computing, [...] the technical solution has to be simple and user friendly and just easy to use and adopt” </italic>(Manitoba).</p>", "<p> One of the main strategies for development, spread, and scale-up was to begin by addressing users’ needs and to subsequently adapt to their preferences while maintaining a functional eConsult service.</p>", "<p> To ensure a relative advantage in terms of usability and ease of implementation, and to reduce adoption burden on professionals, the design of eConsult mirrored traditional referral processes as much as possible. For example, mandatory close-out surveys (all provinces) collected user feedback, and a user advisory committee (Manitoba) adapted the service to user feedback (eg, problems, frustrations, and suggested improvements) to make it user-friendly and ensure integration into the existing workflows of specialists and primary care professionals. Research teams regularly analyzed responses and used them to continually improve the innovation.</p>", "<p> Refinement of the eConsult model largely took place during the stages of the pilot project in Ontario. The other provinces followed this model on the BASE<sup>TM</sup> platform (Manitoba, Newfoundland and Labrador) or on a local platform managed by a private company (Quebec). In the three other provinces, changes made to eConsult related mainly to technical issues or requests to add new specialties to the service.</p>", "<p> In all provinces studied, regional coordinators provided training and ongoing support to help professionals with the onboarding process to the eConsult platform and to troubleshoot issues. In some cases, clinical administrative staff were trained or a train-the-trainer approach was used to ensure access to local support. Training videos and guides, remote virtual training sessions, and in-person training further facilitated adoption and implementation.</p>", "<p> Integrating eConsult with other existing services was another strategy used to ensure its relative advantage. Although the eConsult platform started as a standalone service, both Newfoundland & Labrador and Ontario integrated eConsult with existing services within electronic health records or with other telemedicine services. Newfoundland & Labrador’s use of a single electronic health record facilitated eConsult’s integration across the province. Ontario integrated eConsult into targeted electronic health records as a pilot project. In Quebec, in 2021, work was underway to integrate eConsult within regional dispatch centers for referrals to specialists.</p>", "<p> To ensure potential adopters were aware of eConsult’s relative advantages (eg, simplicity, effectiveness, ease of use for professionals, and usefulness for patient care), information about eConsult was promoted through a variety of channels, including institutional newsletters, social media, news media (eg, newspaper advertisements and press coverage), eConsult websites, information booths at relevant events, word of mouth (eg, physician champions and patient partners), webinars, presentations, policy briefs, infographics, and promotional material. In Ontario, traditional referral requests that could be answered by eConsult were often returned to the primary care professionals with a recommendation to send the request as an eConsult, thereby helping to promote the service. Promotional messages describing eConsult and promoting its relative advantages were evidence-based, focused, and consistent. For example, Canada Health Infoway created short videos featuring professionals’ testimonials about their positive experiences with eConsult for publication on their website. Patients’ stories of the perceived benefits of eConsult also promoted eConsult to policy-makers. Finally, the favouring of images over words (eg, infographics and images) increased the accessibility and retention of the promotional messages.</p>", "<p>\n##TAB##3##Table 4## presents a summary of the strategies used in each province to address relative advantage.</p>", "<title> Knowledge Transfer </title>", "<title> Why Is This Enabling Factor Key to the Scale-Up of eConsult? </title>", "<p> Transferring learnings from Ontario to the other provinces helped to accelerate some aspects of the scale-up process by enabling them to benefit from other’s experiences. Additionally, it generated excitement about eConsult among key actors and increased national momentum for its spread and scale-up. Finally, this key enabling factor created positive peer pressure among provincial actors.</p>", "<title> What Strategies Were Used? </title>", "<p> Ontario was the first province to begin scaling up eConsult, and they freely shared their evidence and tools (eg, business case, policy brief, implementation guide, training tools; see <uri xlink:href=\"https://www.champlainbaseeconsult.com/\">https://www.champlainbaseeconsult.com/</uri>) with the other three provinces. For instance, Ontario leaders shared the eConsult platform they developed with other jurisdictions for a small system maintenance fee. Ontario leaders also shared lessons learned, experiences acquired from spreading and scaling up eConsult, tools, and strategies used to address the challenges they encountered. In doing so, the provinces were able to benefit from the work others had done and adapt it to their jurisdiction, saving them the time and effort of starting from scratch. As a result, they drafted plans to avoid some of the challenges others had faced and devised creative solutions to overcome known barriers to scaling up eConsult. The National eConsult Forums also played a fundamental role in supporting knowledge transfer. At each edition of the forum, participants not only shared learnings from their jurisdiction but also collectively brainstormed potential solutions to challenges.</p>", "<p> “<italic toggle=\"yes\">I think one of the first turning points for me was the national gatherings – the forum. There were a lot of ‘ ahas ’ in the room. People were curious. [...] The forum is a great opportunity to showcase success, discuss challenges but also to sell the concept.</italic> […] <italic toggle=\"yes\">For those who are less sure about it, to be in a room, to talk about it for a day and a bit, it’s difficult to walk away not thinking that this is a good idea” </italic>(National).</p>", "<p> eConsult was part of the CFHI’s Connected Medicine Collaborative, which engaged key actors from different provinces in a formal program aiming to help spread remote consultation services (eg, eConsult and phone consultations). The work of the CFHI collaborative included hosting webinars, developing business cases, establishing governance and scale-up plans, providing coaching from innovation leads, and organizing regular meetings to foster the sharing of lessons learned across provinces.</p>", "<p> “<italic toggle=\"yes\">I think it was really good to be involved from the get-go with the other folks that are doing similar things across the country. Having that opportunity to collaborate and to meet in person, in particular to learn what others are doing, was very valuable. It helped us to figure out what kind of metrics we should be looking at from the get-go” </italic>(Newfoundland & Labrador).</p>", "<p> Ontario’s eConsult leads also acted as mentors to those in other provinces. They regularly participated in eConsult steering committee meetings and in discussions with high-level policy-makers by presenting evidence and offering suggestions. This enabled the leads to remain informed of progress in each jurisdiction and facilitated the exchange of strategies used among jurisdictions. For instance, they shared insight into various strategies to build a convincing rationale for scaling up eConsult and for securing funds from alternative sources to help transition eConsult from a research project to a sustainable innovation.</p>", "<p>\n##TAB##4##Table 5## presents a summary of the strategies used to address knowledge transfer.</p>", "<title> Strong Evidence Base </title>", "<title> Why Is This Enabling Factor Key to the Scale-Up of eConsult? </title>", "<p> Research funds initially supported the development and piloting of eConsult, and research played an important role throughout all stages of eConsult’s development. The fact that eConsult was embedded within a research infrastructure fostered the creation of a strong evidence base. Several domains contributed data to the evidence base, including the effectiveness (number of non-urgent in-person visits avoided, patient satisfaction, increased access to specialized care), cost-effectiveness (cost per eConsult, cost per eConsult avoided), feasibility (growth projections for volume of eConsults), acceptability (primary care professionals and specialist satisfaction), adoption (volume per professional, number of active professionals), and potential reach (number of eConsults completed per clinic and region) of the eConsult pilot projects. This large evidence base, built over 12 years, lent credibility to the innovation and demonstrated the benefits and value of eConsult to policy-level actors and funding organizations.</p>", "<p> “<italic toggle=\"yes\">I feel that the publications that Clare and Erin (co-founders) have done over the years add credibility and provide a lot of expertise into informing the model. […] I think it’s instrumental to informing the policy decisions and I think it was a key success factor in making the case for eConsult to be a provincial program</italic>” (Ontario).</p>", "<p> The well-established evidence base also helped address actors’ concerns regarding patient safety and acceptance of the service. For instance, actors initially questioned the safety of an eConsult compared to an in-person appointment. However, the evidence indicating that only a small proportion of eConsults led to in-person appointments with a specialist, despite this not having been initially planned by the primary care professionals, reassured them. Additionally, in each province, the current evidence base generated by the research team informed policy discussions and negotiations. For example, economic evidence from Ontario on the cost per eConsult and volume data informed remuneration negotiations in other provinces. Needs assessments also helped eConsult teams establish spread and scale-up priorities, such as implementing eConsult for specialties with long wait times or in areas where access to specialists was limited.</p>", "<title> What Strategies Were Used? </title>", "<p> Our results suggest that embedding eConsult within a research infrastructure helped to create a continuously-growing evidence base. Beginning with the pilot studies in the provinces, a research infrastructure was created and maintained throughout the spread and scale-up of eConsult. Research grants obtained from local, provincial, and national funding bodies financed the human resources needed to implement the eConsult service and maintain it until funding was institutionalized, covered fees for specialists’ time, and allowed for evaluations and needs assessments to be conducted to explore further implementation (eg, in correctional and long-term care facilities) and uses (eg, continuing medical education). Furthermore, negotiations with provincial health authorities regarding long-term funds for sustainability resulted in a portion of the budget being dedicated to the continuing evaluation of the service.</p>", "<p> The collection and analysis of relevant data (eg, audits, mandatory close-out survey, and patient and professional surveys to assess effectiveness, cost-effectiveness, feasibility, acceptability, adoption, and potential reach) using quantitative and qualitative research methods built the evidence base. A variety of knowledge translation strategies shared the results of the research projects and the evidence base to inform scale-up. Over 100 scientific publications were produced, primarily by the Ontario team, providing a credible, peer-reviewed body of literature to build a convincing rationale to scale-up eConsult. Other provinces perceived the data collected in Ontario as being transferable to their own contexts.</p>", "<p> “<italic toggle=\"yes\">I think [the evidence base] really informed and shaped how they (the co-founders) do deployment, how they frame the benefits of the system... It’s much easier, I think, for people to go to a doctor’s office and say, ‘You should use this system. It’s really valuable,’ when they have evidence to back that up</italic>” (Ontario).</p>", "<p>\n##TAB##5##Table 6## presents a summary of the strategies used in each province to address a strong evidence base.</p>", "<title> Physician Leadership </title>", "<title> Why Is This Enabling Factor Key to the Scale-Up of eConsult? </title>", "<p> Two physician leaders in Ontario, one family physician and one specialist, pioneered the initial development and piloting of eConsult. We defined a physician leader as a physician who played a key role in deploying the intervention. Originally, eConsult emerged from clinical needs and was adapted to the reality and workflow of professionals (ie, innovation users). In addition, the engagement of physician leaders was a key factor in identifying priorities for expanding eConsult to other specialties. For example, in all provinces studied, primary care professionals determined the order in which the eConsult service integrated specialties based on their observations and experiences regarding patient needs as well as specialist care services with the longest wait times. Strong physician leadership also helped to gain valuable support from provincial and federal medical associations for scale-up and to secure their participation in the process. Physician leaders recruited local eConsult users as clinical champions to promote the innovation among their colleagues. This facilitated the recruitment of additional family physicians and specialist users and lent credibility to the innovation, thereby increasing its uptake and adoption among professionals.</p>", "<title> What Strategies Were Used? </title>", "<p> Ontario and Quebec formalized the role of physician leader in the eConsult scale-up process. Specifically, the Ontario eConsult Center of Excellence named the two initial physician leaders as co-executive directors, and Quebec’s Ministry of Health and Social Services appointed the main physician leader in Quebec as a medical advisor on eConsult. Manitoba and Newfoundland & Labrador used this strategy of formalizing the role of physician leaders less often.</p>", "<p> The CFHI’s Connected Medicine Collaborative engaged several physician leaders in each province, providing training, webinars, and tools designed to encourage and support clinicians to take on key roles in the spread and scale-up of eConsult in their province.</p>", "<p> During the eConsult pilot projects in each province, physician leaders used their personal networks in a strategic way to build a clinical “coalition of the willing” (ie, enthusiastic professionals who were convinced of the benefits of the innovation) to advocate for eConsult among their colleagues. This provided momentum to increase the use of eConsult and recruit additional professionals to join the coalition.</p>", "<p> Physician leaders recruited local physician champions (ie, clinicians who believed in the innovation and were willing to help recruit their local colleagues) as volunteers from among the attendees of their eConsult presentations at scientific and medical conferences (ie, Family Medicine Forum, North American Primary Care Research Group) and at regional tables. Physician champions shared their eConsult experience with their peers, encouraged them to become users, and acted as a resource to help resolve minor issues that users faced. They did not receive incentives for their role as champions.</p>", "<p> Physician leaders also sought the endorsement of provincial and federal medical associations to help grow the provincial and national momentum surrounding eConsult and provide support for scale-up efforts (eg, funding, negotiations, political influence, and promoting eConsult to members).</p>", "<p> “<italic toggle=\"yes\">I think [the medical associations’] biggest role in the collaborative was helping get the word out and putting their stamp of approval. Like saying this is something that we can get behind even before they put it as a standard of practice” </italic>(National).</p>", "<p>\n##TAB##6##Table 7## presents a summary of the strategies used in each province to address physician leadership.</p>", "<title> Resource Acquisition </title>", "<title> Why Is This Enabling Factor Key to the Scale-Up of eConsult? </title>", "<p> We identified the final key enabling factor as resource acquisition, which include human and financial resources to coordinate and manage eConsult, an adequate electronic platform, remuneration for primary care professionals and specialists, and continuous evaluation of eConsult. Our results suggest that it is essential to secure resources for three phases: (1) development and pilot testing; (2) transitioning from pilot to scale-up (to maintain achievements and spread eConsult to new contexts while policy issues are being addressed); and (3) ensuring sustainability (eg, recurring resources, including government funding, physician remuneration, and human resources to manage and oversee eConsult, as necessary, at the health system level).</p>", "<title> What Strategies Were Used? </title>", "<p> Since 2009, the eConsult team leads have applied for many research grants and innovation funds from various local, provincial, and national funding bodies (eg, Canadian Institutes for Health Research) to pilot and evaluate eConsult in various settings (eg, interdisciplinary chronic pain care and long-term care) and with various actors (eg, allied health professionals). Physician leaders, in close collaboration with professionals, patient partners, policy-makers, and researchers, wrote detailed study protocols included in grant applications. The CFHI’s Connected Medicine Collaborative provided key multi-jurisdictional funding to support pilot projects and to spread eConsult to new regions across different provinces.</p>", "<p> “<italic toggle=\"yes\">[The CFHI] really provided the infrastructure and leadership and funding for people to join the connected medicine collaborative, which has meant to really increase capacity across the country as well as implementation</italic>” (Ontario).</p>", "<p> Our findings suggest that obtaining transition resources is important for maintaining achievements and spreading eConsult to new contexts while policy issues are being addressed. The transition period begins when initial research and innovation funds run out and teams must be creative to find sources of funding. However, obtaining transition resources can be difficult, as traditional Canadian funding bodies do not typically fund transition projects. In Quebec, Manitoba, and Ontario, eConsult teams and their partners advocated for eConsult to their respective provincial governments and obtained temporary transition funds to pay for specialists’ time (pro-rated fee used in research projects) and coordinate and manage the service when the research grant ended. This ensured the maintenance of eConsult services for onboarding professionals and for growth through a limited amount of spread until the establishment of fee-for-service tariffs. Non-traditional funding sources, including small funds obtained through innovation challenges or contests launched by the CFHI, medical associations, and family medicine departments, as well as in-kind resources from key partners (eg, regional organizations, research infrastructure, and medical associations) also supported the service until it was institutionally funded.</p>", "<p> Establishing fee-for-service tariffs or alternate funding for specialists and primary care professionals secured, for the most part, sustainable resources. In Ontario, the Ministry of Health and Long-Term Care funded the remuneration of specialists through a prorated fee of $200 CAD/hour. This rate was used in pilot projects in Ontario (beginning in 2009) and in the other three provinces for specialists paid through a fee-for-service payment model. Newfoundland & Labrador and Quebec approved fee-for-service tariffs for specialists in May 2020 and June 2021, respectively. Ontario and Quebec also secured provincial remuneration for primary care professionals from provincial payers. Members of the provincial steering committees and eConsult advocates participated in remuneration negotiations, leveraging the eConsult evidence base. Additionally, to advocate for the establishment of provincial physician remuneration, eConsult steering committee members used a combination of complementary strategies, including sending letters to the Minister of Health, requesting a fee code from provincial payers, and encouraging professionals to contact their medical association and request a tariff. New or existing provincial infrastructure also secured sustainable human resources. For instance, in Ontario the newly created Ontario eConsult Centre of Excellence took on the management of the eConsult service, including physician remuneration. In Newfoundland & Labrador, the existing provincial payer managed physician remuneration and monitored the number of eConsults per physician to ensure that previously established limits per professional (400 eConsults per year) were respected.</p>", "<p>\n##TAB##7##Table 8## presents a summary of the strategies used in each province to address resources for scale-up.</p>" ]	[ "<title>Discussion</title>", "<p> This study provides an in-depth analysis of the strategies used to scale up a promising innovation and related key factors based on data from four rich cases. For each key enabling factor, we described its importance to the scale-up of eConsult and identified and described the strategies used to address it. To our knowledge, our study is the first to distinguish between factors and strategies. By delving into the strategies used to address enabling factors and providing guidance on how to implement them, our paper makes a substantial and original contribution to the science of scale-up. Furthermore, as our study is one of the first conducted in a high-income primary care context like Canada,<sup>##REF##26264351##4##</sup> our results are unique within the literature.</p>", "<p> In this study, we identified a total of 31 strategies related to six key factors that enabled the scale-up of eConsult in four Canadian provinces: (1) multi-actor engagement; (2) relative advantage; (3) knowledge transfer; (4) physical leadership; (5) a strong evidence base; and (6) resource acquisition. These six identified factors are similar to those identified in the literature,<sup>##REF##29166911##1##,##REF##26264351##4##,##REF##27993138##9##,##REF##31519185##10##,##REF##32493357##15##,##REF##21738450##16##</sup> although the labels and categories vary among articles.</p>", "<p> Similar to other studies,<sup>##REF##29166911##1##,##REF##32493357##15##</sup> our results show that a key enabling factor is the engagement of a range of actors. We add to this by identifying six strategies that address this factor. These strategies include creating multi-actor steering committees to oversee eConsult pilot projects and spread and providing actors with ready-to-use communication materials they can use to advocate for eConsult.</p>", "<p> Another key factor identified as enabling the scale-up of eConsult was transferring learnings from Ontario to the other provinces. Four strategies addressed this factor, including sharing evidence, experience, knowledge, and tools, holding National eConsult Forums to facilitate shared learning, and mentoring other provinces. A previous study on key policy strategies for the spread and scale-up of eConsult highlighted the importance of building on current strategies and existing policies in the context of eHealth.<sup>##REF##32493357##15##</sup> Although that study did not report on shared learning, the authors proposed similar strategies to those we identified as enabling this factor in the present study.</p>", "<p> We identified physician leadership as a key enabling factor that was addressed by strategies such as formalizing the role of physician leaders, engaging physician champions, and seeking the endorsement of medical associations to grow momentum and support scale-up efforts. Similarly, Moroz et al<sup>##REF##32493357##15##</sup> highlighted the importance of the support provided by “change” champions.</p>", "<p> Additionally, we further refined the key enabling factor of evaluation and monitoring, which Milat et al<sup>##REF##26264351##4##</sup> found to be important, by suggesting that a strong evidence base is needed to enable scale-up and that this can be developed by embedding the innovation in research.</p>", "<p> We found that resource acquisition was a key enabling factor addressed by different strategies during the pilot and testing, transition, and sustainability phases. A recent study identified different funding models to move beyond initial financial resources.<sup>##REF##33036633##32##</sup> Long-term funding was reported as a key factor to enable sustainability. The authors proposed to include long-term fundings in proposals or plan agreements for funding renewal under certain conditions of innovation performance.<sup>##REF##33036633##32##</sup> In addition, the existing literature highlights commonly reported scale-up barriers and facilitators related to human, financial, and technical resources, the capacity and will to scale-up, relational and political connections, active engagement of diverse actors and organizations, leadership, approaches tailored to context, and evaluation.<sup>##REF##29166911##1##,##UREF##0##3##,##REF##26264351##4##,##REF##27993138##9##,##REF##31519185##10##,##REF##23216748##33##, ####REF##28687532##34##, ##REF##24735455##35##, ##REF##21738450##36##, ##REF##20071454##37##, ##REF##27352864##38##, ##REF##24199749##39####24199749##39##</sup></p>", "<p> Identifying enabling factors at play in different contexts is useful to understand how they influence the scale-up of innovations. However, knowing the necessary enabling factors is not sufficient. A better understanding of these strategies, including concrete actions that actors can take to support scale-up efforts and address key enabling factors, is crucial to advance our ability to scale-up promising health innovations. The strategies and factors we have identified and described are grounded in both empirical evidence and theoretical frameworks on the scaling up of innovations<sup>##REF##29166911##1##,##REF##26264351##4##,##UREF##8##30##</sup> as well as key enabling factors identified in the literature.<sup>##REF##32493357##15##</sup> To our knowledge, this study is one of the first to provide ideas for actions that different types of actors with varying roles (eg, professionals, researchers, and policy-makers) and at multiple levels of governance (eg, regional, provincial, national) can take to scale up an innovation.</p>", "<p> In this research, we studied the scale-up of an innovation with demonstrated effectiveness that was expanded at the healthcare system level in four jurisdictions, each with its own health system. Dedicated teams implemented and supported many strategies, but they also described these strategies as very time and resource intensive. Many actors noted that the scale-up of innovations remains incredibly complex and is a constant “uphill battle” that is poorly supported by our health systems. Promising innovations need support to improve health systems through scale-up. Creating supportive infrastructures and programs may help innovators overcome the challenges of scaling up innovations.<sup>##UREF##10##40##</sup> For instance, creating more national infrastructures that promote learning, increasing funding, and facilitating structured interactions between multiple actors across jurisdictions may enable scale-up of other innovations. To achieve this, one potential approach could involve the creation of “scale-up accelerators” that catalyze the process of aligning innovations with health system priorities, facilitate connections with relevant actors, provide scale-up coaching (eg, business case, scale-up plan), and help innovators navigate policy (eg, IT requirements, legislation, and resources).<sup>##REF##37329836##20##</sup> Laur et al<sup>##REF##33795027##41##</sup> proposed to support innovators and transition innovations from pilot projects to larger scale-up by creating capacity-building programs. These programs could facilitate the development of strong and long-term partnerships between key actors.<sup>##REF##33795027##41##</sup></p>", "<title> Strengths and Limitations </title>", "<p> In terms of limitations, it is worth noting that we may not have captured all of the relevant strategies employed in the provinces, particularly strategies for securing sustainable resources, as some of the provinces had not completed the scale-up process during the study period. Certain provinces started the scale-up process earlier, which might have influenced strategies used in other provinces. Furthermore, given that Canada provides universal healthcare, with distinct publicly-funded health systems in each province, the results observed in this study may not necessarily be replicable in other contexts. It is necessary to take contextual factors such as these into consideration when adapting these findings to other settings.</p>", "<p> We undertook several strategies to ensure the trustworthiness of our findings. The study design, which covered multiple contexts and involved the triangulation of data collected over 3 years, supports the credibility of our results, as does the peer debriefing conducted with all co-authors during two 60-minute virtual meetings. Moreover, we ensured confirmability by, for example, involving multiple co-authors in the data analysis, as described above.</p>" ]	[ "<title>Conclusion</title>", "<p> The key strategies for scaling up an innovation that we identified and described offer concrete ideas for action that may help policy-makers, researchers, patients, and professionals who are interested in scaling up promising innovations. Scaling up innovations is context dependent, and our study provides strategies used in four jurisdictions in a high-income country to scale up an innovation. Further studies are needed to build an evidence base for key strategies that will help those who wish to scale up innovations while making efficient use of resources. Moreover, identifying and describing strategies that fail to address scale-up factors and why may contribute to understanding the complexity of scaling up innovations and how to ensure their sustainability. Building a comprehensive scale-up knowledge base will help actors bring their promising innovations to the masses for the benefit of all.</p>" ]	[ "<p>\n<bold>Background:</bold> Effective healthcare innovations are often not scaled up beyond their initial local context. Lack of practical knowledge on how to move from local innovations to large-system improvement hinders innovation and learning capacity in health systems. Studying scale-up processes can lead to a better understanding of how to facilitate the scale-up of interventions. eConsult is a digital health innovation that aims to connect primary care professionals with specialists through an asynchronous electronic consultation. The recent implementation of eConsult in the public health systems of four Canadian jurisdictions provides a unique opportunity to identify different enabling strategies and related factors that promote the scaling up of eConsult across jurisdictions.\n</p>", "<p>\n<bold>Methods:</bold> We conducted a narrative case study in four Canadian provinces, Quebec, Ontario, Manitoba, and Newfoundland & Labrador, over a 3-year period (2018–2021). We observed provincial eConsult committee meetings (n=65) and national eConsult forums (n=3), and we reviewed internal documents (n=93). We conducted semi-structured interviews with key actors in each jurisdiction (eg, researchers, primary care professionals, specialists, policy-makers, and patient partners) (n=40). We conducted thematic analysis guided by the literature on factors and strategies used to scale up innovations.\n</p>", "<p><bold>Results:</bold> We identified a total of 31 strategies related to six key enabling factors to scaling up eConsult, including: (1) multi-actor engagement; (2) relative advantage; (3) knowledge transfer; (4) strong evidence base; (5) physician leadership; and (6) resource acquisition (eg, human, material, and financial resources). More commonly used strategies, such as leveraging research infrastructure and bringing together various actors, were used to address multiple enabling factors.\n</p>", "<p>\n<bold>Conclusion:</bold> Actors used various strategies to scale up eConsult within their respective contexts, and these helped address six key factors that seemed to be essential to the scale-up of eConsult.</p>", "<p>\n<bold>Citation:</bold> Breton M, Lamoureux-Lamarche C, Smithman MA, et al. Scaling-Up eConsult: promising strategies to address enabling factors in four jurisdictions in Canada. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7203. doi:10.34172/ijhpm.2023.7203</p>" ]	[ "<title>Acknowledgements</title>", "<p> The authors would like to acknowledge the contribution of all stakeholders from the four provinces and thank them for accepting to collaborate on the study. We also wish to thank the Canadian Institutes of Health Research, the McGill Observatory on Health and Social Services Reforms and all organizations that provided matching funds and in-kind support.</p>", "<title>Ethical issues</title>", "<p> All participants gave written consent to participate in the study. This study was approved by the St. Mary’s Hospital Center Research Ethics Committee (Quebec, #SMHC-18-15), the Bruyère Continuing Care Research Ethics Board (Ontario, #M16-19-006), the Newfoundland & Labrador Health Research Ethics Board (NL, #2019.070), and the Bannatyne Campus Health Research Ethics Board (Manitoba, #H2019:307).</p>", "<title>Competing interests</title>", "<p> Clare Liddy and Erin Keely are co–executive directors of the Ontario eConsult Centre of Excellence, funded by the Ontario Ministry of Health. They co-founded the Champlain BASE<sup>TM</sup> (Building Access to Specialists through eConsultation) eConsult service but do not retain any proprietary rights. Erin Keely answers eConsults through the service, fewer than one per month.</p>", "<title>Funding</title>", "<p> This study was funded by the Canadian Institutes of Health Research (#402867), Réseau-1 Québec, Fonds de recherche Québec-Santé, Research Centre - Charles-Le Moyne-Saguenay-Lac-St-Jean sur les innovations en santé, Initiative Patient Partenaire from the University of Sherbrooke, the Manitoba SPOR Primary and Integrated Health Care Innovation Network, C.T. Lamont Primary Health Care Research Centre, and the McGill Observatory on Health and Social Services Reforms. The funders played no role in the design of the study, collection, analysis, or interpretation of the data, or writing of the manuscript.</p>", "<title>Disclosure of Relationships and Activities</title>", "<p> Research grants from the Canadian Institutes of Health Research [grant number #402867], Réseau-1 Québec, Fonds de recherche Québec-Santé, Research Centre - Charles-Le Moyne-Saguenay-Lac-St-Jean sur les innovations en santé, Initiative Patient Partenaire from the University of Sherbrooke, the Manitoba SPOR Primary and Integrated Health Care Innovation Network, C.T. Lamont Primary Health Care Research Centre, and the McGill Observatory on Health and Social Services Reforms were received to support this work.</p>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nThe eConsult Innovation Implemented in Four Canadian Provinces. Abbreviations: EMR, electronic medical record; PCP, primary care professionals.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nSummary of Key Factors Enabling eConsult Scale-Up and Strategies Used to Address Them.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Data Collection for Each Jurisdiction\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n</td><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Methods</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Non-participant Observation Meetings</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Review of Internal Documents </bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Key Actor Interviews </bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Ontario</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">19</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">35</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">11</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Quebec</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">22</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">26</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Manitoba</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">16</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">21</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Newfoundland & Labrador</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Total</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">68</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">93</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">40</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Jurisdiction Characteristics\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Year eConsult Started</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Volume of eConsults (2020)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Average Population Served/Million Inhabitants (2020)</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Summary of eConsult Scale-Up Progression</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Ontario</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">2009</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">65 672</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">14.7</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Province-wide scale-up began in 2018</p></list-item><list-item><p>Service managed through the Ontario eConsult Centre of Excellence, which was created in 2018</p></list-item><list-item><p>Provincial pro-rated fee for specialists (2009) and fee-for-service tariff for PCPs (2012)</p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Quebec</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2017</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2446</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8.6</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Pilot project in three regions ran from 2017 to 2021</p></list-item><list-item><p>Province-wide service launched in May 2021</p></list-item><list-item><p>Provincial fee-for-service tariff approved for specialists and PCPs (June 2021)</p></list-item><list-item><p>Service integration with regional dispatch centers for referrals to specialists was underway as of August 2021</p></list-item></list>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Manitoba </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2017</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1926</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Pilot project ran from 2017 to 2021</p></list-item><list-item><p>SharePoint platform set up for pilot project used during the transition period (beginning April 2021)</p></list-item><list-item><p>Specialists paid (pro-rated fee) through transitional funds from government</p></list-item><list-item><p>Spread put on hold in April 2020 </p></list-item><list-item><p>Onboarding, support, and training managed through provincial infrastructure as of April 2021 </p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Newfoundland & Labrador</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2016</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">3074</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.5</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Developmental project ran from 2016 to 2020</p></list-item><list-item><p>Provincial service integrated into provincial EMR launched in 2020</p></list-item><list-item><p>Fee-for-service tariff approved for specialists in May 2020</p></list-item><list-item><p>Ongoing scale-up of the service province-wide</p></list-item></list>\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Strategies Used to Address Multi-actor Engagement\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ontario</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quebec</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Manitoba</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Newfoundland & Labrador</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Work with multiple types of actors, including knowledge users and patient partners, to prepare research grant applications </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Recruit actors strategically through personal and professional leaders’ networks </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Create a steering committee to oversee eConsult pilot project and spread </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Maintain engagement for the duration of the scale-up process (eg, follow-up regularly, provide real-time results, celebrate milestones and accomplishments)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Provide ready-to-use communication materials actors could use to advocate for eConsult</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Invite a variety of actors to participate in annual National eConsult Forums</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T4\"><label>Table 4</label><caption><title>Strategies Used to Address Relative Advantage\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ontario</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quebec</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Manitoba</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Newfoundland & Labrador</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Maintain simplicity of the eConsult design to focus on its core elements</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Ensure eConsult is user-friendly and can be integrated into users’ workflows</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Offer training and ongoing support to encourage uptake and troubleshoot issues</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Integrate eConsult into electronic health records and other eReferral services</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Promote the relative advantages of eConsult (eg, healthcare organization newsletters, eConsult websites, word of mouth, webinars, fax backs sent by specialists to primary care professionals, and patient stories)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T5\"><label>Table 5</label><caption><title>Strategies Used to Address Knowledge Transfer\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ontario</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quebec</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Manitoba</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Newfoundland & Labrador</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Share evidence, experience, knowledge, and tools (either free-of-charge or for a nominal fee) </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Hold National eConsult Forums to facilitate shared learning and collectively brainstorm potential solutions to challenges</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mentoring from pioneers through the CFHI Connected Medicine Collaborative </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Provide active mentoring to actors in other provinces by participating in provincial steering committee meetings</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T6\"><label>Table 6</label><caption><title>Strategies Used to Address a Strong Evidence Base\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ontario</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quebec</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Manitoba</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Newfoundland & Labrador</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Embed eConsult within research infrastructure (research grants to support the innovation)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Negotiate provincial funding to continually evaluate the service</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Use quantitative and qualitative research methods to evaluate the innovation (eg, think tank discussions, interviews, surveys, audits)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Embed research into quality improvement efforts </td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T7\"><label>Table 7</label><caption><title>Strategies Used to Address Physician Leadership\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ontario</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quebec</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Manitoba</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Newfoundland & Labrador</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Formalize the role of physician leaders</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Train and mentor physician leaders through a national collaborative</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Form a coalition of enthusiastic professionals from the outset </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Engage physician champions through scientific and medical conferences and regional tables</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Seek endorsement from provincial and federal medical associations to grow momentum and support scale-up efforts</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T8\"><label>Table 8</label><caption><title>Strategies Used to Address Resource Acquisition for Scale-Up\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ontario</bold>\n</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quebec</bold>\n</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Manitoba</bold>\n</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Newfoundland & Labrador</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"5\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\">Resources for development and pilot testing</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Secure initial funding through research grants and innovation funds</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"5\" style=\"vertical-align:middle;\" rowspan=\"1\">Resources for transition</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Advocate for eConsult to provincial governments to obtain transition funding to maintain eConsult services</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Obtain funds from non-traditional sources to manage and coordinate eConsult during the transition period (eg, innovation challenges and contests, remaining research funds, in-kind resources from key partners, research infrastructure, medical associations)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"5\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">Resources for sustainability</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Establish fee-for-service tariffs or alternate funding to secure sustainable funding</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Enlist key actors to participate and advocate for eConsult in remuneration negotiations</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Use complementary methods to advocate for the establishment of provincial physician remuneration (eg, sending letters to the Minister of Health, requesting fee codes from provincial payers, encouraging physicians to request a tariff from their medical association)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Use existing and new infrastructure to provide human resources to sustain the service</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">√</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Unlike previous work on scale-up in healthcare, this study makes an empirical contribution by identifying practical scale-up strategies used to address key enabling factors. </p></list-item><list-item><p>A better understanding of these strategies is crucial to advance our ability to scale up promising health innovations and suggest concrete actions that actors can take to support scale-up efforts. </p></list-item><list-item><p>Many identified strategies involve leveraging research infrastructure and bringing together various actors. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> This study identified strategies used in four Canadian provinces to support the expansion of eConsult. eConsult is a platform that allows primary care professionals to asynchronously consult specialists regarding their patients’ medical problems. It has been demonstrated to effectively improve access, patient satisfaction, and equity and reduce system costs. Expanding promising healthcare innovations by learning from strategies that supported the scale-up of eConsult will help improve care for the population.</p></sec></boxed-text>" ]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p> Abbreviations: EMR, electronic medical record; PCPs, primary care professionals.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviation: CFHI, Canadian Foundation for Health Improvement.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7203-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7203-g002\" position=\"float\"/>" ]	[]	[{"label": ["3"], "mixed-citation": [" World Health Organization (WHO). Nine Steps for Developing a Scaling-Up Strategy. WHO; 2010. "]}, {"label": ["13"], "mixed-citation": [" Naylor D, Girard F, Mintz JM, Fraser N, Jenkins T, Power C. Unleashing Innovation: Excellent Healthcare for Canada: Report of the Advisory Panel on Healthcare Innovation. Ottawa, ON: Health Canada; 2015. "]}, {"label": ["17"], "mixed-citation": [" de Carvalho Cor\u00f4a RC, Gogovor A, Ben Charif A, et al. Evidence on scaling in health and social care: an umbrella review. Milbank Q. 2023. "], "pub-id": ["10.1111/1468-0009.12649"]}, {"label": ["23"], "person-group": ["\n"], "surname": ["Liddy", "Drosinis", "Deri Armstrong", "McKellips", "Afkham", "Keely"], "given-names": ["C", "P", "C", "F", "A", "E"], "article-title": ["What are the cost savings associated with providing access to specialist care through the Champlain BASE eConsult service? A costing evaluation"], "source": ["BMJ Open"], "year": ["2016"], "volume": ["6"], "issue": ["6"], "fpage": ["e010920"], "pub-id": ["10.1136/bmjopen-2015-010920"]}, {"label": ["26"], "mixed-citation": [" Stake RE. The Art of Case Study Research. SAGE Publications; 1995. "]}, {"label": ["27"], "mixed-citation": [" Creswell JW. Research Design: Qualitative, Quantitative, and Mixed Methods Approaches. 4th ed. London: SAGE Publications; 2013. "]}, {"label": ["28"], "mixed-citation": [" Canadian Foundation for Health Improvement. Connected Medicine Collaborative \u2013 Participating Teams. "], "uri": ["https://www.cfhi-fcass.ca/sf-docs/default-source/collaborations/connected-medicine-team-descriptions-e.pdf?sfvrsn=3c54a944_4"]}, {"label": ["29"], "mixed-citation": [" Canadian Foundation for Health Improvement. Connected Medicine: Enhancing Primary Care Access to Specialist Consult - A 15-Month Quality Improvement Collaborative \u2013 Prospectus. 2017. "], "uri": ["https://www.cfhi-fcass.ca/sf-docs/default-source/collaborations/connected-medicine-prospectus-e.pdf?sfvrsn=4"]}, {"label": ["30"], "mixed-citation": [" Rogers EM. Diffusion of Innovations. Simon and Schuster; 2010. "]}, {"label": ["31"], "mixed-citation": [" Miles MB, Huberman AM, Huberman MA, Huberman M. Qualitative Data Analysis: An Expanded Sourcebook. SAGE Publications; 1994. "]}, {"label": ["40"], "person-group": ["\n"], "surname": ["Smithman", "Dumas-Pilon", "Campbell", "Breton"], "given-names": ["MA", "M", "MJ", "M"], "article-title": ["Evaluation of a Dragons\u2019 Den-inspired symposium to spread primary health care innovations in Quebec, Canada: a mixed-methods study using quality-improvement e-surveys"], "source": ["CMAJ Open"], "year": ["2022"], "volume": ["10"], "issue": ["1"], "fpage": ["E247"], "lpage": ["E254"], "pub-id": ["10.9778/cmajo.20200251"]}]	{ "acronym": [], "definition": [] }	41	CC BY	no	2024-01-13 00:00:40	Int J Health Policy Manag. 2023 Sep 5; 12:7203	oa_package/bf/27/PMC10590220.tar.gz
PMC10590221	0	[ "<title>Background</title>", "<p> In 2015, the global malaria community celebrated the achievements of halting and reversing the global malaria incidence.<sup>##REF##27282148##1##,##UREF##0##2##</sup> A more than two-fold increase in funding between 2000 and 2015 had permitted the expansion of key malaria control interventions, with this scale-up contributing to dramatically reduce the burden of malaria.<sup>##REF##26375008##3##</sup> Since this remarkable period, the level of investments and the disease burden have remained virtually unchanged.<sup>##UREF##1##4##,##UREF##2##5##</sup> Each year less than half of the investments needed to reach the global 2030 burden reduction targets are invested and more than 240 000 million cases and 590 000 related deaths are reported.<sup>##UREF##1##4##</sup> Malaria is also closely associated with other health conditions, such as anaemia and cognitive deficits.<sup>##REF##16553922##6##, ####REF##30340592##7##, ##REF##34051141##8##, ##REF##33399043##9####33399043##9##</sup></p>", "<p> Globally, malaria mortality affects predominantly young children while clinical malaria affects all age groups throughout life.<sup>##REF##34051141##8##,##REF##17123898##10##</sup> The resulting deaths and illnesses have been reported to have significant economic consequences now and for the future.<sup>##REF##23584052##11##</sup> At a micro level, malaria expenditures burden households and governments with most of primary healthcare spending for malaria paid out from domestic sources.<sup>##UREF##3##12##,##REF##36199078##13##</sup> At household level, malaria reduces labour participation and productivity because of work absenteeism due to adults own sickness or time spent caring for a child.<sup>##REF##31796071##14##, ####REF##33272293##15##, ##REF##31903422##16####31903422##16##</sup> Malaria also reduces older children and young adolescents’ educational attainments and future adult employment.<sup>##UREF##4##17##, ####REF##26453016##18##, ##REF##26509337##19####26509337##19##</sup> Like other diseases, malaria affects economic progress through lost capital and future income. Financial and physical capital may be depleted through reduced savings, dis-savings, the sale of household assets and livestock and/or borrowing.<sup>##REF##25834529##20##,##REF##8235756##21##</sup> At business level, a decrease in labour participation can reduce the production of firms if the productive contribution of workers cannot be compensated by other production factors or if absent workers cannot be replaced by new workers with sufficient skills and experience.<sup>##REF##19356235##22##,##REF##27599835##23##</sup> At a macro level, malaria mortality can reduce the total size of the labour force while aggregated morbidity may reduce the total size and productivity of the workforce, human capital accumulation, and ultimately national economic output.<sup>##REF##31903422##16##</sup> Malaria also absorbs a significant amount of domestic resources for prevention and treatment,<sup>##UREF##5##24##</sup> diverting part of these resources from other productive investments, notably infrastructure, equipment and machinery among others, which can ultimately also impact aggregate economic output.</p>", "<p> Quantifying the economic burden of malaria and the return of investing in malaria control can encourage political and financial commitment.<sup>##REF##35562336##25##</sup> The inclusion of impacts beyond health can thus better reflect the wide impact of a disease such as malaria and can help raise awareness among policy-makers of the implications of these economic consequences for national economic progress.<sup>##REF##35562336##25##</sup></p>", "<p> There is ample literature on the economic burden and benefits of malaria control, especially in terms of the micro- and macro-economic effects of changes in morbidity and mortality, treatment cost and productivity. Yet limited consideration has been given to the effects of changes in savings that can hamper economy-wide physical capital accumulation and as a result economic outcomes. Many studies have used the cost-of-illness (COI) approach to estimate the direct and indirect costs of malaria including treatment costs and losses in labour force participation and associated income.<sup>##REF##28969643##26##, ####REF##31711489##27##, ##REF##34717637##28##, ##REF##34399767##29##, ##REF##27955665##30##, ##REF##24004482##31####24004482##31##</sup> The underlying assumption is that the estimated economic value in COI studies represents the potential benefits of malaria control and elimination if it had been implemented.<sup>##REF##25548737##32##</sup> Several other studies use econometric methods such as cross-country growth regression, quasi-experiments studies or macroeconomic models to estimate the impact of malaria on aggregate economic outcomes.<sup>##REF##31903422##16##,##REF##26509337##19##,##REF##11425181##33##, ####REF##31628735##34##, ##UREF##6##35##, ##REF##32959760##36##, ##REF##37432972##37####37432972##37##</sup> For example, these studies may consider the relationship between the gross domestic product (GDP) and malaria incidence or/and between the growth of industries with the same share of labor intensity and malaria incidence,<sup>##REF##31903422##16##,##REF##11425181##33##,##REF##31628735##34##</sup> or the effects of changes in economic growth on malaria transmission due to changes in household preventive behaviours.<sup>##REF##32959760##36##</sup> Compared to COI analyses, econometric studies are more complex and can incorporate economic adjustment mechanisms. However these studies generally assume that malaria control or particular malaria control interventions are funded by external donors,<sup>##REF##31903422##16##,##REF##32959760##36##</sup> and thus do not consider the effects that changes in investment levels may have on savings and thus on investments in other production factors. Whereas investing in malaria control contributes to reduce the number of lives lost and work absenteeism because of illness, and thereby increase the size and quality of the labour force, it reduces capital accumulation. At the same time, a decline in morbidity reduces treatment costs and thus mitigates capital accumulation loss. Thus it is not clear how investment in malaria control ultimately affects economic growth through changes in labour force and physical accumulation.</p>", "<p> The current study uses World Health Organization’s (WHO’s) Economic Projections of Illness and Costs macroeconomic model (EPIC) to estimate the impact of malaria control on projected GDP from (<italic toggle=\"yes\">i</italic>) changes in malaria mortality and morbidity on the size of the labor force augmented by educational returns and work experience accumulated over time, (<italic toggle=\"yes\">ii</italic>) changes in the accumulation of physical capital due to reduced savings from increased investments in malaria control, and (<italic toggle=\"yes\">iii</italic>) changes in treatment costs from reduced morbidity. For this EPIC application, the model is adapted to account for the effects of changes in malaria morbidity among children and young adolescents on working adult productivity. As malaria burden reductions and funding levels have stagnated since the launch of the global malaria strategy for 2016-2030, the current study aims at estimating the potential gains in projected GDP that could have been achieved across 26 high burden countries if progress in malaria control and associated investments had matched the vision of the global malaria strategy for 2016-2030.<sup>##UREF##7##38##</sup></p>" ]	[ "<title>Methods</title>", "<title> Economic Projections of Illness and Costs Modelling Framework</title>", "<p> EPIC was originally developed by the WHO and subsequently adapted and applied to tuberculosis<sup>##REF##37432972##37##,##REF##34327358##39##</sup> and selected non-communicable chronic diseases.<sup>##UREF##8##40##, ####UREF##9##41##, ##REF##36821107##42##, ##REF##30383802##43####30383802##43##</sup> The model quantifies the macroeconomic consequences of investing in health based on a yearly recursive production function accompanied by the evolution of two production factors: the effective labour supply and the physical capital. First, health improvements from intensified disease control increase the stock of the labour force composed of different age groups of workers that have different levels of education and skills accrued over time. Reductions in mortality increase the number of working-age individuals while reductions in morbidity increase their productivity. Productivity losses are measured in terms of years lost to disability (YLDs). One YLD represents one full year of healthy life lost due to ill health and is assumed to be equivalent to one year of full productivity lost. Second, the accumulation of physical capital (tangible assets used in production) depends on the depreciation rate of the stock of physical capital and on savings that is the amount of disposable income saved rather than consumed. Changes in domestic spending due to investments in health interventions (net of the external donor share for these investments) are assumed to be partly financed by savings and thereby reduce the total stock of physical capital. ##SUPPL##0##Supplementary file 1## describes the technical specification of the EPIC model.</p>", "<title> Adaptation of EPIC to Malaria</title>", "<p> While malaria affects all age groups in endemic countries, it disproportionally affects young children mortality and morbidity, typically under the age of five years in countries where transmission is intense (eg, sub-Saharan Africa). Older children (5-9 years old) and young adolescents (10-14 years old) are also at higher risk of malaria than older age groups (15 and above), notably because of immunological and hormonal factors. We adapted EPIC to capture these effects including the effects of caring for children and young adolescents infected by malaria on adult productivity in addition to the effects of malaria infections in working-age adults on labour productivity (##SUPPL##0##Supplementary file 1##). We differentiated the effects of malaria morbidity in young children and in older children and young adolescents on adult productivity. In addition, the number of averted deaths in these age groups were subsequently added to the future stock of labour once they reach the age of 15 while considering mortality risks from other diseases. We also developed an analytical approach to estimate the effects of changes in malaria morbidity and mortality on GDP (##SUPPL##0##Supplementary file 1##). This EPIC application used R v4.3 and RStudio Cherry Blossom Release (2023.03.1).<sup>##UREF##10##44##,##UREF##11##45##</sup></p>", "<title> Scope of the Analysis</title>", "<p> To quantify the potential macroeconomic impact of reaching the burden reduction targets set out in the global malaria strategy for 2016-2030,<sup>##UREF##7##38##</sup> we compare the projected aggregated GDP of 26 malaria endemic countries over the 2016-2030 period between two scenarios: a business-as-usual scenario in which the coverage of key malaria interventions is sustained at their 2015 level (“Sustain” scenario) and the scale-up scenario in which intervention coverage levels increase between 50% and 90% of the population in needs depending on the intervention considered (“Scale-up” scenario). The two scenarios thus differ in terms of the level of investment required to sustain or scale-up intervention coverage. Considering population growth, the level of investments needed under the Sustain scenario increase at a slower rate than under the Scale-up scenario.</p>", "<p> All malaria control interventions considered in the global strategy for malaria 2016-2030 are considered, including long-lasting insecticidal nets and complementary vector control interventions, seasonal malaria chemoprevention in children, intermittent preventive treatment of pregnant women, diagnostics by blood testing and treatment of confirmed cases, and surveillance activities such as routine epidemiological and entomological information systems. Information on the modelled interventions and coverage scale-up rates is provided inTable S1 (##SUPPL##0##Supplementary file 1##). The malaria vaccine recommended by WHO since 2021 and subsequently prequalified in the middle of 2022 is not considered in this analysis.</p>", "<p> Twenty-six countries, which together accounted for more than 90% of the global number of malaria cases and deaths in 2016 were included in the analysis. Of these, two countries including Nigeria and the Democratic Republic of the Congo accounted for nearly 40% of the global malaria burden (Table S2, ##SUPPL##0##Supplementary file 1##). Of the 26 countries considered, 16 were categorized as low-income countries and 10 as middle-income countries, including nine lower-middle income countries and one higher-middle income country.</p>", "<title> Data Sources and Analysis</title>", "<p> All data sources are summarized in Table S3, ##SUPPL##1##Supplementary file 2##.<sup>##UREF##5##24##,##UREF##12##46##, ####UREF##13##47##, ##UREF##14##48##, ##UREF##15##49##, ##REF##26809816##50##, ##REF##1801150##51##, ##REF##9289349##52##, ##UREF##16##53##, ##UREF##17##54####17##54##</sup> Investment need and health impact estimates were obtained from linked modelling work conducted to inform the development of the global malaria strategy 2016-2030. Estimates on the total investment needs per year and per country (country-specific annual total costs) were obtained for each scenario in constant 2014 US$ from Patouillard et al<sup>##UREF##14##48##</sup> (##SUPPL##1##Supplementary file 2##).We subtracted from these estimates the amount assumed to be financed by external donors, using data on the share of donor funding in total malaria expenditures for each country available from the Global Health Expenditure Database.<sup>##UREF##5##24##</sup> We assumed that in each country the share of donor funding stayed constant at 2016-2020 average level throughout the study period. We then assumed that the total cost of the Sustain scenario, net of external donor funding would be funded by domestic consumption while the incremental cost of the Scale-up scenario (net of donor funding) would be paid out by both domestic consumption and savings. In a base-case analysis, 10% of the incremental cost of the Scale-up scenario were assumed to be paid out by savings and 90% by domestic consumption, a situation that is not uncommon in many low- and middle-income countries.<sup>##UREF##5##24##</sup> We varied these assumptions in sensitivity analysis (see later).</p>", "<p> Health impact estimates were obtained by combining malaria burden projections from WHO<sup>##UREF##14##48##</sup> and from Griffin et al.<sup>##REF##26809816##50##</sup> Griffin et al developed a malariatransmission model to quantify the potential reductions in malaria burden in the Sustain and Scale-up scenarios, as envisaged by the global malaria strategy 2016-2030 (##SUPPL##1##Supplementary file 2##). These modelled mortality estimates were available under each scenario for population groups aged under and above five years of age. We distributed these data proportionally into five-year age groups using WHO’s mortality projections.<sup>##UREF##14##48##</sup> In addition, for morbidity estimates, we converted the effects of malaria control on YLD using the ratio of the impact on malaria deaths modelled by Griffin et al to those projected by the WHO.<sup>##UREF##14##48##</sup> To model morbidity and mortality effects on the effective labour supply, we then merged five-year age groups from the age of 15 and above into age groupings used in ILO labor force participation rate dataset (15-29, 30-44, 45-59, 60-64, 65-69)<sup>##UREF##13##47##</sup> (##SUPPL##1##Supplementary file 2##).</p>", "<p> To transfer malaria morbidity in children and young adolescents on the productivity of working adults, we assumed that one year lost to child morbidity in the 0-4 age group and in the 5-14 age group was equivalent to one full year and 0.5 year productivity loss in working adults, respectively.<sup>##REF##31903422##16##,##UREF##4##17##,##UREF##6##35##,##REF##1801150##51##,##REF##9289349##52##,##REF##12468115##55##, ####REF##9226789##56##, ##REF##8844931##57####8844931##57##</sup> We varied these assumed transfer rates in sensitivity analysis (see below).</p>", "<p> EPIC’s parameters including the saving rate (percentage of disposable income saved rather than spent on consumption), the growth rate of total factor productivity (the change in economic growth that occurs due to factors other than changes in the labour force and capital stock), the output elasticity of physical capital (the change in the output that results from a change in physical capital), the growth rate of educational capital (returns to education that increase the quality of the labour force) and the depreciation rate (the percentage decrease in the monetary value of tangible assets over time) for each country were derived from the Penn World Table 10.01 (##SUPPL##1##Supplementary file 2##).<sup>##UREF##12##46##</sup> Missing values for country-specific data extracted from published sources were imputed using the mean of data in countries from the same income group.</p>", "<p> For each country, macroeconomic parameters were assigned a normal distribution informed by their respective mean and standard deviation over the 2005-2014 period (Table S4 and Figure S1, ##SUPPL##1##Supplementary file 2##) and were combined with investment need and health impact estimates to generate 1000 estimated projections of annual GDP for each scenario and country over the 2016-2030 period.</p>", "<p> We calculated the mean difference and 95% uncertainty intervals (UIs) in annual GDP between the two scenarios for each country. We summarized results as percentage differences in GDP aggregated across the 26 countries and according to World Bank country income groups, per year and for the entire study period. We calculated the relative contribution of morbidity and mortality changes to the difference in GDP between the two scenarios (##SUPPL##0##Supplementary file 1##).</p>", "<p> These main results are presented for a base-case analysis in which 10% of incremental investment needs would be paid out of savings in the Scale-up scenario while in both scenarios, the morbidity transfer rate of one YLD in the 0-4 age group would be equivalent to one full year productivity loss in working adults and in the 5-14 age group to 0.5-year productivity loss in working adults.</p>", "<title> Sensitivity Analysis</title>", "<p> Given the published estimates on the effect of malaria on labour productivity across different settings, age groups and occupations, we varied the morbidity transfer rates from 1 to 0.6 for one year lost to morbidity in the 0-4 age group and from 0.5 to 0.3 for one year lost to morbidity in the 5-14 age group. The percentage of investment needs (net of external donor funding) paid out by domestic savings in the Scale-up scenario was varied from 10% to 50% and from 10% to 90%. These increases in the proportion of incremental domestic investments needs paid out by savings may correspond to situations in which governments cannot raise sufficient revenues, out of taxation from example, such that a larger share of investment needs is paid out from savings. Thus, it was assumed that in the Scale-up scenario, intensifying malaria control does not rely on increasing household consumption given the significant share of malaria expenditures that are already paid out of pocket by households in many low- and middle-income countries.<sup>##UREF##5##24##</sup></p>" ]	[ "<title>Results</title>", "<p> Across all 26 countries and over the entire study period, an additional 12 million malaria related deaths and 60 million YLD to malaria could be averted under the Scale-up scenario compared to the Sustain. Forty percent of the averted burden would take place in three of the 26 countries (Nigeria, India, and the Democratic Republic of Congo), reflecting their large population size and malaria burden in absolute terms. Net of assumed external donor funding, total domestic investment needs were estimated at US$ 22.92 billion under the Sustain scenario (64% of total scenario investment needs) and US$ 45.17 under the Scale-up scenario (61% of total scenario investment needs) (Figure S2, ##SUPPL##2##Supplementary file 3##). Under both scenarios, nearly 70% of total domestic investment needs were estimated in four of the 26 countries studied: India (about 30%), Nigeria (about 25%) and the Democratic Republic of Congo and the United Republic of Tanzania (each about 6%).</p>", "<title> Estimated Total Macroeconomic Impact </title>", "<p> In the base-case analysis, the macroeconomic dividend from scaling-up malaria control as set out by the global malaria strategy 2016-2030 was estimated at US$ 152.50 billion (95% UI 152.00-153.00) in total across all 26 modelled countries over the study period.</p>", "<p> These estimated gains would be equivalent to a 0.1750% increase in total GDP projected for the study period for all 26 countries (Table S5), with around 95% of the mean total GDP gain attributable to averted malaria morbidity (Table S6). Across the 16 low-income countries, the economic dividend was estimated to be higher, equivalent to 0.3193% in total GDP projected for the study period while in the nine lower-middle income countries, it would be about half at 0.1567% of total projected GDP. Gains were estimated to be higher in Sub-Saharan countries, at 0.5684% of projected GDP in Niger, 0.4315% in Mozambique, 0.4144% in Mali and 0.3541% in Nigeria, for example. Outside sub-Saharan African countries where the burden of malaria on children and young adolescent is relatively smaller, gains would be lower, such as, for example, in India at 0.1149% of projected GDP.</p>", "<p> Assuming lower transfer rates of children morbidity on working adult productivity across all 26 modelled countries, the mean total gain over the study period declined slightly but was still significant, equivalent to 0.1439% of total GDP projected over the study period (Table S7). In the above-mentioned sub-Saharan African countries, gains would be 0.05 to 0.20% point lower than in the base-case analysis, at 0.3812% of projected GDP in Niger, 0.3542% in Mozambique, 0.2913% in Mali and 0.2714% in Nigeria, for example. By contrast, in India, the gain would not change very much compared to the base-case analysis (0.1014% of projected GDP), reflecting the relatively lower burden of malaria in children and younger adolescents in this country and thus a lower sensitivity to changes in the morbidity transfer rates.</p>", "<p> Finally, increasing the percentage share of domestic investments paid out from savings from 10% to 50% and from 10% to 90% under the Scale-up scenario reduced the economic dividend from 0.1750% to respectively 0.1391% and 0.1031% of total GDP projected over the study period (Tables S8 and S9).</p>", "<title> Estimated Macroeconomic Impact Over Time</title>", "<p> Across all 26 countries, macroeconomic annual benefits would increase over time (##FIG##0##Figure 1##). The mean gains would be equivalent to 0.0858% in total projected GDP between 2016 and 2020, 0.1855% between 2021 and 2025 and 0.2152% between 2026 and 2030. In the 16 low-income countries, mean gains were estimated at 0.1380% of projected total GDP between 2016 and 2020, 0.3278% between 2021 and 2025 and 0.3798% between 2026 and 2030 and in the 9 lower-middle income countries at 0.08%, 0.17% and 0.19% over the three periods respectively (##FIG##1##Figure 2##). Trends in projected GDP annual gains (in billion US$ and percentages) over the entire study period by country income group are available in Figures S3 and S4.The relative contribution of averted mortality to the gain in projected GDP increased over the study period, reflecting the increasing number of children reaching working-age (Figure S5), with additional gains expected beyond the study period.</p>" ]	[ "<title>Discussion</title>", "<p> We used the WHO’s EPIC macroeconomic model to estimate the potential gain in projected GDP of reducing the burden of malaria in 26 high malaria burden, as set out by the global malaria strategy for 2026-2030. For this application of EPIC to malaria, a disease responsible for significant mortality in young children and ill-health throughout life, we adapted the model to account for, not only the direct effects of childhood mortality and adult morbidity on the effective labour supply but also the effects of morbidity in childhood and early adolescence on the productivity of working adults. In our base-case analysis, scaling-up malaria control to reach the global burden reduction targets for 2016-2030 could have generated economic gains of around 0.17% in projected GDP across all 26 countries, with these potential gains increasing over the time period. These gains were estimated to be, on average, nearly twice higher (0.32%) in low-income countries, including countries with some of the highest malaria burden in the world. Potential gains in projected GDP over the studied period were found to be sensitive to changes in key assumptions. First, assuming lower morbidity transfer rates from children and young adolescents to working-age adults reduced the estimated gains, which were still significant at 0.14% of projected GDP between 2016 and 2030 across all 26 countries. Second, greater reliance on domestic savings for malaria investments decreased potential gains down to 0.14% or 0.10% of projected GDP across all modelled countries, depending on the assumptions made. Despite these sensitivities to changes in key assumptions, gains in the low-income country groups and in countries with the highest burden of malaria remained above the average gain estimated in the base-case analysis. These results imply that, under the modelled assumptions, the health benefits of reducing malaria could outweigh the economy-wide opportunity cost of malaria control, in terms of the productive potential of these investments in other important areas.</p>", "<p> Given the stagnating levels in malaria investments and burden since 2015, it is evidently unlikely that the economic gains estimated in this study would materialize by 2030, including if malaria control efforts were to intensify dramatically over the next decade. Our analysis did not consider the disruptions of the COVID-19 pandemic on malaria control, which resulted in an increased number of malaria cases in 2020 and 2021. Thus, whilst global trends in malaria case incidence and deaths have been broadly stable since 2015, notably due to a slight decline in the burden of malaria in 2018, the estimated potential GDP gains should be seen as retrospective estimates of the direction and potential magnitude of the economic benefits associated with the global malaria strategy for 2016-2030. Focusing on 26 countries instead of the 84 countries with malaria endemicity in 2021 allowed us to focus on the potential economic benefits of malaria control in the highest burden and poorer endemic countries. In low malaria burden or elimination settings, the interruption of malaria transmission requires expanding the range of interventions which often imply high costs, greater uncertainty, and risk of failure whilst the incremental health benefits decline, bringing additional challenges in the interpretation of results from benefit-cost analyses.<sup>##REF##35562336##25##,##REF##31511196##58##</sup></p>", "<p> Various methodological approaches have been used to estimate the economic value of malaria control. While these approaches have their own strengths and limitations, EPIC offers an alternative analytical framework to conduct investment cases in health that can account for the opportunity costs of health interventions from an economy-wide perspective. The usefulness and flexibility of the EPIC framework have been demonstrated in earlier applications to selected non-communicable diseases and to tuberculosis.<sup>##REF##37432972##37##,##REF##34327358##39##, ####UREF##8##40##, ##UREF##9##41##, ##REF##36821107##42##, ##REF##30383802##43####30383802##43##</sup> For example, a recent EPIC application estimated that the worldwide economic burden of cancers could represent an annual tax on global GDP of 0.55% between 2020 and 2050.<sup>##REF##36821107##42##</sup> Another recent EPIC-based study estimated that introducing a novel tuberculosis vaccine for infants and for adolescents and adults could generate an economic dividend equivalent to an increase in projected GDP of, respectively, 0.004% and 0.033% across 105 low- and middle-income countries between 2028 and 2080.<sup>##REF##37432972##37##</sup> Focusing on the recent malaria literature, a macroeconomic modelling study accounting for changes in household preventive behaviour estimated that malaria vaccination in children below five years of age could increase Ghana’s GDP by 0.5% per year over a 30-year period assuming 100% vaccine coverage and external funding.<sup>##REF##31903422##16##</sup> Also in Ghana, a similar model was used to explore the potential for existing malaria control interventions alongside economic development to achieve malaria elimination.<sup>##REF##32959760##36##</sup> Given the differences in methods, it is challenging to make comparative observations on results. <sup>##REF##32959760##36##</sup> In terms of methodological approach, EPIC offers a relatively simple analytical framework that can be easily adapted to different diseases and interventions in one or several countries. Whilst our application did not integrate demographic, epidemiologic, costing and macroeconomic models in a shared framework, it used health impacts and resources needs estimates stemming from linked epidemiologic and costing models, while accounting for the opportunity costs of malaria control interventions, one aspect not considered to date in other macroeconomic models applied to malaria and of relevance for priority setting. Future work will aim to integrate EPIC to the suite of methodologies that WHO develops to support value for money assessments and address the common resource and capacity gaps for conducting economic evaluations in many countries.<sup>##UREF##18##59##, ####REF##34634892##60##, ##REF##33619929##61####33619929##61##</sup></p>", "<p> Our study has some limitations. Whilst by using a standard augmented Solow framework we conform to well-accepted norms in economic modelling, EPIC does not account for endogenous changes that may occur on key parameters due to changes in health status. The population growth rate, saving behaviour and thus the accumulation of physical capital, as well as human capital accumulation and future labour productivity may be affected by changes in health interventions and associated improvements in health status over time. While our study period is relatively short, which likely mitigates the impact of such changes during the study period, future applications of EPIC could consider modelling household behaviours and decision-making over time. In addition, the specification of the manner in which health investments affect capital accumulation could draw on an improved national accounting identity framework.</p>" ]	[ "<title>Conclusion</title>", "<p> Our results offer insights on the benefits that investing in malaria control can have beyond health. More generally, it shows that the EPIC modelling framework offers a simple approach that may be adapted to different diseases and interventions for investment cases in health.</p>" ]	[ "<p>\n<bold>Background:</bold> Malaria remains a major public health problem. While globally malaria mortality affects predominantly young children, clinical malaria affects all age groups throughout life. Malaria not only threatens health but also child education and adult productivity while burdening government budgets and economic development. Increased investments in malaria control can contribute to reduce this burden but have an opportunity cost for the economy. Quantifying the net economic value of investing in malaria can encourage political and financial commitment.\n</p>", "<p><bold>Methods:</bold> We adapted an existing macroeconomic model to simulate the effects of reducing malaria on the gross domestic product (GDP) of 26 high burden countries while accounting for the opportunity costs of increased investments in malaria. We compared two scenarios differing in their level of malaria investment and associated burden reduction: sustaining malaria control at 2015 intervention coverage levels, time at which coverage levels reached their historic peak and scaling-up coverage to reach the 2030 global burden reduction targets. We incorporated the effects that reduced malaria in children and young adolescents may have on the productivity of working adults and on the future size of the labour force augmented by educational returns, skills, and experience. We calibrated the model using estimates from linked epidemiologic and costing models on these same scenarios and from published country-specific macroeconomic data.\n</p>", "<p><bold>Results:</bold> Scaling-up malaria control could produce a dividend of US$ 152 billion in the modelled countries, equivalent to 0.17% of total GDP projected over the study period across the 26 countries. Assuming a larger share of malaria investments is paid out from domestic savings, the dividend would be smaller but still significant, ranging between 0.10% and 0.14% of total projected GDP. Annual GDP gains were estimated to increase over time. Lower income and higher burden countries would experience higher gains.\n</p>", "<p><bold>Conclusion:</bold> Intensified malaria control can produce a multiplied return despite the opportunity cost of greater investments.</p>", "<p>\n<bold>Citation:</bold> Patouillard E, Han S, Lauer J, Barschkett M, Arcand JL. The macroeconomic impact of increasing investments in malaria control in 26 high malaria burden countries: an application of the updated EPIC model. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7132. doi:10.34172/ijhpm.2023.7132</p>" ]	[ "<title>Acknowledgment</title>", "<p> We thank the members of the WHO’s Scientific Advisory Group on Malaria Eradication for insightful advice.</p>", "<title>Ethical issues</title>", "<p> No ethical approval was sought as this is secondary data analysis.</p>", "<title>Competing interests</title>", "<p> Edith Patouillard is staff member of the WHO. Other authors declare that they have no competing interests.</p>", "<title>Disclaimers</title>", "<p> The views expressed are those of the authors and do not necessarily represent the views of their respective organizations.</p>", "<title>Funding</title>", "<p> Funders include the WHO and the Bill & Melinda Gates Foundation. The funders had no role in the design, writing or the decision to submit the manuscript for publication.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nAnnual Gains in Projected GDP (2014 Billion US$ and 95% UI) for All 26 Modelled Countries Between 2016 and 2030. Trend in annual gains in GDP projected for all modelled countries between 2016 and 2010 in the Scale-up scenario compared to the Sustain scenario. Thicker blue line shows greater uncertainty using 95% UIs. Abbreviations: UI, uncertainty interval; GDP, gross domestic product.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nPercent Gain in Projected GDP in the Scale-up Scenario Compared to the Sustain Scenario, Across All 26 Countries in 2016-2020, 2021-2025 and 2026-2030 and Trend in Projected GDP Gain Across 16 Low-Income Countries and 9 Low-Middle Income Countries Between 2016 and 2030 (Base-Case Analysis).Boxplots represent the distribution of percent gains (median and upper and lower quartiles) in projected GDP across 26 individual modelled countries for each 5-year period. Whiskers indicate the variability in results outside upper and lower quartiles. Dots indicate individual point estimate outliers. Dashed and solid lines indicate the arithmetic mean of the gain in projected GDP for 16 low-income countries and the 9 low-middle-income countries respectively. Abbreviation: GDP, gross domestic product.</p></statement></fig>" ]	[]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>There is ample evidence on the economic benefits of malaria control. The potential net gains in projected gross domestic product (GDP) from reduced malaria burden on one hand and increased investments that divert resources from other important areas on the other hand have not been previously estimated. </p></list-item><list-item><p>Under a range of assumptions, this study shows that intensified malaria control could produce a multiplied net return in terms of economic growth. </p></list-item><list-item><p>The study used a macroeconomic model called Economic Projections of Illness and Costs (EPIC) that can be easily adapted to different diseases and conditions and calibrated to different countries to support the development of investment cases in health. </p></list-item><list-item><p>EPIC can complement other types of tools to inform priority-setting in health. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> After remarkable success in the fight against malaria, investments in malaria control and disease burden reductions have plateaued. Malaria continues to have a devastating impact on population lives and livelihoods: deaths, notably in young children, reduce the total size of the future workforce, while infections throughout life reduce productivity because of work and school absenteeism. Intensifying malaria control requires substantial resources, which, on one hand, averts infections and treatment costs while, on the other hand, reduces investment opportunities in other important areas. Quantifying the net economic return of investing in malaria can better reflect the wide impact of the disease and provide useful information for decision makers.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. EPIC Technical Specification and Adaptation to Malaria.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 2. Data Sources.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 3. Results.\n</p></caption></supplementary-material>" ]	[]	[ "<graphic xlink:href=\"ijhpm-12-7132-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7132-g002\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7132-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7132-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7132-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["2"], "mixed-citation": [" World Health Organization (WHO). World Malaria Report 2015. WHO; 2015. "]}, {"label": ["4"], "mixed-citation": [" World Health Organization (WHO). World Malaria Report 2022. WHO; 2022. "]}, {"label": ["5"], "mixed-citation": [" World Health Organization (WHO). Global Technical Strategy for Malaria 2016-2030, 2021 Update. WHO; 2021. "]}, {"label": ["12"], "mixed-citation": [" World Health Organization (WHO). Global Expenditure on Health: Public Spending on the Rise? WHO; 2021. "]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Cutler", "Fung", "Kremer", "Singhal", "Vogl"], "given-names": ["D", "W", "M", "M", "T"], "article-title": ["Early-life malaria exposure and adult outcomes: evidence from malaria eradication in India"], "source": ["Am Econ J Appl Econ"], "year": ["2010"], "volume": ["2"], "issue": ["2"], "fpage": ["72"], "lpage": ["94"], "pub-id": ["10.1257/app.2.2.72"]}, {"label": ["24"], "mixed-citation": [" World Health Organization (WHO). Global Health Expenditures Database. "], "uri": ["https://apps.who.int/nha/database/"]}, {"label": ["35"], "person-group": ["\n"], "surname": ["Bleakley"], "given-names": ["H"], "article-title": ["Malaria eradication in the Americas: a retrospective analysis of childhood exposure"], "source": ["Am Econ J Appl Econ"], "year": ["2010"], "volume": ["2"], "issue": ["2"], "fpage": ["1"], "lpage": ["45"], "pub-id": ["10.1257/app.2.2.1"]}, {"label": ["38"], "mixed-citation": [" World Health Organization (WHO). Global Technical Strategy for Malaria 2016-2030. WHO; 2015. "]}, {"label": ["40"], "person-group": ["\n"], "surname": ["Bloom", "Chen", "McGovern"], "given-names": ["DE", "S", "ME"], "article-title": ["The economic burden of noncommunicable diseases and mental health conditions: results for Costa Rica, Jamaica, and Peru"], "source": ["Rev PanamSalud Publica"], "year": ["2018"], "volume": ["42"], "fpage": ["e18"], "pub-id": ["10.26633/rpsp.2018.18"]}, {"label": ["41"], "person-group": ["\n"], "surname": ["Bloom", "Chen", "Kuhn", "McGovern", "Oxley", "Prettner"], "given-names": ["DE", "S", "M", "ME", "L", "K"], "article-title": ["The economic burden of chronic diseases: estimates and projections for China, Japan, and South Korea"], "source": ["J Econ Ageing"], "year": ["2020"], "volume": ["17"], "fpage": ["100163"], "pub-id": ["10.1016/j.jeoa.2018.09.002"]}, {"label": ["44"], "mixed-citation": [" R Core Team. R: A Language and Environment for Statistical Computing. Version 4.3. R Foundation for Statistical Computing; 2021. "], "uri": ["https://www.r-project.org/"]}, {"label": ["45"], "mixed-citation": [" R Studio: Integrated Development for R. RStudio; 2020. "], "uri": ["http://www.rstudio.com/"]}, {"label": ["46"], "person-group": ["\n"], "surname": ["Feenstra", "Inklaar", "Timmer"], "given-names": ["RC", "R", "MP"], "article-title": ["The next generation of the Penn World Table"], "source": ["Am Econ Rev"], "year": ["2015"], "volume": ["105"], "issue": ["10"], "fpage": ["3150"], "lpage": ["3182"], "pub-id": ["10.1257/aer.20130954"]}, {"label": ["47"], "mixed-citation": [" ILOSTAT. Statistics on the Population and Labour Force. Geneva: International Labour Organization; 2015. "], "uri": ["https://ilostat.ilo.org/"]}, {"label": ["48"], "mixed-citation": [" World Health Organization (WHO). Projection analysis based on Global Health Estimates (GHE) 2016: Deaths by Cause, Age, Sex, by Country and by Region, 2000-2016. WHO; 2018. "]}, {"label": ["49"], "person-group": ["\n"], "surname": ["Patouillard", "Griffin", "Bhatt", "Ghani", "Cibulskis"], "given-names": ["E", "J", "S", "A", "R"], "article-title": ["Global investment targets for malaria control and elimination between 2016 and 2030"], "source": ["BMJ Glob Health"], "year": ["2017"], "volume": ["2"], "issue": ["2"], "fpage": ["e000176"], "pub-id": ["10.1136/bmjgh-2016-000176"]}, {"label": ["53"], "mixed-citation": [" The World Bank. DataBank, World Development Indicators. "], "uri": ["https://databank.worldbank.org/reports.aspx?source=World-Development-Indicators"]}, {"label": ["54"], "mixed-citation": [" UN Population Division. World Population Prospects. New York: United Nations; 2015. "]}, {"label": ["59"], "person-group": ["\n"], "surname": ["Bertram", "Stenberg", "Brindley"], "given-names": ["MY", "K", "C"], "article-title": ["Disease control programme support costs: an update of WHO-CHOICE methodology, price databases and quantity assumptions"], "source": ["Cost Eff ResourAlloc"], "year": ["2017"], "volume": ["15"], "fpage": ["21"], "pub-id": ["10.1186/s12962-017-0083-6"]}]	{ "acronym": [], "definition": [] }	61	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Oct 4; 12:7132	oa_package/56/ce/PMC10590221.tar.gz
PMC10590222	0	[ "<title>Background</title>", "<p> Medical deserts are known by many names. While the World Health Organization (WHO) defined “underserved areas” as “geographical areas where populations have limited access to qualified healthcare providers and quality healthcare services,”<sup>##UREF##0##1##</sup> such definition varies by country.<sup>##REF##19558682##2##</sup> Also, the definition of “medical deserts”<sup>##REF##30067211##3##</sup> itself is not uniform, as countries differ in their geographical characteristics (eg, islands or mountain areas), what is considered as a “rural and remote area,”<sup>##REF##30846013##4##</sup> and in terms of the type of health workforce (HWF) that is undersupplied (eg, medical specialists, dentists, etc), respectively. Therefore, there is a lack of understanding on medical deserts in the absence of a clear definition and categorization – which causes confusion in both research and policy discourse leading to misleading comparisons.<sup>##UREF##1##5##</sup></p>", "<p> Medical deserts are increasingly considered a problematic issue for many countries which try to employ a multitude of policies, actions and initiatives to achieve a better distribution of the HWF.<sup>##UREF##2##6##</sup> WHO’s Regional Office for Europe underlined the severity of the problem in its recent European Programme of Work 2020-2025, and considered medical deserts as the main HWF priority for Europe.<sup>##UREF##3##7##</sup></p>", "<p> A maldistribution of the HWF can have severe negative effects. A systematic review confirmed this fact by finding strong evidence for an association between health outcomes and patient travel time: the further away patients lived from the healthcare facility they needed to attend, the worse were their health outcomes (eg, survival rates, length of stay in hospital, and non-attendance at follow-up).<sup>##UREF##4##8##</sup></p>", "<p> Although many countries acknowledge the severity of medical deserts and take action, they do so without a strong rationale underlying the choice of specific policies and other measures.<sup>##UREF##2##6##,##UREF##3##7##</sup> As an example, in the OECD (Organisation for Economic Co-operation and Development) Health Systems Characteristics Survey of 2012 and 2016, countries reported which policies they had in place to address physician supply problems. Half of the countries indicated to use financial incentives to correct perceived geographical maldistribution, while it is known from the literature that financial incentives alone are unlikely to attract HWF to underserved areas and are more effective if combined with other types of measures.<sup>##REF##26324418##9##</sup></p>", "<p> Furthermore, when choosing a certain policy response or action, other contextual factors need to be taken into account. In the case of financial incentives, there are other reasons that should be considered that make physicians choose (not) to work in certain regions or possible legal barriers in place related to the choice of practice location.</p>", "<p> The purpose of this scoping review was to systematically map the research done in the area of HWF issues in medical deserts, to provide an overview of the different definitions, characteristics of medical deserts as well as the contributing factors and approaches to mitigate their HWF issues. Based on the information gathered from this review we will identify knowledge clusters and gaps for further research, which also will allow defining recommendations for all potential end users such as policy-makers and different stakeholders involved in HWF issues in medical deserts.</p>", "<p> This work was conducted as part of the “ROUTE-HWF” (a Roadmap OUT of mEdical deserts into supportive Health WorkForce initiatives and policies) project, a European Union (EU)-funded project that aims to reduce disparities in population’s health within the EU by ensuring timely access to high-quality healthcare in all regions of the EU.</p>" ]	[ "<title>Methods</title>", "<p> We registered the protocol of the scoping review prospectively in Open Science Framework on June 25, 2021 with doi:10.17605/OSF.IO/UEBXY and adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist<sup>##REF##30178033##10##</sup> for reporting (##SUPPL##0##Supplementary file 1##).</p>", "<p> We used Arksey and O’Malley<sup>##UREF##5##11##</sup> five-stage framework for scoping reviews: defining the research question, identifying relevant studies, study selection, data charting and collation and summarizing the results.</p>", "<title> Defining the Research Question</title>", "<p> The following research questions were formulated: (<italic toggle=\"yes\">i</italic>) What are medical deserts, and what are their main characteristics? (<italic toggle=\"yes\">ii</italic>) What are the factors that contribute to medical deserts and their HWF issues? and (<italic toggle=\"yes\">iii</italic>) What are the approaches to mitigate them?</p>", "<title> Identifying Relevant Studies</title>", "<p> To identify relevant published studies, we searched the following bibliographic databases from inception to June 2021: Embase, Medline, CINAHL, Web of Science Core Collection, Google Scholar, and the Cochrane Library. The search strategies were drafted by the author team and further refined by an experienced biomedical information specialist and through discussion within the members of the research team. We followed PRESS Peer Review of Electronic Search Strategies recommendations.<sup>##REF##27005575##12##</sup> The electronic search strategy for MEDLINE database is provided in ##TAB##0##Table 1##.</p>", "<p> The final search strategy as used for the electronic bibliographic databases can be found in ##SUPPL##1##Supplementary file 2##.</p>", "<p> In the review we included qualitative, quantitative, and mixed methods primary research studies addressing medical deserts with a focus on the definition, characteristics, contributing factors and approaches to mitigate the HWF issues in medical deserts.</p>", "<p> Peer-reviewed journal papers were included if they were written in English or a language that one of the authors was proficient in, were situated in Europe, the United States, Canada, Australia or New Zealand. Excluded were case reports, editorials, and articles without details about methods and/or results (##TAB##1##Table 2##).</p>", "<p> Furthermore, we searched for potential eligible studies that were not captured by our electronic database searches by checking the reference lists of included studies, relevant reviews, and by carrying out a cited reference search (forward citation tracking of the most relevant papers). Studies were included according to the same criteria as those found in the search of electronic databases.</p>", "<title> Study Selection </title>", "<p> The final search results of the electronic databases were exported into Endnote<sup>©</sup>, and duplicates were removed by the biomedical information specialist. Document information was uploaded in Rayyan<sup>©</sup> after the removal of the duplicates. Three reviewers (AIGG, LEF, and JB) independently screened the title and abstracts. Disagreement among the three reviewers were resolved by consensus and discussion. To increase consistency, a calibration exercise of 50 studies was performed with the aim of achieving 80% of agreement between the three reviewers.<sup>##REF##8532986##13##</sup> The inclusion and exclusion criteria were reviewed during the calibration period. Two reviewers (AIGG and LEF) independently screened the full texts of the selected abstracts. Also, the full-texts disagreements on study selection were resolved by consensus and discussion. Furthermore, two reviewers (AIGG and LS) assessed the potential eligible studies gathered by other type of searches (eg, reference lists of already included studies) and included the ones that met the inclusion criteria.</p>", "<title> Data Charting and Collation </title>", "<p> A data charting form was jointly developed by two reviewers (AIGG and LEF) to determine which subjects and variables to extract. The two reviewers each charted half of the selected data. During the charting, the data form was updated in an iterative process between the two reviewers.</p>", "<p> We extracted data on article characteristics (eg, country of origin), type of HWF addressed (eg, general practitioner [GP]), type of medical desert (eg, island) and ‘outcome’ (ie, definition, characteristics, contributing factors, and approaches to mitigate HWF issues in medical deserts). The studies were grouped by the type of outcomes analyzed (ie, definition, characteristics, contributing factors of medical deserts and approaches to mitigate their HWF issues) and summarized by type of HWF and study design for each group, along with broad findings.</p>" ]	[ "<title>Results</title>", "<p> The primary search produced over 2000 records. After removal of duplicates, 979 records were left for further assessment based on title and abstract resulting in 307 abstracts for retrieval of full texts. For 20 articles from the primary search, no full text could be retrieved. In total, 165 articles were excluded on the basis of the full-text, 105 reported about a population that was out of scope (eg, wrong country of origin), 59 did not meet the inclusion criteria, eight were not about medical deserts, seven were not about HWF and three were written in an excluded language. ##SUPPL##2##Supplementary file 3## presents all excluded studies and reasons for exclusion.</p>", "<p> One hundred and five studies were included in the scoping review after the electronic databases search and selection based on all inclusion and exclusion criteria (##FIG##0##Figure 1##). As 80% agreement between reviewers was achieved in the first calibration exercise, inclusion and exclusion criteria remained unchanged. Additionally, 135 studies were included after hand searching the reference lists of included studies and relevant reviews, and in addition by carrying out a cited reference search.</p>", "<title> Key Characteristics of Included Studies</title>", "<p>\n##TAB##2##Table 3## and ##SUPPL##3##Supplementary file 4## show the key characteristics of the 240 articles that were finally included. Most were conducted in Australia and New Zealand (48%) and North America (44%). Eight percent of the articles were situated in Europe. Most studies were observational quantitative (80%) and focused on a variety of HWF groups, with a majority focusing on medical students and physicians (mostly GPs).</p>", "<p>\n##FIG##1##Figure 2## shows detailed information about the number of studies found per country.</p>", "<p> Of the included 240 articles, 71% (n = 171) referred, used or described a definition of medical desert, 40% (n = 95) described its characteristics, 47% (n = 112) described contributing or associated factors for medical deserts and 36% (n = 87) approaches to mitigate the HWF issues in medical deserts. These four themes will be further explored below.</p>", "<title> Definition and Characteristics of Medical Deserts</title>", "<p> Most studies considered medical deserts as rural areas, underserved areas or used a measure of distance/time to a facility or a combination of the three.</p>", "<p> Of these, 69 studies did not define the term rural area.<sup>##REF##8614165##14##, ####REF##16134954##15##, ##REF##20051543##16##, ##REF##26515456##17##, ##REF##17300480##18##, ##REF##15946108##19##, ##REF##19469660##20##, ##REF##19089729##21##, ##UREF##6##22##, ##REF##17760915##23##, ##REF##23378076##24##, ##REF##20028277##25##, ##REF##22091493##26##, ##REF##14641232##27##, ##REF##19451850##28##, ##REF##25169650##29##, ##REF##19769650##30##, ##REF##9785529##31##, ##REF##15690834##32##, ##REF##21988627##33##, ##UREF##7##34##, ##UREF##8##35##, ##REF##25700220##36##, ##REF##21988900##37##, ##REF##21568620##38##, ##REF##16454619##39##, ##REF##15859056##40##, ##REF##11111421##41##, ##REF##8336575##42##, ##UREF##9##43##, ##UREF##10##44##, ##REF##18382840##45##, ##REF##20455635##46##, ##REF##19382828##47##, ##REF##26949236##48##, ##REF##16201837##49##, ##REF##20334760##50##, ##REF##18336949##51##, ##REF##20447007##52##, ##REF##17441817##53##, ##REF##16426427##54##, ##REF##20636179##55##, ##REF##22935122##56##, ##REF##16043525##57##, ##REF##24612383##58##, ##REF##11978724##59##, ##REF##15932485##60##, ##REF##14526866##61##, ##REF##22998200##62##, ##REF##18673106##63##, ##REF##18808483##64##, ##REF##15315545##65##, ##REF##9852661##66##, ##REF##28683808##67##, ##REF##16544958##68##, ##REF##22239835##69##, ##REF##9883107##70##, ##REF##14996332##71##, ##REF##20881694##72##, ##REF##33525999##73##, ##REF##17970901##74##, ##REF##14513084##75##, ##REF##22713111##76##, ##REF##15923977##77##, ##REF##18241180##78##, ##UREF##11##79##, ##REF##11894793##80##, ##UREF##12##81##, ##REF##22445533##82##, ##REF##11676768##83####11676768##83##</sup> Fifty-eight reported a definition of rural area and used a single criterion to define it:</p>", "<p>the ratio between the population and the HWF,<sup>##REF##31953862##84##, ####REF##6229488##85##, ##REF##18785798##86##, ##UREF##13##87##, ##REF##27957773##88##, ##REF##10437338##89##, ##REF##16835193##90##, ##REF##18427021##91##, ##REF##24252634##92##, ##REF##23619079##93####23619079##93##</sup></p>", "<p>the size of the population in an area,<sup>##UREF##9##43##,##REF##30480342##94##, ####REF##10234346##95##, ##REF##17300482##96##, ##REF##12585774##97##, ##REF##19747755##98##, ##REF##10105941##99##, ##REF##14768743##100##, ##REF##26596864##101##, ##REF##31461585##102##, ##REF##24606624##103##, ##REF##30293435##104##, ##REF##26839448##105##, ##REF##18208648##106##, ##REF##22283714##107##, ##REF##21429224##108##, ##REF##23069366##109##, ##REF##17187535##110##, ##REF##21919544##111##, ##REF##15167324##112##, ##REF##25890081##113##, ##REF##24528153##114##, ##REF##29540400##115##, ##REF##8553635##116##, ##REF##15027080##117##, ##REF##11768926##118##, ##REF##16840879##119##, ##REF##30238625##120##, ##REF##11879514##121##, ##REF##9682579##122##, ##REF##29852744##123##, ##REF##15885026##124##, ##UREF##14##125##, ##REF##3815198##126##, ##REF##16926939##127##, ##REF##23752037##128##, ##UREF##15##129####15##129##</sup></p>", "<p>the distance to the HWF,<sup>##REF##10721346##130##, ####REF##30227352##131##, ##REF##30615678##132##, ##REF##32830329##133##, ##REF##27585025##134##, ##REF##16614327##135##, ##REF##30961405##136####30961405##136##</sup></p>", "<p>the distance to the nearest town,<sup>##REF##12389749##137##</sup> or </p>", "<p>the number of hospital beds in the region.<sup>##REF##23350830##138##,##REF##27812820##139##</sup></p>", "<p> These criteria were mostly part of several more ‘formal’ definitions that were used by 78 studies as shown in ##SUPPL##4##Supplementary file 5##. Twenty studies used a combination of factors or criteria to define rural areas.<sup>##REF##25700220##36##,##REF##33220701##140##, ####REF##1518110##141##, ##REF##10429591##142##, ##REF##16426429##143##, ##UREF##16##144##, ##REF##23895494##145##, ##UREF##17##146##, ##REF##25250749##147##, ##UREF##18##148##, ##REF##28930761##149##, ##REF##28678105##150##, ##REF##24160687##151##, ##REF##21040081##152##, ##REF##8326777##153##, ##REF##9919079##154##, ##REF##18186719##155##, ##REF##30827118##156##, ##REF##28460530##157##, ##REF##30577775##158####30577775##158##</sup> All definitions, except the Rural Ranking scale, were defined from the perspective of the population. The Rural Ranking scale is a criterion that defines medical deserts from the perspective of GPs (see ##SUPPL##4##Supplementary file 5##).</p>", "<p> If we focus on the definitions from the perspective of the population, the following elements or criteria were identified:</p>", "<p>population size of the area, </p>", "<p>percentage of poverty in the area, </p>", "<p>percentage of population aged 65 and over, </p>", "<p>infant mortality rate in the area, </p>", "<p>mobility of the population in the area, </p>", "<p>health needs of the population in the area, </p>", "<p>number of HWF in the area, </p>", "<p>economic resources in the area, </p>", "<p>education and occupation options in the area, </p>", "<p>presence of a hospital or other health services in the area, </p>", "<p>population to provider ratio, and </p>", "<p>distance/time to facilities, distance/adjacent to metropolitan area. </p>", "<p> These elements can be divided into four categories: (<italic toggle=\"yes\">i</italic>) Size of the population, (<italic toggle=\"yes\">ii</italic>) characteristics of the population, (<italic toggle=\"yes\">iii</italic>) number of services in the area, and (<italic toggle=\"yes\">iv</italic>) distance to services. Although all these elements seem relevant to define if an area is a potential medical desert, different definitions remain of how an ‘area’ is defined or demarcated as such. Therefore, it is not always possible to apply the definition elements presented above in countries if a different area definition is applied. For example, some studies defined areas as a community, county, province, mountain or island, while one study defined an area as a square kilometer.<sup>##REF##30238625##120##</sup> To define if an area is a medical desert, dividing a country in ‘blocks’ of a prespecified size might be an objective approach to compare countries on their medical desert areas and relevant criteria.</p>", "<p> For studies that based their definition of a medical desert on the perspective of GPs (ie, the Rural Ranking scale), the definition elements are shown in ##SUPPL##4##Supplementary file 5##.<sup>##REF##24694262##159##</sup></p>", "<title> Contributing Factors to Medical Deserts</title>", "<p> One hundred and twelve studies addressed contributing factors that may (have) enhanced or diminish medical deserts and their HWF issues. The factors extracted from the studies are presented below in four categories. Most factors were considered as both, positively as well as negatively influencing the workplace decision of HWF, depending on the individual preferences. Therefore, factors are described as influencing factors in general. In case that a factor was solely considered as positively or negatively influencing medical deserts, it is described as such within the results.</p>", "<title> 1. Work-Related Factors</title>", "<p> Fifty-five studies identified work-related factors that could contribute positively or negatively to medical deserts and their HWF issues:</p>", "<p>Low level of <italic toggle=\"yes\">job satisfaction</italic><sup>##REF##23378076##24##,##REF##14641232##27##,##REF##9785529##31##,##REF##20334760##50##,##REF##11978724##59##,##REF##31461585##102##,##REF##21411473##160##,##REF##8588774##161##</sup> and <italic toggle=\"yes\">burnout</italic> rates<sup>##REF##14641232##27##,##REF##9785529##31##,##REF##17441817##53##,##REF##31461585##102##</sup> were found to be associated with working location, in favor of working in rural versus urban placements. </p>", "<p>Higher <italic toggle=\"yes\">workload</italic> (eg, patient list, working hours, patient-related hours, on-call arrangements)<sup>##REF##23378076##24##,##REF##21988900##37##,##REF##30238625##120##</sup> in rural areas was reported by seventeen studies<sup>##REF##23378076##24##,##REF##14641232##27##,##REF##9785529##31##,##UREF##8##35##,##REF##21988900##37##,##REF##11111421##41##,##REF##20447007##52##,##REF##11978724##59##,##REF##9883107##70##,##REF##11768926##118##,##REF##30238625##120##,##REF##12389749##137##,##REF##9444118##162##, ####REF##12065010##163##, ##REF##20423202##164##, ##REF##26321030##165##, ##REF##15107883##166####15107883##166##</sup> and considered a worrisome issue, and therefore contributing negatively to the willingness of working in rural areas. </p>", "<p>\n<italic toggle=\"yes\">Working conditions</italic> such as working atmosphere,<sup>##UREF##7##34##,##REF##15859056##40##,##REF##20455635##46##,##REF##20334760##50##,##REF##31953862##84##,##REF##8588774##161##,##REF##20423202##164##,##REF##15107883##166##</sup> having a single hand or group practice<sup>##REF##9883107##70##,##REF##30238625##120##,##REF##12389749##137##,##REF##8326777##153##</sup> or full-time versus part time job,<sup>##UREF##7##34##,##REF##17970901##74##,##REF##21438950##167##</sup> can have a negative but as well a positive influence on the choice of working in a rural location, depending on personal preferences of the HWF. </p>", "<p>Furthermore, characteristics related to <italic toggle=\"yes\">the informal nature of rural practice</italic> in general,<sup>##UREF##6##22##,##REF##20334760##50##,##REF##17441817##53##,##REF##10105941##99##,##REF##11768926##118##,##REF##8588774##161##,##REF##12603445##168##</sup> travel hours,<sup>##REF##20334760##50##,##REF##17970901##74##,##REF##11676768##83##</sup> level of autonomy,<sup>##REF##11111421##41##,##REF##17970901##74##,##REF##10105941##99##,##REF##9444118##162##</sup> and flexibility in practice structure<sup>##REF##15023221##169##</sup> were identified as factors influencing the decision to work in rural or urban areas, depending as well on personal preferences of the HWF. </p>", "<p>The <italic toggle=\"yes\">work variety</italic> of rural practices, along with other factors such as <italic toggle=\"yes\">closer doctor-patient relationship</italic>, good team collaboration, multidisciplinary and student experiences, positively influenced the attitude of the HWF towards working in rural areas. This relationship was found by 11 studies.<sup>##REF##20455635##46##,##REF##11978724##59##,##REF##18808483##64##,##REF##16544958##68##,##REF##17970901##74##,##REF##31953862##84##,##REF##16926939##127##,##REF##9444118##162##,##REF##12065010##163##,##UREF##19##170##,##REF##14558865##171##</sup></p>", "<p>Five studies<sup>##REF##15859056##40##,##REF##11978724##59##,##REF##17970901##74##,##REF##15023221##169##,##REF##20364544##172##</sup> identified the lack of <italic toggle=\"yes\">personal recognition</italic> and 22 <italic toggle=\"yes\">financial</italic> issues such as lack of financial recognition, financial security, financial incentives and loan forgiveness<sup>##REF##17300480##18##,##REF##17760915##23##,##REF##23378076##24##,##REF##9785529##31##,##UREF##7##34##,##REF##15859056##40##,##REF##11111421##41##,##REF##20455635##46##,##REF##20447007##52##,##REF##11978724##59##,##REF##9852661##66##,##REF##31953862##84##,##REF##10105941##99##,##REF##14768743##100##,##REF##17187535##110##,##REF##15167324##112##,##REF##11768926##118##,##REF##15885026##124##,##REF##16926939##127##,##REF##28930761##149##,##REF##15023221##169##,##REF##10511758##173##</sup> when working in rural settings as a negative factor influencing the career choices of the HWF against working in rural. </p>", "<p>Lack of <italic toggle=\"yes\">career prospects</italic><sup>##REF##17760915##23##,##UREF##10##44##,##REF##17441817##53##,##REF##17970901##74##,##REF##10105941##99##,##REF##11768926##118##,##REF##21265924##174##</sup> and <italic toggle=\"yes\">educational and professional development</italic> opportunities,<sup>##REF##17970901##74##,##REF##11676768##83##,##REF##31953862##84##,##REF##17187535##110##,##REF##11768926##118##,##REF##15885026##124##,##REF##12065010##163##,##REF##20423202##164##</sup> lack of professional support<sup>##REF##8614165##14##,##REF##14641232##27##,##REF##9785529##31##,##UREF##10##44##,##REF##17970901##74##,##UREF##12##81##,##REF##12065010##163##,##REF##20423202##164##,##REF##12603445##168##,##REF##15023221##169##</sup> and <italic toggle=\"yes\">management support</italic><sup>##REF##17441817##53##,##REF##11676768##83##,##REF##17187535##110##,##REF##20423202##164##</sup> and <italic toggle=\"yes\">professional isolation</italic><sup>##REF##14641232##27##,##UREF##12##81##,##REF##11676768##83##,##REF##12389749##137##,##REF##9444118##162##</sup> as well as lack of access to <italic toggle=\"yes\">healthcare resources</italic> (eg, equipment, personnel)<sup>##REF##8614165##14##,##REF##15859056##40##,##REF##17970901##74##,##REF##15885026##124##,##REF##28460530##157##</sup> were found as factors negatively associated with working in a rural setting. </p>", "<p>Furthermore, the lack of <italic toggle=\"yes\">availability of jobs,</italic><sup>##UREF##7##34##,##REF##8588774##161##</sup> the <italic toggle=\"yes\">length of employment</italic> in the position (higher risk of turnover during the first six months),<sup>##REF##10105941##99##,##REF##21438950##167##</sup> the lack of <italic toggle=\"yes\">intellectual challenge</italic> (eg, scientific curiosity, complex care, research, procedural specialty),<sup>##REF##20334760##50##</sup> the willingness to get <italic toggle=\"yes\">professional specialization</italic> education<sup>##REF##1518110##141##,##REF##22394086##175##</sup> as well as <italic toggle=\"yes\">personal traits</italic><sup>##REF##11111421##41##,##REF##10511758##173##</sup> also were found as factors that negatively influenced the choice of working in rural locations. </p>", "<title> 2. Lifestyle-Related Factors</title>", "<p> Thirty-three studies investigated lifestyle-related factors that may influence the recruitment and retention of HWF in medical deserts:</p>", "<p>Ten studies<sup>##REF##9785529##31##,##REF##11111421##41##,##REF##17441817##53##,##REF##16544958##68##,##REF##11676768##83##,##REF##15167324##112##,##REF##16926939##127##,##REF##8588774##161##,##REF##9444118##162##,##REF##12603445##168##</sup> identified <italic toggle=\"yes\">rural lifestyle</italic> in general as positively associated with the willingness to work in rural areas. </p>", "<p>\n<italic toggle=\"yes\">Work-life balance</italic> was a positively influential factor described in three studies.<sup>##REF##22283714##107##,##REF##15107883##166##,##REF##21265924##174##</sup></p>", "<p>\n<italic toggle=\"yes\">Family issues</italic> such as finding employment for the spouse or good children education were as well considered as very relevant factors in 17 studies<sup>##REF##14641232##27##,##REF##9785529##31##,##REF##20334760##50##,##REF##17441817##53##,##REF##9852661##66##,##REF##16544958##68##,##REF##14768743##100##,##REF##22283714##107##,##REF##11768926##118##,161–164,##REF##12603445##168##,##REF##15023221##169##,##REF##22394086##175##,##REF##19943714##176##</sup> diminishing the willingness to work in rural areas. </p>", "<p>\n<italic toggle=\"yes\">Feelings of isolation</italic>,<sup>##REF##14641232##27##,##REF##9883107##70##,##REF##9444118##162##,##REF##15107883##166##,##UREF##19##170##,##REF##27233683##177##</sup> lack of access to other <italic toggle=\"yes\">desirable services</italic> such as internet<sup>##UREF##19##170##</sup> or <italic toggle=\"yes\">leisure activities</italic><sup>##REF##20455635##46##,##REF##11676768##83##</sup> and <italic toggle=\"yes\">anonymity</italic><sup>##REF##17760915##23##,##REF##28460530##157##,##REF##20364544##172##</sup> were other relevant lifestyle-related factors described that influenced negatively the willingness to work in rural settings. </p>", "<p>Furthermore, <italic toggle=\"yes\">high costs of living</italic> and <italic toggle=\"yes\">travelling</italic> were considered as a significant incentive not to work and live in urban areas but in rural settings instead.<sup>##REF##18808483##64##,##REF##11676768##83##,##REF##21429224##108##</sup></p>", "<title> 3. Migration</title>", "<p> One study<sup>##UREF##18##148##</sup> from Romania identified <italic toggle=\"yes\">migration</italic> of the HWF to other countries as a contributing factor to medical deserts. This single outcome is probably specific for Romania, known as a typical ‘source country’ in cross-border HWF mobility like some other Eastern European countries.</p>", "<title> 4. Socio-demographics or Other HWF Characteristics</title>", "<p> Seventy-nine studies showed socio-demographic or other characteristics of the HWF that also may contribute to their career choices and subsequently influence HWF issues in medical deserts:</p>", "<p>\n<italic toggle=\"yes\">Age</italic> was a factor described in nine studies<sup>##REF##17300480##18##,##REF##20881694##72##,##REF##10105941##99##,##REF##25250749##147##,##REF##8326777##153##,##REF##15107883##166##,##REF##21438950##167##,##REF##19335596##178##,##REF##25890081##179##</sup> influencing HWF turnover in rural areas; in some studies it was found that retirement due to aging of the HWF was not compensated by the inflow of health workers of younger age, because of their preference to work in urban placements. </p>", "<p>Both <italic toggle=\"yes\">male</italic><sup>##REF##3815198##126##,##REF##8326777##153##</sup> and <italic toggle=\"yes\">female</italic><sup>##REF##30293435##104##,##REF##25250749##147##,##REF##28930761##149##,##REF##26618314##180##,##REF##25315743##181##</sup> (from 2014 onwards) health workers appear to be more willing to work in rural practice depending on the year of publication of the studies. Gender apparently has mixed effects on this career choice and therefore on HWF issues in medical deserts. </p>", "<p>Forty-five studies described<sup>##REF##17300480##18##,##UREF##6##22##,##REF##25169650##29##,##REF##19769650##30##,##REF##20455635##46##,##REF##20447007##52##,##REF##16426427##54##,##REF##18808483##64##,##REF##22239835##69##,##REF##14996332##71##,##REF##20881694##72##,##REF##14513084##75##,##REF##10234346##95##,##REF##24606624##103##,##REF##30293435##104##,##REF##18208648##106##,##REF##25890081##113##,##REF##11768926##118##,##REF##11879514##121##,##REF##9682579##122##,##REF##15885026##124##,##REF##3815198##126##,##REF##16926939##127##,##REF##28678105##150##,##REF##8588774##161##,##REF##10511758##173##,##REF##19943714##176##,##REF##27233683##177##,##REF##25315743##181##, ####REF##15720310##182##, ##REF##24300320##183##, ##REF##25588445##184##, ##REF##27380824##185##, ##REF##25945452##186##, ##REF##28686628##187##, ##REF##28814216##188##, ##REF##22361786##189##, ##REF##11559288##190##, ##REF##10937001##191##, ##REF##27554000##192##, ##REF##24645878##193##, ##REF##33567159##194##, ##REF##21114701##195####21114701##195##</sup>\n<italic toggle=\"yes\">rural background</italic> as a positive factor associated with working in a rural setting.<sup>##REF##19769650##30##,##REF##15720310##182##,##REF##24300320##183##,##REF##27554000##192##, ####REF##24645878##193##, ##REF##33567159##194####33567159##194##,##REF##25123620##196##</sup></p>", "<p>Forty-seven studies described <italic toggle=\"yes\">rural training</italic> as a factor positively associated with working in rural areas.<sup>##REF##17300480##18##</sup>, <sup>##UREF##6##22##,##REF##25169650##29##,##REF##21988627##33##,##UREF##7##34##,##UREF##9##43##,##REF##20447007##52##,##REF##16426427##54##,##REF##22935122##56##,##REF##16043525##57##,##REF##18808483##64##,##REF##16544958##68##,##REF##22239835##69##,##REF##14513084##75##,##REF##10234346##95##,##REF##24606624##103##,##REF##30293435##104##,##REF##18208648##106##,##REF##21919544##111##,##REF##25890081##113##,##REF##11879514##121##,##REF##9682579##122##,##REF##16926939##127##,##REF##30961405##136##,##REF##25250749##147##,##REF##8326777##153##,##REF##30827118##156##,##REF##8588774##161##,##REF##12603445##168##,##UREF##19##170##,##REF##22394086##175##,##REF##19943714##176##,##REF##15720310##182##,##REF##28686628##187##, ####REF##28814216##188##, ##REF##22361786##189##, ##REF##11559288##190####11559288##190##,##REF##27554000##192##,##REF##24645878##193##,##REF##21114701##195##, ####REF##25123620##196##, ##REF##32985033##197##, ##REF##30907206##198##, ##REF##26204255##199##, ##REF##1308662##200##, ##REF##23751066##201####23751066##201##</sup> One study though, showing controversial results.<sup>##REF##10234346##95##</sup></p>", "<p>Furthermore, having a lower <italic toggle=\"yes\">socio-economic status</italic><sup>##REF##27812820##139##,##REF##26618314##180##,##REF##25315743##181##</sup> or <italic toggle=\"yes\">educational level,</italic><sup>##REF##28460530##157##</sup> having a high medical school <italic toggle=\"yes\">admission score,</italic><sup>##REF##28678105##150##</sup> belonging to a <italic toggle=\"yes\">minority</italic>group,<sup>##REF##20881694##72##,##REF##25250749##147##,##REF##28930761##149##,##REF##28460530##157##,##REF##10937001##191##,##REF##25123620##196##</sup> having general <italic toggle=\"yes\">interest in rural practice</italic><sup>##REF##20051543##16##,##REF##24606624##103##,##REF##19943714##176##,##REF##27380824##185##,##REF##22361786##189##,##REF##10937001##191##,##REF##22435768##202##</sup> or specific professional <italic toggle=\"yes\">interest in primary care,</italic><sup>##REF##10511758##173##,##REF##19943714##176##,##REF##26618314##180##,##REF##25315743##181##,##REF##22361786##189##,##REF##11559288##190##,##REF##1308662##200##,##REF##26692500##203##</sup> and getting <italic toggle=\"yes\">financial support</italic> (ie, scholarships or funding)<sup>##REF##19769650##30##,##REF##18808483##64##,##REF##25588445##184##,##REF##11559288##190##,##REF##10937001##191##,##REF##1308662##200##</sup> were all positively associated with working in a rural setting. Besides, <italic toggle=\"yes\">rural familiarity</italic><sup>##REF##17760915##23##,##REF##16544958##68##,##REF##11768926##118##,##REF##3815198##126##</sup> and certain <italic toggle=\"yes\">character traits</italic> (eg, altruism, self-confidence, curiosity, loyalty)<sup>##REF##14641232##27##,##REF##20455635##46##,##REF##16544958##68##,##REF##22283714##107##,##REF##16926939##127##,##REF##28678105##150##,##REF##12603445##168##</sup> were also found to positively influence the choice of working in rural practice. </p>", "<p>Finally, one study found that having a <italic toggle=\"yes\">non-English speaking background,</italic> when working in English-speaking countries, was negatively associated with taking up rural practice.<sup>##REF##27812820##139##</sup></p>", "<p> The above mentioned four categories of factors (columns) involved in HWF issues in medical deserts (in most cases being defined as rural areas), are summarized in ##FIG##2##Figure 3##. Here the size of the bubbles indicates the number of studies reporting contributing factors, broken down by type of HWF (rows), and study design (by color). Characteristics of the HWF were found by the largest number of studies as contributing factors, next to work-related and lifestyle factors. Migration as a contributing factor was found by only one study. In addition, our extraction shows that the studies vary by the type of HWF that was subject of the study, as well as the type of study design.</p>", "<title> Approaches to Mitigate Medical Deserts</title>", "<p> We found eighty-three studies that described approaches to mitigate HWF issues in medical deserts. Comparable to our previous analysis, we present the approaches found in five categories.</p>", "<title> 1. Undergraduate Training Focused on Increased Rural Exposure</title>", "<p> The following approaches were found in the studies that can be classified under this category:</p>", "<p>\nSeven studies<sup>##REF##8336575##42##,##REF##20636179##55##,##REF##23619079##93##,##REF##32985033##197##,##REF##23751066##201##,##REF##26245841##204##,##REF##31878913##205##</sup> assessed approaches that are executed by <italic toggle=\"yes\">university-based rural clinical schools</italic> which emphasize rural recruitment. Results from these studies showed that such approach had a positive effect regarding the number of graduates that stay near or in the same rural areas where they attended undergraduate training.\n</p>", "<p>\nTwenty-two studies<sup>##REF##15946108##19##,##REF##19469660##20##,##REF##25169650##29##,##REF##21568620##38##,##UREF##9##43##,##REF##16201837##49##,##REF##22935122##56##,##REF##18673106##63##,##REF##28683808##67##,##REF##22713111##76##,##UREF##14##125##,##REF##30961405##136##,##REF##33220701##140##,##REF##10429591##142##,##REF##30827118##156##,##REF##26204255##199##,##REF##31878913##205##, ####REF##24329657##206##, ##REF##20354374##207##, ##REF##21605228##208##, ##REF##19877852##209##, ##UREF##20##210##, ##REF##24484114##211####24484114##211##</sup> assessed the effect of <italic toggle=\"yes\">rural clinical rotations</italic> (eg, rural internships, rural immersion programs) during undergraduate training on the intentions to work in rural settings or actual recruitment and retention rates of the rural HWF. These studies can be broken down in two subcategories:\n</p>", "<p>\n<list list-type=\"simple\"><list-item><p>\no Twelve studies<sup>##REF##15946108##19##,##REF##19469660##20##,##REF##25169650##29##,##REF##21568620##38##,##REF##16201837##49##,##REF##28683808##67##,##REF##14513084##75##,##REF##22713111##76##,##REF##33220701##140##,##REF##24329657##206##,##REF##21605228##208##,##REF##19877852##209##</sup> evaluated the effect of such programs on the intention of students to practice in rural areas. Eight studies<sup>##REF##15946108##19##,##REF##19469660##20##,##REF##25169650##29##,##REF##21568620##38##,##REF##28683808##67##,##REF##33220701##140##,##REF##24329657##206##,##REF##19877852##209##</sup> showed that an extended rural placement influenced medical and health science graduates’ intentions towards a rural career. The longer the clinical rotation, the more effective this was to increase the eventual choice of workplace location and future interest in a rural career.<sup>##REF##15946108##19##,##REF##19877852##209##</sup> Williamson et al<sup>##REF##22713111##76##</sup> reported that the positive effects of a seven-week rural undergraduate placement on the attitudes towards rural health workplaces persisted in postgraduate years; but also found that the undergraduate training itself is unlikely to result in a significant effect. Furthermore, Orpin and Gabriel<sup>##REF##16201837##49##</sup> identified that the ‘rural exposure’ had actually influenced two-thirds of health science students away from a rural career. Two studies<sup>\n##REF##14513084##75##,##REF##21605228##208##</sup> evaluated specific rural clinical-rotation programs: the so-called John Flynn Placement Program and the fifth-year rural health curriculum at Dunedin School of Medicine. Both appeared to have a positive influence on students’ intentions to enter and work in rural areas.\n</p></list-item><list-item><p>\no Twenty studies<sup>##REF##20051543##16##,##UREF##9##43##,##REF##22935122##56##,##REF##18673106##63##,##REF##18241180##78##,##REF##11879514##121##,##UREF##14##125##,##REF##30961405##136##,##REF##30827118##156##,##REF##24645878##193##,##REF##26204255##199##,##REF##22435768##202##,##REF##31878913##205##,##REF##20354374##207##,##UREF##20##210##, ####REF##24484114##211##, ##REF##26332428##212##, ##REF##23807101##213##, ##REF##12950945##214##, ##REF##19335596##215####19335596##215##</sup> assessed the recruitment and retention rates of graduates in rural areas after undergoing rural clinical rotations. Nineteen studies<sup>##REF##20051543##16##,##UREF##9##43##,##REF##22935122##56##,##REF##18673106##63##,##REF##18241180##78##,##REF##11879514##121##,##REF##30961405##136##,##REF##30827118##156##,##REF##24645878##193##,##REF##26204255##199##,##REF##22435768##202##,##REF##31878913##205##,##REF##20354374##207##,##UREF##20##210##, ####REF##24484114##211##, ##REF##26332428##212##, ##REF##23807101##213##, ##REF##12950945##214##, ##REF##19335596##215####19335596##215##</sup> showed an increase in the number of graduates choosing rural placements associated with undergraduate rural clinical rotations. However, Butler and Sheppard<sup>##UREF##14##125##</sup> reported that the undergraduate program was only adequate to prepare physiotherapy students for their professional roles but did not necessarily encourage students to accept rural positions.\n</p></list-item></list>\n</p>", "<p>\nFour studies<sup>##REF##17300482##96##,##REF##29540400##115##,##REF##12950945##214##,##REF##19930198##216##</sup> evaluated the effectiveness of <italic toggle=\"yes\">rural student recruitment</italic> programs to increase the low number of rural students enrolled into medical faculties. They concluded that a program that enrolls students interested in rural healthcare areas, and provides training in rural communities, were successful to stimulate graduates to practice in rural areas.\n</p>", "<p>\nTen studies assessed the effect of school programs <italic toggle=\"yes\">supporting early-entry rural and generalist pathways</italic><sup>##REF##16043525##57##,##REF##22445533##82##,##REF##9682579##122##,##REF##11559288##190##,##REF##24645878##193##,##REF##24506734##217##, ####REF##3405255##218##, ##REF##8446141##219##, ##REF##23288277##220##, ##REF##9918481##221####9918481##221##\n</sup> on rural recruitment and retention. Wood<sup>##REF##9682579##122##\n</sup> showed that nursing students who attended a nursing program focusing on ‘rural nursing’ were twice as likely to practice in rural areas. Two studies<sup>##REF##24645878##193##,##REF##24506734##217##</sup> presented that early career practice locations and movements of medical graduates from different rural clinical training programs positively influenced the likelihood to choose rural career paths. Six studies<sup>##REF##16043525##57##,##REF##11559288##190##,##REF##3405255##218##, ####REF##8446141##219##, ##REF##23288277##220##, ##REF##9918481##221####9918481##221##</sup> evaluated the Physician Shortage Area Program as an educational approach focusing on recruitment and retention of rural GPs demonstrating its success. Longenecker et al<sup>##REF##33244824##222##</sup> showed that medical school characteristics and activities may result in more graduates choosing rural general practice. Finally, Bennett et al<sup>##REF##22445533##82##</sup> described a structured and comprehensive educational clinical placement experience on undergraduate nurses. The authors showed that this enhanced the level of confidence of these nurses in the area of primary care.\n</p>", "<title> 2. Postgraduate Training and Continuing Medical Education Adapted to the Scope of Rural Practice</title>", "<p> For this category the following approaches were found in the studies:</p>", "<p>Postgraduate training as a <italic toggle=\"yes\">family or GP</italic> has been associated with an increase in the likelihood of working in urban underserved and rural areas, in contrast with other specialists working in primary care.<sup>##REF##8553635##116##,##REF##27581268##223##</sup> Another study showed that training in community health centers not only meets the HWF needs in rural areas, but also enhances the recruitment of GPs in underserved settings.<sup>##REF##18382840##45##</sup> Furthermore, exposing family practice residents to rural family practice training has shown to increase the number of GPs working in these rural areas.<sup>##REF##26515456##17##,##REF##14526866##61##,##REF##29540400##115##,##REF##10429591##142##,##REF##12950945##214##</sup></p>", "<p>Six studies<sup>##REF##24612383##58##,##REF##24528153##114##,##REF##19335596##178##,##UREF##21##224##, ####REF##15885019##225##, ##REF##24330603##226####24330603##226##</sup> assessed the need of <italic toggle=\"yes\">continuing education</italic> strategies with the aim of developing procedural and non-procedural skills specific to rural practice. Hajat et al<sup>##UREF##21##224##</sup> and Rourke et al<sup>##REF##14526866##61##</sup> identified job-specific continuing education as the most important training needs of rural local public health agencies and GPs, respectively. Two studies<sup>##REF##15690834##32##,##REF##15932485##60##</sup> evaluated the development of an interdisciplinary palliative care education program. Both showed that the program increased the capacity to deliver palliative care as reported by rural and remote communities as well as the job satisfaction of the healthcare workers. </p>", "<p>\n<italic toggle=\"yes\">Online courses</italic>were identified as the preferred means for receiving continuing education by nurses in rural schools.<sup>##REF##24612383##58##</sup> In Newman et al<sup>##REF##19382828##47##</sup> survey findings showed that videoconferencing was an overall success with general positive feedback of nurses working in rural areas. Ray et al<sup>##REF##24947941##227##</sup> evaluated the educational impact of videoconferencing to increase the confidence of healthcare workers to deliver quality palliative care in rural and remote areas. Results showed that the confidence level indeed increased significantly for all the types of HWFs. </p>", "<p>In three studies,<italic toggle=\"yes\">rural mentoring</italic> was considered central to recruitment and retention of allied HWFs in rural areas.<sup>##REF##15315545##65##,##REF##24528153##114##,##REF##15023221##169##</sup></p>", "<p>Furthermore, <italic toggle=\"yes\">scholarships</italic> to follow management of education programs in rural settings showed to have significantly increased rural nurses’ intention to stay in their current rural positions.<sup>##REF##15923977##77##</sup></p>", "<title> 3. Professional Support and Infrastructure</title>", "<p> This category of approaches was found in eight studies<sup>##REF##16454619##39##,##REF##14526866##61##,##REF##33525999##73##,##REF##10105941##99##,##REF##1518110##141##,##REF##15885019##225##,##REF##22250870##228##,##REF##29262798##229##</sup> describing or assessing approaches to support rural HWF and provide them with improved infrastructure.</p>", "<p>Jones et al<sup>##REF##15885019##225##</sup> examined the effectiveness of a set of recruitment and retention <italic toggle=\"yes\">incentives</italic>from the perspective of rural GPs. The GPs were asked to rate the importance of such approaches in terms of their impact. The two strategies that were rated most important were (1) better remuneration and (2) better after hours and on-call arrangements. Better locum availability and funding to improve practice infrastructure were rated as medium importance. Better education and professional support activity were rated as the least important. In Rourke et al,<sup>##REF##14526866##61##</sup> a different outcome of a similar study was presented. GPs working in rural areas rated funding for learner-driven continuing medical education as one of the most important solutions, along with reducing the number of on-call duty nights. Pathman et al<sup>##REF##1518110##141##</sup> compared the retention rates of a rural national scholarship program with other rural programs, showing that the effect of the scholarship program on retention rate of physicians was poor. </p>", "<p>In Kuhn et al,<sup>##REF##29262798##229##</sup> almost three quarters of local politicians agreed that one of the strategies that might improve primary care is the availability of allied health professional services. Lin and Goodale<sup>##REF##16454619##39##</sup> also showed that allied health professional services increased satisfaction among the HWF in rural areas. </p>", "<p>Humphreys et al<sup>##REF##22250870##228##</sup> defined <italic toggle=\"yes\">six sentinel indicators</italic> as the best way to support recruitment and retention of GPs in rural areas (ie, total hours, public hospital, on-call, time-off, partner employment and schooling). Their study was based on a data collected in four population size groups and comparing five levels of rural areas. </p>", "<p>Hanson et al reported that having relatively perceived <italic toggle=\"yes\">autonomy</italic> within their professional work settings<sup>##REF##10105941##99##</sup> has been a satisfactory approach for retaining nurses in rural areas. </p>", "<p>White et al<sup>##REF##33525999##73##</sup> developed and implemented a <italic toggle=\"yes\">stress management</italic> and reduction program among healthcare workers in rural areas. Participants that used such intervention reported between 25% to 72% reduced stress levels. </p>", "<title> 4. Planning and Monitoring the HWF Distribution</title>", "<p> Three studies<sup>##REF##18785798##86##,##REF##30577775##158##,##REF##24330603##226##</sup> focused on strategies to better plan and monitor the HWF maldistribution in rural and underserved areas. The approach proposed by Bowman<sup>##REF##18785798##86##</sup> and McGrail et al<sup>##REF##30577775##158##</sup> is <italic toggle=\"yes\">to align general practice training distribution</italic> to meet the needs of rural and underserved communities. Russell et al<sup>##REF##24330603##226##</sup> identified <italic toggle=\"yes\">benchmarks</italic> to analyze the length of stay of primary care HWF in rural and remote areas, by using survival analysis of longitudinal data on healthcare workers to inform rural HWF planning and retention strategies.</p>", "<title> 5. Innovative Models of Care</title>", "<p> This final category consists of nine studies<sup>##REF##20028277##25##,##REF##19451850##28##,##REF##25700220##36##,##REF##22998200##62##,##UREF##13##87##,##REF##29852744##123##,##REF##23350830##138##,##REF##29262798##229##,##REF##22356527##230##</sup> that described and/or evaluated innovative models of care as a solution to mitigate HWF issues in medical deserts. These approaches can be distinguished as follows:</p>", "<p>Four studies<sup>##REF##20028277##25##,##REF##19451850##28##,##REF##22998200##62##,##REF##22356527##230##</sup> evaluated approaches that substituted in-person consultations of specialized HWF by using <italic toggle=\"yes\">telemedicine</italic> in underserved rural areas. Such approaches comprised a ward-based geriatric consultation service delivered via a mobile videoconferencing system which showed to be highly accepted by patients and cost-effective.<sup>##REF##20028277##25##</sup> Also, a pediatric critical care telemedicine consultation was found to improve patient care<sup>##REF##19451850##28##</sup> and a program which placed telemonitors in rural satellite clinics to increase access to a pediatric obesity clinic which improved weight status compared with conventional treatment.<sup>##REF##22356527##230##</sup> A similar study was on a tele-oncology model of care which allowed cancer patients to receive specialist consultations and chemotherapy treatments closer to home.<sup>##REF##22998200##62##</sup></p>", "<p>Wood et al<sup>##REF##29852744##123##</sup> evaluated in a quasi-experimental study the implementation of a <italic toggle=\"yes\">satellite specialized HIV clinic</italic> program which showed improved patient-related outcomes and increased access to best practice HIV care. </p>", "<p>Two studies<sup>##REF##25700220##36##,##UREF##13##87##</sup> assessed <italic toggle=\"yes\">interprofessional student-run clinics</italic> providing care to vulnerable and underserved populations. Bradley et al<sup>##UREF##13##87##</sup> demonstrated, through a three-year evaluation, substantial improvement of health-related outcomes as well as reduction of use of health resources such as number of emergency department visits and hospital admissions. Lawrence et al<sup>##REF##25700220##36##</sup> reported in a quasi-experimental study high levels of patients satisfaction. </p>", "<p>Ceronsky et al<sup>##REF##23350830##138##</sup> described the framework of a <italic toggle=\"yes\">rural palliative care</italic> initiative consisting of individualized action plans tailored to the community’s needs and resources and verified its feasibility. They formulated five recommendations and conditions to support rural palliative care development: (1) external resources and support, (2) networking, (3) defining community-based metrics, (4) reimbursement for palliative care services, and (5) alignment of the palliative care program with other efforts to redesign care delivery. </p>", "<p>Kuhn et al<sup>##REF##29262798##229##</sup> analyzed different innovative models of care which can improve local primary care by discussing these with respondents from a local government point of view. Half of the respondents supported the implementation of patient buses as model (where patients come to the physician’s office), while less than one-third voted for mobile physician’s offices (where physicians or allied health workers go near the patient’ home). Telemedicine, which allows both the patient and the HWF to stay at home or office, respectively, appeared to be a model that was seen less suitable by the local politicians. </p>", "<p> The above list and categories of approaches to mitigate HWF issues in medical deserts (in most cases being defined as rural areas), is summarized in ##FIG##3##Figure 4##. Here the size of the circles shows the number of studies, broken down by type of approach (columns), type of HWF (rows), and study design (by color). The figure makes clear that most studies described approaches with regard to undergraduate and postgraduate training, either directed to medical or nurse students, or physicians working in rural areas.</p>" ]	[ "<title>Discussion</title>", "<p> This paper provides a systematic overview of primary research published in scientific journals on the definitions and characteristics of medical deserts, and the contributing factors and approaches to mitigate the HWF issues in medical deserts with a focus on Western countries.</p>", "<title> Summary of Results and Comparison With Literature</title>", "<p> This scoping review included a significant body of 240 empirical studies relevant to the subject of medical deserts in the context of their HWF issues. Most of the peer-reviewed articles found were from Australia, New Zealand and North America (92%). On the one hand this reflects the bias of Anglo-Saxon publications often seen in literature reviews.<sup>##REF##26324418##9##,##REF##31854339##231##</sup> On the other, it also reflects the size and maturity of the challenge related to medical deserts in such large countries and geographical settings. We also found a number of studies on medical deserts in European countries such as Germany and Greece, among others. Most of the studies found used an observational study design (98%), a few used an observational longitudinal design (22%) and just a small percentage used a quasi-experimental design (2%), as it has as well been reported in other reviews.<sup>##REF##26324418##9##,##REF##20461133##232##,##REF##27067255##233##</sup></p>", "<p> Most medical deserts were defined in the studies by population-based characteristics, ie, population density which is mostly referred to as rural areas.<sup>##UREF##9##43##,##REF##30480342##94##, ####REF##10234346##95##, ##REF##17300482##96##, ##REF##12585774##97##, ##REF##19747755##98##, ##REF##10105941##99##, ##REF##14768743##100##, ##REF##26596864##101##, ##REF##31461585##102##, ##REF##24606624##103##, ##REF##30293435##104##, ##REF##26839448##105##, ##REF##18208648##106####18208648##106##,##REF##21429224##108##,##REF##17187535##110##, ####REF##21919544##111##, ##REF##15167324##112##, ##REF##25890081##113##, ##REF##24528153##114##, ##REF##29540400##115##, ##REF##8553635##116####8553635##116##,##REF##11768926##118##, ####REF##16840879##119##, ##REF##30238625##120##, ##REF##11879514##121##, ##REF##9682579##122##, ##REF##29852744##123##, ##REF##15885026##124##, ##UREF##14##125##, ##REF##3815198##126##, ##REF##16926939##127##, ##REF##23752037##128##, ##UREF##15##129####15##129##,##REF##22250870##228##,##REF##22873948##234##</sup> However, a relevant number of studies referred to rural areas without a proper definition and furthermore without a consistent definition of what an area was considered defaulting the comparison among them or the generalizability of the results.</p>", "<p> The contributing factors that enhance or sustain HWF issues in medical deserts seem to mainly depend on the background and previous job characteristics of the HWF, followed by work-related and lifestyle related factors but to a lesser extent. Without claiming this as the ultimate study, we refer to Godwin et al<sup>##REF##25074243##235##</sup> as an example. Their systematic review with a focus on dental practitioners working in rural areas showed that the most mentioned motivational factor for recruitment and retention was the effect of prior ‘rural exposure’ for dental practitioners. The study showed that having a rural background (39%) and having received rural training were the most frequently (42%) and positively associated factors with working in a rural setting. These findings have been corroborated in a review of reviews performed by Asghari et al<sup>##REF##31854339##231##</sup> about the most influential factors for recruitment and retention of GPs.</p>", "<p> Finally, the studies included in our review show that approaches and strategies to mitigate HWF issues in medical deserts mostly focused on training; and thereby the early recruitment and exposure of students and HWF to rural areas. Next improving the scope of rural practice was also frequently found as an effective approach as also shown in one recently published review of the literature.<sup>##REF##34973053##236##</sup> Verma et al<sup>##REF##27067255##233##</sup> confirmed in their systematic review that although the evidence base for recruitment strategies was weak, they found evidence to support undergraduate and postgraduate placements in medical deserts. Buykx et al<sup>##REF##20579020##237##</sup> found that as multiple factors influence recruitment and retention of the HWF, a flexible and multifaceted response is needed. According to Dolea et al<sup>##REF##20461133##232##</sup> there is frequently a lack of coherence between the proposed strategy for recruitment and retention of the HWF and the factors that matter most to health workers in their choice of practice location. Therefore, a situation analysis should be mandatory before selecting the most appropriate approach or approaches to encourage the HWF to choose and stay in a medical desert.</p>", "<title> Strengths and Limitations</title>", "<p> To the best of our knowledge, our study provides the first scoping review of empirical studies on (1) the definitions and characteristics of medical deserts, and (2) the contributing factors and approaches to mitigate HWF issues in medical deserts in Western countries. Our study has also contributed to a categorization of studies on medical deserts, enabling further analyses of the relationship between different types of medical deserts, types of HWF groups and issues, and the related contributing factors and potential solutions. Our review also provides a base and an agenda for further research in this field. We found that observational studies were the most common type of design of the studies included, which shows the scarcity of longitudinal studies that actually investigate the impact of factors contributing to HWF issues in medical deserts. Also, we identified the absence of interventional studies to evaluate the effectiveness of approaches to mitigate medical deserts. Therefore, longitudinal studies as well as controlled experimental studies should be increasingly encouraged and funded. We also identified that the majority of the studies focused on medical students or physicians (mostly GPs) and more efforts should be made to determine the factors and evaluate programs targeted at other types of health workers.</p>", "<p> A limitation of this study is that we did not include ‘grey literature’ that might have been published in non-scientific journals, national, regional or sector-specific sources. We explored this type literature but it has been found not to identify additional studies in a way that justifies the effort involved in this type of search.<sup>##REF##17040510##238##</sup> We also excluded studies from lower-middle income countries and therefore, results can only be generalized to high income countries from Australia and Zealand, North America and (to a lesser extent) Europe. Additionally, we did not use specific related terms in our search to identify studies performed in European countries and thus to increase the sensitivity of the search to the detriment of specificity, which may have caused a loss of studies focused on Europe. Contributing factors to medical deserts and approaches to mitigate them may not be comparable across continents, as may not be across countries, and therefore not generalizable.</p>" ]	[ "<title>Conclusions</title>", "<p> This scoping review has collected, classified, extracted and synthesized the available empirical studies related to medical deserts and their HWF issues, published until June 2021 in Western countries. Whilst most studies originate from Australia, New Zealand and North America, studies from European countries were also included. Next to descriptive results we identified several gaps in the set of 240 studies included. One is the omission of longitudinal studies that measure the actual impact of factors contributing to HWF issues in medical deserts. Related is the lack of interventional studies that evaluate the effectiveness of approaches to mitigate HWF issues in medical deserts. We therefore advocate that more and next studies should invest in larger scaled and more rigor research, to fulfill the need for more evidence and research-based policy in medical deserts. This review shows that this research can be well based on the current studies, as new studies are now required to enable best practice outcomes for HWF policies in medical deserts.</p>" ]	[ "<p>\n<bold>Background:</bold> Medical deserts are considered a problematic issue for many Western countries which try to employ multitude of policies and initiatives to achieve a better distribution of their health workforce (HWF). The aim of this study was to systematically map research and provide an overview of definitions, characteristics, contributing factors and approaches to mitigate medical deserts within the European Union (EU)-funded project \"ROUTE-HWF\" (a Roadmap OUT of mEdical deserts into supportive Health WorkForce initiatives and policies).\n</p>", "<p><bold>Methods:</bold> We performed a scoping review to identify knowledge clusters/research gaps in the field of medical deserts focusing on HWF issues. Six databases were searched till June 2021. Studies reporting primary research from Western countries on definitions, characteristics, contributing factors, and approaches were included. Two independent reviewers assessed studies for eligibility, extracted data and clustered studies according to the four defined outcomes.</p>", "<p><bold>Results:</bold> Two-hundred and forty studies were included (n=116, 48% Australia/New Zealand; n=105, 44% North America; n=20, 8% Europe). All used observational designs except for five quasi-experimental studies. Studies provided definitions (n=171, 71%), characteristics (n=95, 40%), contributing factors (n=112, 47%), and approaches to mitigate medical deserts (n=87, 36%). Most medical deserts were defined by the density of the population in an area. Contributing factors to HWF issues in medical deserts consisted in work-related (n=55, 23%) and lifestyle-related factors (n=33, 14%) of the HWF as well as sociodemographic characteristics (n=79, 33%). Approaches to mitigate them focused on training adapted to the scope of rural practice (n=67, 28%), HWF distribution (n=3, 1%), support/infrastructure (n=8, 3%) and innovative models of care (n=7, 3%). </p>", "<p><bold>Conclusion:</bold> Our study provides the first scoping review that presents and categorizes definitions, characteristics, contributing factors, and approaches to mitigate HWF issues in medical deserts. We identified gaps such as the scarcity of longitudinal studies to investigate the impact of factors contributing to medical deserts, and interventional studies to evaluate the effectiveness of approaches to mitigate HWF issues.</p>", "<p>\n<bold>Citation:</bold> Flinterman LE, González-González AI, Seils L, et al. Characteristics of medical deserts and approaches to mitigate their health workforce issues: a scoping review of empirical studies in Western countries. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7454. doi:10.34172/ijhpm.2023.7454</p>" ]	[ "<title>Acknowledgements</title>", "<p> The authors wish to thank Elise Krabbendam from the Erasmus MC Medical Library for developing and updating the search strategies.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Disclaimer</title>", "<p> The views expressed in this paper represent the opinions of the authors and not an official position of the institutions of their affiliations.</p>", "<title>Funding</title>", "<p> This work was co-funded by the European Union’s Health Programme (2014-2020) under grant agreement no. 101018379 - ROUTE-HWF. The publication is co-funded by the Polish Ministry of Education and Science within the project “PMW” in the years 2021-2024; agreement no. 5176/HP3/2021/2.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nFlowchart of Review Search Strategy.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nNumber of Publications Per Country.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nTypes of Contributing Factors by Type of Health Work Force and Study Design. Abbreviation: HWF, health workforce.</p></statement></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4</label><statement><p>\nTypes of Approaches by Type of Health Work Force and Study Design. Abbreviation: HWF, health workforce.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Search Strategy in MEDLINE (Ovid)\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Step. No.</bold>\n</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Search Strategy in Medline</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Health Personnel/ OR (nurse-patient-ratio* OR ((health* OR dental* OR care* OR medical* OR hospital* OR nursing) ADJ3 (personnel* OR workforce* OR labor-force* OR labour-force* OR manpower* OR work-force* OR resource)) OR ((nurs OR physician) ADJ3 (shortage))).ab,ti,kf.</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Rural Health/ OR Rural Health Services/ OR Rural Population/ OR (island OR villager* OR ((rural* OR countryside* OR village) ADJ3 (health OR care* OR setting* OR area* OR population* OR communit* OR dweller* OR people* OR resident* OR societ* OR worker* OR nurs)) OR medical-desert OR ((underserv* OR remote* OR isolated OR mountain* OR far) ADJ3 (area OR neighborhood* OR neighbourhood* OR district* OR province))).ab,ti,kf.</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">(taxonomy OR taxonomic OR indicator* OR definition* OR defining* OR classificat* OR index* OR indice* OR scalogram* OR Gini).ab,ti,kf.</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 and 2 and 3</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">(exp animal/) NOT (human/)</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6</td><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4 not 5</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7</td><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">(news OR congres* OR abstract* OR book* OR chapter* OR dissertation abstract).pt. </td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6 not 7 </td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Inclusion and Exclusion Criteria\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Inclusion Criteria</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Exclusion Criteria</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Publication type: Original research ie, quantitative (observational and interventional), qualitative, and mixed methods studies.</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Books, editorials, correspondences, case reports, expert opinions, review articles, duplicative reports, study protocols, conference proceedings with unpublished results, and ongoing studies.</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Population: HWF medical deserts (eg, due to shortage of physicians/nurses).</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Studies outside of this population.</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Outcomes: Definition and characteristics, contributing factors and approaches to mitigate/eliminate medical deserts.</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Studies outside of these outcomes.</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Restrictions: Western countries (ie, EU, the United States, Australia, and New Zealand).</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Low- and middle-income countries.<break/>Asia, Africa, and South America.</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Restrictions: Languages of publication restricted to Croatian, Dutch, English, Finnish, French, German, Polish, Spanish, Romanian, and Russian.</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Studies outside of these languages.</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Descriptive Summary of Included Studies (n = 240)\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Variable</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Total, No. (%)</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Study characteristics</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Geographical location<sup></sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">North America</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">105 (44)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Europe</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">20 (8)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Australia and New Zealand</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">116 (48)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Design</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Observational, quantitative </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">193 (80)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Observational, qualitative</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">28 (12)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Observational, mixed methods</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14 (6)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Quasi-experimental</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5 (2)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Data collection method<sup>*</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Existing databases</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">96 (40)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Survey/questionnaire</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">126 (52)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Interviews</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">30 (13)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Focus group</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3 (1)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<bold>Participants’ characteristics</bold>\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Type of HWF</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Medical students/other students</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80 (33)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Physicians</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">85 (35)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Nurses</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14 (6)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Allied HWF</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">23 (10)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Combination of HWF</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">27 (11)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Institutes/practices</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">11 (5)</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 1. PRISMA-ScR Checklist.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 2. Search Strategies by Electronic Databases.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 3. Excluded Studies and Reasons for Exclusion.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl4\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 4. Key Characteristics of the Included Studies.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl5\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 5. Definitions of Medical Deserts.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: EU, European Union; HWF, health workforce.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviation: HWF, health workforce.</p><p> *Studies may be included in more than one category.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7454-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7454-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7454-g003\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7454-g004\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7454-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7454-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7454-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7454-s004.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7454-s005.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" World Health Organization (WHO). Increasing Access to Health Workers in Remote and Rural Areas Thorugh Improved Retention: Global Policy Recommendations. Geneva: WHO; 2010. "]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Wong"], "given-names": ["C"], "article-title": ["Indicators in use: challenges to urban and environmental planning in Britain"], "source": ["Town Plan Rev"], "year": ["2000"], "volume": ["71"], "issue": ["2"], "fpage": ["213"], "lpage": ["239"]}, {"label": ["6"], "mixed-citation": [" Ono T, Schoenstein M, Buchan J. Geographic Imbalances in Doctor Supply and Policy Responses. Paris: OECD; 2014. "]}, {"label": ["7"], "mixed-citation": [" WHO Regional Office for Europe. United Action for Better Health in Europe, Draft European Programme of Work, 2020-2025. Copenhagen: WHO Regional Office for Europe; 2020. "]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Kelly", "Hulme", "Farragher", "Clarke"], "given-names": ["C", "C", "T", "G"], "article-title": ["Are differences in travel time or distance to healthcare for adults in global north countries associated with an impact on health outcomes? A systematic review"], "source": ["BMJ Open"], "year": ["2016"], "volume": ["6"], "issue": ["11"], "fpage": ["e013059"], "pub-id": ["10.1136/bmjopen-2016-013059"]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Arksey", "O\u2019Malley"], "given-names": ["H", "L"], "article-title": ["Scoping studies: towards a methodological framework"], "source": ["Int J Soc Res Methodol"], "year": ["2005"], "volume": ["8"], "issue": ["1"], "fpage": ["19"], "lpage": ["32"], "pub-id": ["10.1080/1364557032000119616"]}, {"label": ["22"], "person-group": ["\n"], "surname": ["Elliott-Schmidt", "Strong"], "given-names": ["R", "J"], "article-title": ["Rural occupational therapy practice: a survey of rural practice and clinical supervision in rural Queensland and Northern New South Wales"], "source": ["Aust J Rural Health"], "year": ["1995"], "volume": ["3"], "issue": ["3"], "fpage": ["122"], "lpage": ["131"], "pub-id": ["10.1111/j.1440-1584.1995.tb00164.x"]}, {"label": ["34"], "person-group": ["\n"], "surname": ["Lasala"], "given-names": ["K"], "article-title": ["Nursing workforce issues in rural and urban settings: looking at the difference in recruitment, retention and distribution"], "source": ["Online J Rural Nurs Health Care"], "year": ["2000"], "volume": ["1"], "issue": ["1"], "fpage": ["8"], "lpage": ["24"], "pub-id": ["10.14574/ojrnhc.v1i1.499"]}, {"label": ["35"], "person-group": ["\n"], "surname": ["Lavanchy", "Connelly", "Grzybowski", "Michalos", "Berkowitz", "Thommasen"], "given-names": ["M", "I", "S", "AC", "J", "HV"], "article-title": ["Determinants of rural physicians\u2019 life and job satisfaction"], "source": ["Soc Indic Res"], "year": ["2004"], "volume": ["69"], "issue": ["1"], "fpage": ["93"], "lpage": ["101"], "pub-id": ["10.1023/B:SOCI.0000032662.79752.e8"]}, {"label": ["43"], "person-group": ["\n"], "surname": ["Matthews", "Bagg", "Yielder", "Mogol", "Poole"], "given-names": ["C", "W", "J", "V", "P"], "article-title": ["Does Pukawakawa (the regional-rural programme at the University of Auckland) influence workforce choice?"], "source": ["N Z Med J"], "year": ["2015"], "volume": ["128"], "issue": ["1409"], "fpage": ["35"], "lpage": ["43"]}, {"label": ["44"], "person-group": ["\n"], "surname": ["Mills", "Millsteed"], "given-names": ["A", "J"], "article-title": ["Retention: an unresolved workforce issue affecting rural occupational therapy services"], "source": ["Aust OccupTher J"], "year": ["2002"], "volume": ["49"], "issue": ["4"], "fpage": ["170"], "lpage": ["81"], "pub-id": ["10.1046/j.1440-1630.2002.00293.x"]}, {"label": ["79"], "person-group": ["\n"], "surname": ["Sullivan Havens", "Warshawsky", "Vasey"], "given-names": ["D", "NE", "J"], "article-title": ["RN work engagement in generational cohorts: the view from rural US hospitals"], "source": ["J NursManag"], "year": ["2013"], "volume": ["21"], "issue": ["7"], "fpage": ["927"], "lpage": ["940"], "pub-id": ["10.1111/jonm.12171"]}, {"label": ["81"], "person-group": ["\n"], "surname": ["Allan", "Crockett", "Ball", "Alston", "Whittenbury"], "given-names": ["J", "J", "P", "M", "K"], "article-title": ["\u2018It\u2019s all part of the package\u2019 in rural allied health work: a pilot study of rewards and barriers in rural pharmacy and social work"], "source": ["Internet J Allied Health Sci Pract"], "year": ["2007"], "volume": ["5"], "issue": ["3"], "fpage": ["1"], "lpage": ["11"], "pub-id": ["10.46743/1540-580x/2007.1161"]}, {"label": ["87"], "mixed-citation": [" Bradley KJ, Wros P, Bookman N, et al. The Interprofessional Care Access Network (I-CAN): achieving client health outcomes by addressing social determinants in the community. J Interprof Care. 2018:1-8. "], "pub-id": ["10.1080/13561820.2018.1560246"]}, {"label": ["125"], "person-group": ["\n"], "surname": ["Butler", "Sheppard"], "given-names": ["C", "L"], "article-title": ["The impact of undergraduate rural education on recently graduated physiotherapists"], "source": ["Aust J Physiother"], "year": ["1999"], "volume": ["45"], "issue": ["1"], "fpage": ["23"], "lpage": ["31"], "pub-id": ["10.1016/s0004-9514(14)60339-1"]}, {"label": ["129"], "person-group": ["\n"], "surname": ["Cramer", "Nienaber", "Helget", "Agrawal"], "given-names": ["M", "J", "P", "S"], "article-title": ["Comparative analysis of urban and rural nursing workforce shortages in Nebraska hospitals"], "source": ["Policy Polit NursPract"], "year": ["2006"], "volume": ["7"], "issue": ["4"], "fpage": ["248"], "lpage": ["260"], "pub-id": ["10.1177/1527154406296481"]}, {"label": ["144"], "person-group": ["\n"], "surname": ["Rohova"], "given-names": ["M"], "article-title": ["Regional imbalances in distribution of Bulgarian health professionals"], "source": ["J IMAB"], "year": ["2017"], "volume": ["23"], "issue": ["1"], "fpage": ["1427"], "lpage": ["1431"], "pub-id": ["10.5272/jimab.2017231.1427"]}, {"label": ["146"], "person-group": ["\n"], "surname": ["Zhu", "Mueller", "Vaughn", "Ullrich"], "given-names": ["X", "KJ", "T", "F"], "article-title": ["A rural taxonomy of population and health-resource characteristics"], "source": ["Rural Policy Brief"], "year": ["2015"], "issue": ["2015 4"], "fpage": ["1"], "lpage": ["6"]}, {"label": ["148"], "mixed-citation": [" Duma O, Anton D, Tar\u0163\u0103u L, Mocanu V. [Medical-social aspects of medical staff migration]. Rev Med Chir Soc Med Nat Iasi 2011;115(2):507-511. [Romanian]. "]}, {"label": ["170"], "person-group": ["\n"], "surname": ["Smith", "Cross", "Waller"], "given-names": ["T", "M", "S"], "article-title": ["Ruralization of students\u2019 horizons: insights into Australian health professional students\u2019 rural and remote placements"], "source": ["J MultidiscipHealthc"], "year": ["2018"], "volume": ["11"], "fpage": ["85"], "lpage": ["97"], "pub-id": ["10.2147/jmdh.s150623"]}, {"label": ["210"], "person-group": ["\n"], "surname": ["May", "Brown", "Burrows"], "given-names": ["J", "L", "J"], "article-title": ["In-place training: optimizing rural health workforce outcomes through rural-based education in Australia"], "source": ["Educ Sci"], "year": ["2018"], "volume": ["8"], "issue": ["1"], "fpage": ["20"], "pub-id": ["10.3390/educsci8010020"]}, {"label": ["224"], "person-group": ["\n"], "surname": ["Hajat", "Stewart", "Hayes"], "given-names": ["A", "K", "KL"], "article-title": ["The local public health workforce in rural communities"], "source": ["J Public Health ManagPract"], "year": ["2003"], "volume": ["9"], "issue": ["6"], "fpage": ["481"], "lpage": ["488"], "pub-id": ["10.1097/00124784-200311000-00007"]}]	{ "acronym": [], "definition": [] }	238	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 15; 12:7454	oa_package/6a/c5/PMC10590222.tar.gz
PMC10590223	0	[]	[]	[]	[]	[]	[ "<p>Powell and Mannion’s review of reviews maps the landscape of health policy research, showing a number of problematic and longstanding features. This commentary focuses on the extent to which health parochialism is good for the scientific development of the literature, the extent to which a \"tournament of theories\" actually develops our understanding of health policy process, and, finally, whether circumscribed theories of the policy process might be missing some of the most important and useful findings of broader comparative politics, which focus on the ways policies create politics over time. It concludes that health parochialism and focus on a circumscribed policy process is not likely to be helpful because it distracts attention from the ways in which coalitions and institutions over time shape politics and policy, a finding explored by scholars of many sectors whose findings should influence health policy research.</p>", "<p>\n<bold>Citation:</bold> Greer SL. Policy makes politics: Comment on \"Modelling the health policy process: one size fits all or horses for courses?\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8073. doi:10.34172/ijhpm.2023.8073</p>" ]	[ "<p> One regular theme in scholarly writing on health politics is complaint about the handling of politics and policy in broader health literature. There is complaint about the limited extent and quality many writers see in both scholarship on health policy-making. And there is complaint about the ways in which the putatively apolitical and technical discourses of medicine and public health disguise political interests, foster naivete, and obscure causal mechanisms that might be affected by political action. When policy-making is taught, it is often either oversimplified, or uses approaches that outsiders to the health world might regard as reinventions of the wheel. Even researchers and policy-makers who are privately very sensitive to politics and astute in political analysis will often be blandly technocratic and seemingly naïve in public.</p>", "<p> Powell and Mannion<sup>##REF##37579456##1##</sup> address this issue by looking at reviews of the theories of the policy process that are used in health. These articles are reviews of the choice and deployment of theory in health policy articles and their number means that we can be more confident that individual review authors’ choices are not biasing results.</p>", "<p> The results are probably unsurprising to people versed in the literature, for all that it is nice to see confirmation that they aren’t just impressions born of attending particular conferences or reading particular journals. Powell and Mannion find a large number of articles with what amounts to repeated uses of off-the-shelf theories. They also find a dismayingly large number coded by team after team as not really having a theory of the policy process at all. It is one thing, from the perspective of science, to have repeated tests of a well-known theory, which is what Mannion and Powell appear to find in the literature. That can be valuable and contribute to incremental progress. It is another thing to have articles with no theory at all. What are we supposed to learn from them? That is probably, then, the first significant problem — lack of progress on the problem that Walt and Gilson identified, of too much attention to the content of policy rather than the actors, processes, and context.<sup>##REF##10139469##2##</sup></p>", "<p> There are, however, three other issues raised in the article that merit attention. The first issue, foregrounded in Powell and Mannion’s analysis, is health policy parochialism, notably as seen in theories only found in health policy scholarship. We could speculate on reasons why this parochialism exists. Perhaps health policy researchers have found other debates and topics, such as the social determinants of health, more interesting and productive (could the authors of the articles coded as atheoretical be engaged in those debates?). Perhaps the world of health policy research is so big and well-funded that it can afford to have theories, such as the “health policy analysis triangle” that are unknown outside health policy. It might also be that health policy research is so heavily influenced by the money and power in academic medicine as to introduce distortions. A subtle theory of public policy is likely to far exceed medical or public health journal word counts and citation mechanisms, let alone the patience of referees and editors; funders tend to support work on the content of policies, lots of people want to see “impact,” defined as adoption of a policy or intervention rather than understanding of the process, and it is noteworthy to see an educational program in most areas of biomedicine which has more than one class on the whole of “policy.” This is an ecology of knowledge that might reward the overapplication of very simple theories, and not support the development and testing of more subtle theories as we see in social sciences. The tendency of medical and public health journals to publish what looks like political science and policy analysis in commentary or opinion sections hardly helps by mixing what might be sophisticated policy analysis with senior doctors’ opinions or organizational manifestos. These are just speculative guesses but might add up to what Powell and Mannion report.</p>", "<p> It does seem that health policy research publication is more susceptible than other areas of policy analysis to producing very simple renderings of social science concepts and then mistaking them for complete theories. As Powell and Mannion show, John Kingdon’s theory, known as the multiple streams perspective, is perhaps a good example. An unarguably powerful and parsimonious theory, it can still be be distorted in applications that ignore its difficulties and over-emphasize the policy stream where most public health researchers and students instinctively locate themselves.<sup>##UREF##0##3##</sup></p>", "<p> The second issue is how much scholarly progress is possible through the simple application of well-known theories. Mere use of an established theoretical framework is not necessarily an indicator of theoretical progress since repeatedly testing the applicability or explanatory power of a good theory can leave us in an endless, inconclusive, tournament of theories. The difference between, for example, the multiple streams approach and the advocacy coalition approach lies not in anomalies or limited coverage; they can both explain a vast swathe of health policy. The difference lies in what they foreground, with implications for action and further analysis. Simply showing that they can describe and explain with reliability does not show us which ones merit further development and use. If every public policy theory is as good as every other one, then we should worry about the scope for future theoretical development and its attractiveness to new researchers.</p>", "<p> The third issue is the question of whether theories of the health policy process are studying the right thing at all. Theories of “The policy process” tend to focus on specific pieces of legislation or on characterizing the process which shapes their likelihood of introduction and adoption. As the article notes, there is less attention in the literature that they review to the whole complex of post-adoption politics or to feedback loops in which one policy decision reshapes policy options and political coalitions for the future. These policy legacies and feedbacks go far beyond implementation (in itself a difficult issue) because they change what is possible. That means that even when they appear, circumscribing them to theories of the policy process removes much of their power and generative potential.</p>", "<p> The problem that is obscured by a focus on the policy process is that policy creates politics.<sup>##UREF##1##4##</sup> The ways in which policy creates politics have been a major issue in the analysis of how health systems develop, with decisions taken in the early twentieth century on issues such as the role of employers and the organized medical profession shaping what was politically and practically possible later (this literature is voluminous, but usefully discussed in the course of Tuohy’s important contribution).<sup>##UREF##2##5##</sup> More contemporaneous developments, for example the politics of universal health coverage in middle-income countries such as Brazil and Thailand, likewise tend to be explained by politics over time and path dependency.<sup>##REF##34555293##6##</sup> These are dynamics that are difficult to capture in any “theory of the policy process.”</p>", "<p> Policies create politics by creating institutions which can be sticky, by creating coalitions of beneficiaries and state capacity, and by raising the costs of alternative options.<sup>##UREF##3##7##</sup> Policies and legacies can be more important than formal political institutions. In federations, for example, the structure of healthcare finance and delivery can be stickier and do more to shape money and power among governments than formal constitutional law.<sup>##UREF##4##8##</sup></p>", "<p> The question this literature raises is of how policies become entrenched. Broadly, answers fall into two categories. One is older and grew out of the “historical institutionalist” tradition in comparative politics. It focuses on the ways in which institutions, including policies, shape the rules of the game and the costs of change. Its key concepts are punctuated equilibrium (seen in the scholarship Powell and Mannion review) and path dependency but it has developed a much more elaborate and contested theoretical language for understanding the change.<sup>##UREF##5##9##</sup></p>", "<p> The other broad strand focuses more on coalitions, putting more focus on alliances of interests and less on the tendency of institutions and policies to persist.<sup>##UREF##3##7##,##UREF##6##10##</sup> Who benefits from a policy and what degrees of freedom exist to create new, and different, coalitions? The creation of coalitions can include the creation of identities by politics, eg, by making people aware of a benefit that they are receiving and organizing them around it. This literature has produced some rules of thumb for policy. For example, it suggests emphasizing visibility and simplicity so that beneficiaries understand that they are getting something from the policy, can reward the politicians who created it, and can be alerted to attacks on it.<sup>##UREF##7##11##,##UREF##8##12##</sup> Perhaps the best cases of this logic are National Health Service systems in the United Kingdom, which despite their complexity have clear public profiles and a public that is generally unwilling to support attacks on them.<sup>##UREF##9##13##</sup> It is worth noting that making benefits obvious and simple so that beneficiaries appreciate them might seem like basic politics but intelligent and skilled politicians have often preferred complicated or deliberately obscure schemes, eg, “nudge” policies or tax credits.</p>", "<p> A narrow focus on “the policy process” is not unique to researchers, of course. Policy-makers themselves can have understandably short time horizons or be so focused on optimal policy design and legislative politics that they fail to consider policy feedbacks and the ways that their own policies will build or undermine sustainable supporting coalitions. One article on the United States’ 2010 Affordable Care Act carried the memorable, and accurate, subtitle “Democratic Policy Makers Overlooked Implementation, Post-Enactment Politics, and Policy Feedback Effects.”<sup>##UREF##10##14##</sup> Even when there was sophisticated thinking about how implementation would work, it seemed to not extend past the next elections.<sup>##UREF##11##15##</sup> This suggests that there is some scope for very practical crossover between political science and even sophisticated political actors who can discuss the ways to entrench desired policies by building sticky institutions and stable coalitions of supporters with resources that will enable the policy to survive changes of government and conditions.</p>", "<p> Powell and Mannion conclude by suggesting that there are two reasonable ways to go in the future: either building a specific analytical language for health politics and policy, or by engaging with the broader debates about policy-making and change. It stands to reason that drawing on multiple areas of public policy and political research would increase the odds of strong and parsimonious theoretical claims emerging, while the risk of having health-specific theories would be the creation of an echo chamber that would not improve explanations over time. The answer to their question should primarily depend, though, on the value of the approaches in producing better explanations of events in health policy. If comparative politics scholarship takes us beyond “theories of the policy process” into a broader conversation about policy design, entrenchment, and political sustainability, then we should support more dialogue with comparative politics and other fields. Health policy research might not, as they argue, have assimilated Walt and Gilson’s injunction to focus more on actors, processes, and context, but it might nevertheless be time to add an injunction to think about how policy makes politics.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that he has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["3"], "mixed-citation": [" Greer S. John W. Kingdon, agendas, alternatives and public policy. In: Balla SJ, Lodge M, Page EC, ed. The Oxford Handbook of Classics of Public Policy and Administration. Oxford University Press. 2015:417-432. "], "pub-id": ["10.1093/oxfordhb/9780199646135.013.18"]}, {"label": ["4"], "mixed-citation": [" Schattschneider EE. Politics, Pressures, and the Tariff. New York: Prentice Hall; 1935. "]}, {"label": ["5"], "mixed-citation": [" Tuohy CH. Remaking Policy: Scale, Pace, and Political Strategy in Health Care Reform. University of Toronto Press; 2018. "]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Lynch"], "given-names": ["J"], "article-title": ["The political economy of health: bringing political science in"], "source": ["Annu Rev Polit Sci (Palo Alto)"], "year": ["2023"], "volume": ["26"], "issue": ["1"], "fpage": ["389"], "lpage": ["410"], "pub-id": ["10.1146/annurev-polisci-051120-103015"]}, {"label": ["8"], "mixed-citation": [" Greer SL, B\u00e9land D, Lecours A, Dubin K. Putting Federalism in Its Place: The Territorial Politics of Social Policy Revisited. University of Michigan Press; 2023. "]}, {"label": ["9"], "mixed-citation": [" Mahoney J, Thelen K. Advances in Comparative-Historical Analysis. New York: Cambridge University Press; 2015. "]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Hacker", "Pierson"], "given-names": ["JS", "P"], "article-title": ["After the \u201cMaster Theory\u201d: Downs, Schattschneider, and the Rebirth of Policy-Focused Analysis"], "source": ["Perspect Politics"], "year": ["2014"], "volume": ["12"], "issue": ["3"], "fpage": ["643"], "lpage": ["662"], "pub-id": ["10.1017/s1537592714001637"]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Campbell"], "given-names": ["AL"], "article-title": ["Policy makes mass politics"], "source": ["Annu Rev Polit Sci (Palo Alto)"], "year": ["2012"], "volume": ["15"], "issue": ["1"], "fpage": ["333"], "lpage": ["351"], "pub-id": ["10.1146/annurev-polisci-012610-135202"]}, {"label": ["12"], "mixed-citation": [" Greer SL, Lynch JF, Reeves A et al. The Politics of Healthy Ageing: Myths and Realities. Brussels: European Observatory on Health Systems and Policies; 2022. "]}, {"label": ["13"], "mixed-citation": [" Stewart EA. How Britain Loves the NHS: Practices of Care and Contestation. Bristol: Bristol University Press; 2023. "]}, {"label": ["14"], "person-group": ["\n"], "surname": ["Burgin"], "given-names": ["E"], "article-title": ["Congress, Policy Sustainability, and the Affordable Care Act: democratic policy makers overlooked implementation, post-enactment politics, and policy feedback effects"], "source": ["Congress & the Presidency"], "year": ["2018"], "volume": ["45"], "issue": ["3"], "fpage": ["279"], "lpage": ["314"], "pub-id": ["10.1080/07343469.2018.1498561"]}, {"label": ["15"], "mixed-citation": [" McCann PJ. The Federal Design Dilemma. New York: Cambridge University Press; 2016. "]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 17; 12:8073	oa_package/9c/8e/PMC10590223.tar.gz
PMC10590225	0	[]	[]	[]	[]	[]	[ "<p>\n<bold>Citation:</bold> Rotulo A, Paraskevopoulou C, Kondilis E. The dangers of fiscal decentralisation in healthcare: a response to the recent commentaries. <italic toggle=\"yes\">Int J Health Policy Manag.</italic> 2023;12:8266. doi:10.34172/ijhpm.2023.8266</p>" ]	[ "<p> Decentralisation has always been a key element of health systems strengthening; even back to 1978, the World Health Organization (WHO) Alma Ata Declaration clearly stated that the provision of fair, equal, and accessible healthcare should be decentralised and rooted in community-based approaches.<sup>##REF##16896417##1##</sup> However, decentralisation is not a uniform group of policies. On the contrary, it consists of a heterogeneous set of reforms aiming to the transfer of administrative, political and/or economic power from central governments to subnational authorities.<sup>##REF##34239287##2##</sup> In this sense decentralisation is not a synonym to fiscal decentralisation, nor the former necessarily entails the latter.</p>", "<p> Fiscal decentralisation is a specific type of decentralisation that occurs when the responsibility to generate, distribute, and spend revenues shifts from the central government to local authorities.<sup>##REF##34239287##2##,##UREF##0##3##</sup> That is, when local authorities are financially free of any central regulatory constraint in the pooling and redistribution of resources. This can happen through the introduction of earmarked local taxation and user fees, or through hospital’s autonomization.<sup>##UREF##0##3##</sup> Under this type of decentralisation, providers and regional authorities can compete against each other, in an open market environment, on the offer of different <italic toggle=\"yes\">bundles</italic> of public services for a certain taxation level.<sup>##REF##37579443##4##</sup> In the academic and policy debate the terms “decentralisation” and “fiscal decentralisation” are often used interchangeably,<sup>##UREF##0##3##</sup> a fact that inhibits mutual understanding and adds further ambiguity in the relevant policy discussion.</p>", "<p> Fiscal decentralisation (that is, revenue and expenditure decentralisation, and not decentralisation in general) by definition requires the fragmentation of the national pooling system into multiple regional and municipal pools for the financing of health and other public services.<sup>##REF##34239287##2##,##UREF##0##3##</sup> This shift from national to local pools is expected to increase efficiency, under the assumptions that local authorities are more accountable to local communities and thus can better meet differing demands and preferences across jurisdictions.<sup>##REF##36300257##5##,##REF##37579362##6##</sup> On the other hand, pooling of finances is a foundational principle of healthcare financing. Its primary aim is to distribute the financial risk evenly across the population, preventing any single individual from shouldering the whole burden of healthcare expenses, when in need. Under certain circumstances, a funding pool has the capacity to redistribute funds, enabling cross-subsidization among high- and low-risk individuals and income groups.<sup>##REF##31864355##7##</sup> In financing pooling, size matters: the larger the pool the higher the cross-subsidization.<sup>##UREF##1##8##</sup> This basic principle makes national, centralised pools an indispensable financing policy for equalization and universality.<sup>##REF##31864355##7##</sup> On the contrary, fragmented-local pools weaken the redistributive capacity, as revenues are collected and used within a population sub-group, and limit the cross-subsidisation towards vulnerable and low-income groups at the national level.<sup>##REF##31864355##7##</sup> This fragmentation of a central pool into several local ones, is intrinsic to fiscal decentralisation, making it a regressive policy option in essence.</p>", "<p> Fiscal decentralisation has also the potential of increasing cross-regional disparities.<sup>##UREF##0##3##</sup> In a fiscally decentralised system, sub-national governments engage in a “territorial competition” for the attraction of private or public investments, local revenues, government subsidies, and workforce.<sup>##UREF##2##9##</sup> Richer regions with more developed infrastructure, more mature administrative capacity, more and better educated workforce, larger tax bases, higher influence, and preferential treatment from central governments have an obvious advantage over their less developed competitors.<sup>##UREF##2##9##</sup> Accordingly, poorer regions with weaker governance structures, lower influence to the central government, and smaller tax bases, face the risk of losing the “territorial race” before it has even begun.<sup>##UREF##2##9##,##UREF##3##10##</sup> Under fiscal decentralisation, the central government’s role in redistributing income and wealth from rich to poor regions, is also significantly weakened.<sup>##UREF##0##3##</sup> For all these reasons it is argued that fiscal decentralisation can exacerbate pre-existing inter-regional inequalities, and lead to the concentration of resources to more developed and rich regions.<sup>##UREF##0##3##,##UREF##2##9##,##UREF##3##10##</sup></p>", "<p> Our study has shown that in Italy between 2001-2017, fiscal decentralisation was related to a decrease in the availability, accessibility, and utilisation of healthcare services, with this negative effect being stronger for public healthcare services (relative to private ones) and more prominent in regions with lower fiscal capacity.<sup>##REF##35021611##11##</sup> These findings signal that 30 years of fiscal decentralisation implementation in Italy has perpetuated or even exacerbated the pre-existing, cross-regional healthcare inequalities in the country. The theories on the relationship of fiscal decentralisation and regional disparities offer a useful and meaningful interpretation of the empirical phenomena that our study has observed in the case of Italy. Similar empirical observations have also been made in other countries under fiscal decentralisation,<sup>##UREF##4##12##</sup> supporting the theoretical concerns regarding the negative impact of fiscal decentralisation on spatial, healthcare inequalities.</p>", "<p> While our study aligns with the theoretical expectations that fiscal decentralisation negatively influences the capacities of public healthcare systems and perpetuates geographical disparities,<sup>##REF##35021611##11##</sup> the COVID-19 pandemic proved to be a real-life testing ground for the preparedness of fiscally decentralised healthcare systems. Emerging evidence suggests that fiscal decentralisation policies significantly impaired the preparedness and responsiveness of these health systems, in some cases to the point of requiring swift re-centralisation.<sup>##REF##33431258##13##, ####UREF##5##14##, ##REF##36435630##15####36435630##15##</sup></p>", "<p> Decentralisation is a key element of any healthcare reform that aims to strengthen local healthcare systems and make them more responsive to local health and healthcare needs. In this sense the question in policy debate is not whether to decentralise in general or not, but what functions to decentralise and how.<sup>##UREF##0##3##</sup> Under certain circumstances, decentralising administrative, political, and/or healthcare expenditure powers to subnational authorities can increase local effectiveness. On the contrary decentralising healthcare revenue powers to subnational localities entails too many risks and dangers as theory, pre-pandemic empirical evidence, and the COVID-19 experience in fiscally decentralised health systems actually suggest.</p>", "<p> Even in capitalism, redistribution of income and wealth has historically been (under welfarism) and should remain a responsibility of the central, rather than the local, state.<sup>##UREF##0##3##</sup> Centralised pooling of resources and centralised resource allocation to regions might not be sufficient (depending on tax progressivity and resource allocation equalizers) but are necessary conditions for any meaningful attempt to redistribute income and wealth among individuals and across jurisdictions.<sup>##UREF##0##3##</sup> Accordingly, rejecting fiscal decentralisation might not be a sufficient option to heal inequities and healthcare deficiencies, but it is a necessary condition for any attempt towards that direction.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["3"], "person-group": ["\n"], "surname": ["Prud\u2019homme"], "given-names": ["R"], "article-title": ["The dangers of decentralization"], "source": ["World Bank Res Obs"], "year": ["1995"], "volume": ["10"], "issue": ["2"], "fpage": ["201"], "lpage": ["220"], "pub-id": ["10.1093/wbro/10.2.201"]}, {"label": ["8"], "mixed-citation": [" World Health Organization (WHO). The World Health Report 2000: Health Systems: Improving Performance. Who pays for health systems? WHO; 2000. "], "uri": ["https://www.who.int/whr/2000/en/"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Rodr\u00edguez\u2010Pose", "Gill"], "given-names": ["A", "N"], "article-title": ["On the \u2018economic dividend\u2019 of devolution"], "source": ["Reg Stud"], "year": ["2005"], "volume": ["39"], "issue": ["4"], "fpage": ["405"], "lpage": ["420"], "pub-id": ["10.1080/00343400500128390"]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Martinez-Vazquez", "McNab"], "given-names": ["J", "RM"], "article-title": ["Fiscal decentralization and economic growth"], "source": ["World Dev"], "year": ["2003"], "volume": ["31"], "issue": ["9"], "fpage": ["1597"], "lpage": ["1616"], "pub-id": ["10.1016/s0305-750x(03)00109-8"]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Sanogo"], "given-names": ["T"], "article-title": ["Does fiscal decentralization enhance citizens\u2019 access to public services and reduce poverty? Evidence from C\u00f4te d\u2019Ivoire municipalities in a conflict setting"], "source": ["World Dev"], "year": ["2019"], "volume": ["113"], "fpage": ["204"], "lpage": ["221"], "pub-id": ["10.1016/j.worlddev.2018.09.008"]}, {"label": ["14"], "person-group": ["\n"], "surname": ["Erkoreka", "Hernando-P\u00e9rez"], "given-names": ["M", "J"], "article-title": ["Decentralization: a handicap in fighting the COVID-19 pandemic? The response of the regional governments in Spain"], "source": ["Public Adm Dev"], "year": ["2023"], "volume": ["43"], "issue": ["2"], "fpage": ["129"], "lpage": ["140"], "pub-id": ["10.1002/pad.1988"]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 20; 12:8266	oa_package/5e/05/PMC10590225.tar.gz
PMC10590226	0	[]	[]	[]	[]	[]	[ "<p>\n<bold>Citation:</bold> Lassa S, Saddiq M, Owen J, Burton C, Balen J. Evolving power dynamics in global health: from biomedical hegemony to market dynamics in global health financing; a response to the recent commentaries. <italic toggle=\"yes\">Int J Health Policy Mana</italic>g. 2023;12:8264. doi:10.34172/ijhpm.2023.8264</p>" ]	[ "<p> We would like to appreciate the interest of the four commentaries<sup>##REF##37579392##1##, ####REF##37579388##2##, ##REF##37579361##3##, ##REF##37579487##4####37579487##4##</sup> which were published in this journal in response to our paper<sup>##REF##35461207##5##</sup> and reflect on important aspects highlighted by the authors; biomedical hegemony and colonialism, institutional power, the hybridisation of biomedical power and new public management (NPM).</p>", "<p> We concur with Dalglish et al<sup>##REF##37579487##4##</sup> and Parashar et al,<sup>##REF##37579392##1##</sup> that <italic toggle=\"yes\">‘the dominance of medical professionals in healthcare is global, but it takes a particular shape in many low- and middle-income countries due to the imprint of colonialism.’</italic><sup>##REF##37579388##2##</sup> Johnson argues that an understanding of medical professional power in post-colonial countries can only be achieved by acknowledging the relationship between the medical professionals and their colonial and post-colonial states.<sup>##UREF##0##6##</sup> In the case of Nigeria, the transmission of power, social status and authority of medical professionals has been through a historic colonial symbiotic relationship between the Imperial state and medical professionals,<sup>##UREF##1##7##</sup> discoveries in tropical medicine,<sup>##UREF##2##8##</sup> and more recently (demonstrated in our paper) biomedical epistemic communities.<sup>##REF##35461207##5##</sup> While our paper did not investigate some of these colonial origins in detail, we highlighted the trends that continue to “<italic toggle=\"yes\">situate doctors at the ‘top’ of a biomedical hierarchy and that have traditionally situated biomedicine above public health, traditional systems of medicine and other approaches to health</italic>.”<sup>##REF##37579392##1##</sup> However, (biomedical) power is diffuse and not concentrated; this compels us to conceptualise it within a broader perspective by analysing areas in society where this power is reproduced and how it structures society. Therefore, to explore biomedical power, analysis must go beyond the domains of the medical profession,<sup>##REF##37579487##4##</sup> by analysing biomedical power and its discourse which are tied to specific institutions and actors such as the Global Fund.</p>", "<p> In the global context, the biomedical paradigm has dominated global health institutions such as the World Health Organization (WHO),<sup>##REF##25844390##9##</sup> and this paradigm is established in similar institutions, thus shaping the choices of both global and local actors.<sup>##UREF##3##10##</sup> This is captured in Kapilashrami’s response which acknowledges our argument that the health policy process is a result of the reproductive nature of the biomedical discourse and its structural power over global and local health institutions.<sup>##REF##37579361##3##</sup> Kapilashrami’s response highlights why researchers need to focus not only on the biomedical dominance and medical professional power capture of local policy spaces, but a more nuanced exploration of ‘<italic toggle=\"yes\">the hegemonic structures (systems and protocols) and discourse (ideas and meanings) in constituting and constructing practices that legitimise, give meaning and stabilise the fund and health system governance</italic>.’<sup>##REF##37579361##3##</sup> The institutionalisation of the biomedical discourse in global health institutions has shaped the direction in which decisions are taken in agenda setting, limiting the options available in creating solutions to problems. This biomedical institutionalisation of global health structures has been attributed to epistemic networks that dominate the global health policy spaces.<sup>##REF##25844390##9##</sup> In other words, institutional power may also be understood as certain actors exercising both structural and productive power through institutions in order to exercise indirect control over others.<sup>##UREF##3##10##</sup>\n<italic toggle=\"yes\">‘Institutional power is actors’ control of others in indirect ways…through the rules and procedures that define those institutions, guides, steers, and constrains the actions (or non-actions) and conditions of existence of others.’</italic><sup>##UREF##3##10##</sup> For example, NPM in combination with the biomedical discourse, is one of the tools used in exerting control over actors in health institutions.</p>", "<p> It has been argued that NPM is one of the key components that developing countries need to use effectively in implementing health reforms to deliver equitable healthcare within limited resources.<sup>##UREF##4##11##</sup> The Structural Adjustment Programme of the World Bank and International Monetary Fund was one of the first encounters of developing countries with NPM in healthcare reforms.<sup>##UREF##5##12##</sup> More recently, the encounter of NPM with developing countries has been through aid agencies and donors, facilitated through epistemic knowledge networks.<sup>##UREF##5##12##</sup> The massive increase in international monetary donations by private-public partnerships,<sup>##UREF##5##12##</sup> has advanced the use of a more open competitive and market-oriented approach for better cost-effective use of these resources.<sup>##UREF##6##13##</sup> In achieving perceived efficiency from health providers, an adoption of performance-based funding, incentive structures, market driven research and vertical approaches has consequently shaped the health market.<sup>##REF##37579388##2##</sup> Brown and Rhodes in their response brilliantly summarised this point as follows <italic toggle=\"yes\">‘Recognizing this helps to explain the donor preference for earmarked funding and vertical programs as well as the bias often given to supply-side clinical and biomedical projects.</italic>’<sup>##REF##37579388##2##</sup> However,a review of the empirical evidence concerning ‘pay for performance’ incentives by Global Health Initiatives, shows that incentives can have negative effects on the professionalism of health workers in general, leading to a <italic toggle=\"yes\">‘focus only on achieving the explicit targets that are being rewarded at the expense of other important but unmeasured tasks.’</italic><sup>##UREF##7##14##</sup> This dynamic has limited the opportunities for community-led participation ‘<italic toggle=\"yes\">ultimately side-lining local expertise and community perspectives.</italic>’<sup>##REF##37579388##2##</sup> If this dynamic is left unchecked, we could risk reducing the very idea and values of public health to commodified NPM driven objectives in the form of artificial intelligence (AI) algorithms, consequently, side-lining the community.</p>", "<p> Finally, due to the complexity of the various dimensions of power, researchers need to link the forms of power by answering questions that explain how discourse (productive power) create networks (structural power) and in turn, how these networks influence institutions (institutional power).<sup>##REF##37579487##4##</sup> Even though the biomedical narrative favours certain elite medical professionals, the hybrid of NPM and biomedicine poses potential threats to the professional power of frontline medical professionals through the process of ‘deprofessionalisation’<sup>##REF##1761825##15##</sup> and the subsequent brain drain of frontline medical professionals in low- and middle-income countries. By exploring concurrently professionalisation (professional monopoly) and deprofessionalisation (declining professional monopoly) in the forms of AI and NPM health management tools such as ‘task-shifting,’ we are able to observe the two processes in action that can expose the intersectionality in professional boundary disputes,<sup>##REF##37579392##1##</sup> dominance of biomedical cadres,<sup>##REF##37579487##4##</sup> and market dynamics in global health financing.<sup>##REF##37579388##2##</sup></p>", "<title>Ethical issues</title>", "<p> The original study had ethical approval obtained from the National Health Research Ethics Committee, Nigeria of the Ministry of Health in Nigeria through the University of Jos and the School of Health and Health Related Research (ScHARR) Research Ethics Committee at the University of Sheffield, UK. The CCM in Nigeria also gave approval and consent for their members to be recruited for interviews. Individual written informed consent was obtained from each participant prior to data collection.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["6"], "mixed-citation": [" Johnson T. Imperialism and the professions. In: Halmos P, ed. Professionalisation and Social Change. Series: Sociological Review Monograph; 20. Keele: University of Keele; 1973:218-309. "]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Afolabi"], "given-names": ["MO"], "article-title": ["Entrenched colonial influences and the dislocation of health care in Africa"], "source": ["Journal of Black and African Arts and Civilization"], "year": ["2011"], "volume": ["5"], "issue": ["1"], "fpage": ["229"], "lpage": ["247"]}, {"label": ["8"], "mixed-citation": [" Mutizwa-Mangiza ND. Doctors and the State: The Struggle for Professional Control in Zimbabwe. Aldershot: Ashgate; 1999. "]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Barnett", "Duvall"], "given-names": ["M", "R"], "article-title": ["Power in international politics"], "source": ["Int Organ"], "year": ["2005"], "volume": ["59"], "issue": ["1"], "fpage": ["39"], "lpage": ["75"], "pub-id": ["10.1017/s0020818305050010"]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Russell", "Bennett", "Mills"], "given-names": ["S", "S", "A"], "article-title": ["Reforming the health sector: towards a healthy new public management"], "source": ["J Int Dev"], "year": ["1999"], "volume": ["11"], "issue": ["5"], "fpage": ["767"], "lpage": ["775"], "pub-id": ["10.1002/(sici)1099-1328(199907/08)11:5<767::aid-jid617>3.0.co;2-g"]}, {"label": ["12"], "mixed-citation": [" Lee K, McInnes C. Global Health and International Relations. Polity Press; 2013. "]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Lee", "Zwi"], "given-names": ["K", "AB"], "article-title": ["A global political economy approach to AIDS: Ideology, interests and implications"], "source": ["New Polit Econ"], "year": ["1996"], "volume": ["1"], "issue": ["3"], "fpage": ["355"], "lpage": ["373"], "pub-id": ["10.1080/13563469608406267"]}, {"label": ["14"], "mixed-citation": [" Eichler R. Can \u201cPay for Performance\u201d Increase Utilization by the Poor and Improve the Quality of Health Services? Background Papers for the Working Group on Performance Based Incentives. Washington, DC; Center for Global Development; 2006. "]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Oct 2; 12:8264	oa_package/e3/d8/PMC10590226.tar.gz
PMC10590227	0	[ "<title>Introduction</title>", "<p> “<italic toggle=\"yes\">It was very clear that we weren’t getting to what I thought were the key issues. So, we then switched gears and said, well, let’s ask young people</italic>” (AYHP Author Government 14). This recognition from a Government representative in the published paper, “Between Rhetoric and Reality: Learnings From Youth Participation in the Adolescent and Youth Health Policy in South Africa,”<sup>##REF##35490263##1##</sup> illuminates the essential contribution that youth can make in policy development. The participation of youth offers a unique contribution that cannot be obtained through alternative methods such as interviewing adults, because adults, including parents, are inadequate proxies for capturing the perceptions and perspectives of young people. If youth do not participate in informing policy that affects their lives, the developed policies may be ineffective, detrimental, and insensitive to their rights, needs, and experiences.<sup>##UREF##0##2##</sup> Youth participation in policy development is crucial for understanding key issues and creating appropriate and impactful policies.<sup>##UREF##1##3##</sup> The absence of youth participation in policy development leads to the creation of inappropriate or ineffectual policies, as it overlooks the firsthand experiences, perspectives, and needs of young individuals, resulting in a disconnect between policy decisions and the realities faced by the youth population. In their 2022 paper, Jacobs and George examined youth participation in the Adolescent and Youth Health Policy (AYHP) development process to understand how youth were included in health policy-making in the South African context. Jacobs and George use the term “youth” in their paper when referring to young people between the ages of 10 and 24, and we use the same term in this commentary to maintain definitional congruity. The published work adds an important contribution to the current literature on youth participation to inform health policy with many novel insights highlighted in this commentary. In particular, Jacobs and George’s consideration of perspectives of youth living in a middle-income country is important as these perspectives have received less scholarly attention. The majority of previously published work has centered on adult perspectives and people from high-income countries.<sup>##REF##35659206##4##</sup></p>", "<p> Another novel idea brought forth in the work is the adaptation of Cahill and Dadvand’s P7 Model. The P7 Model is a framework for conceptualizing and planning youth participation that accounts for socio-cultural contexts.<sup>##UREF##2##5##</sup> The original P7 Model of Cahill and Dadvand presents the seven inter-connected domains of <italic toggle=\"yes\">Purpose, Place, Process, Positioning, Protection, Perspective</italic>, and <italic toggle=\"yes\">Power relations</italic>. Jacobs and George expanded the model by adding the two additional domains of <italic toggle=\"yes\">People</italic> and Partnerships, with an accompanying set of new questions. The authors used the adapted conceptual framework to identify the key successes and challenges in policy development that arose during youth participation in the AYHP policy formulation process which may be applicable to other settings. Key findings included that youth participation in the AYHP process was challenged within the fragmented policy landscape and youth participation was supported by academic and government actors with a history of collaborating with youth. These findings add to the evidence-base on the need to support and strengthen capacities of decision-makers and researchers to engage youth in policy, research, and practice.</p>" ]	[]	[]	[]	[ "<title>Conclusion</title>", "<p> In this commentary, we critically reflect on the use of the P7 Model adapted by Jacobs and George to examine youth participation in the development of the AYHP in South Africa. We commend their attention to and support of youth participation in health policy development in a place and space where youth have not historically been involved. We suggest strategies to build off the work of Jacobs and George to ensure future health policy development centers youth perspectives and is more inclusive of a diversity of youth.</p>" ]	[ "<p>In their published study, Jacobs and George examine how youth participation was enabled to advance the Adolescent and Youth Health Policy (AYHP) in South Africa. Using an expanded and adapted conceptual framework of youth participation to inform their work, their findings center on the complexities of youth participation including enablers and the challenges experienced in the South African context. Building upon their foundational work, in this commentary we suggest further insights for consideration to advance youth participation to inform equitable health policies, including the inclusion of youth with intersecting identities and critical reflection to further advance the adapted conceptual framework.</p>", "<p>\n<bold>Citation:</bold> Njelesani J, Hunleth J. Advancing youth participation to inform equitable health policy: Comment on \"Between rhetoric and reality: learnings from youth participation in the Adolescent and Youth Health Policy in South Africa.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7974. doi:10.34172/ijhpm.2023.7974</p>" ]	[ "<title>Building on the Conceptual Framework</title>", "<p> The addition of People and Partnerships into the P7 Model by Jacobs and George proved useful to highlight multi-sector partnerships and how working across government departments proved challenging and hindered youth involvement, a key finding of the study. The addition of the two new domains also enabled a deeper examination of the roles of each of the policy actors within the policy development context. An important finding included that in systems without organized youth health actors, youth participation was challenged by lack of coordination between youth stakeholders.</p>", "<p> The guiding questions derived from the adapted P7 Model, as seen in Box 2 in the original article, are also valuable contributions to the literature as they can be used to guide work that integrates youths’ perspectives into policy. Jacobs and George used the guiding questions to identify how government departments were working in silos which created a lack of synergy and negated a shared vision for youth participation.We are excited about how these questions could be incorporated into our work that advances youth participation. Efforts aimed at enhancing health policy development participation with adolescents can serve as a model for similar initiatives with younger children, as they highlight the importance of including young individuals in decision-making processes, ensuring their voices are heard, and addressing their unique healthcare needs. We envision the guiding questions being juxtaposed alongside the reflective questions previously developed by us (##FIG##0##Figure##) to delve even deeper into issues of meaningful inclusion in research and policy development within the context in that young people live. The Reflective Guide was created as a tool for health researchers to enhance the meaningfulness of children’s participation. Considering the shared goal of health policy-makers, implementing the strategies outlined in the Guide would be appropriate to integrate children and youth’s perspectives more effectively into their work. The Guide primarily emphasizes the importance of recognizing and addressing trends and gaps, improving methodological clarity, diversifying methodological approaches, and addressing power structures that impede meaningful participation of children. Although initially developed for children aged 6-18, the Guide’s principles and recommendations are applicable and relevant to a broader age range, including older youth.</p>", "<p> Cahill and Dadvand’s P7 Model was designed to illuminate how the context and intersecting social and structural determinants, including colonialism, apartheid, poverty, and racial and gender inequality influence youth participation. Using this intersectional lens, one line of inquiry that could have been examined further by Jacobs and George was how youth participation influenced empowerment and how engagement may have reinforced intersecting inequities. Having an enhanced understanding of these issues would be beneficial to know what participatory strategies to build upon and which to avoid to reduce harm when developing future policies with youth.</p>", "<title>Diverse Youth Perspectives</title>", "<p> “<italic toggle=\"yes\">When thinking about policy-making processes we need to ask how participation was gained and how different constituencies of adolescents and youth were considered</italic>” (AYHP Advisory Panel Member 11).Participants recognized that the policy development process did not involve a diverse array of youth. The authors also recognized this concern in their findings and noted how diverse youth engagement was a key challenge in the policy development process. Importantly, the study’s findings show how the policy development process did not include youth with intersecting identities (ie, age, disability, sexuality, and geographical settings) due to broader contextual challenges including resource limitations. These findings make evident the need to advocate for more resources and time to better include youth in policy development so as not to tokenize youth participation. To address these challenges, recommendations in the paper point to the need for health policy decision-makers to systematically include diverse youth in policy-making. They recognize this action is “both an ambitious goal and a vexing challenge to implement in reality” (p. 9). We agree that a lot of work needs to be done, and from our previous work collaborating with youth to facilitate youth participation, we suggest strategies below under future directions to engage youth in policy, research, and practice in meaningful ways.</p>", "<p> When thinking about who is included, we would have liked to better understood about how Jacobs and George accounted for diverse youth participation in their study. Despite the current study focusing only on youth who were involved in the AYHP process, we suggest that opportunities to include more youth in the study may have been missed. The identities (eg, gender, age, race, ethnicity, sexuality, and disability) of youth participants were not shared nor was a reflection on how those identities intersected with social and structural determinants in South Africa. Furthermore, there was no indication in the methods section of how methods were potentially adapted to meet the needs and strengths of youth, in particular youth requiring accommodations to enable participation. We wonder if the same findings about challenges to youth involvement affected the research and, if so, what further research on the AYHP, inclusive of more young people, might reveal about the findings. This limitation of the study is noted by the authors, when they write, the study “does not include perspectives of representative and diverse youth and structures in the general population”; however, no suggestions were provided by them for how to mitigate this limitation in the future.</p>", "<title>Future Directions</title>", "<p> Jacobs and George show us that a lot more work needs to be done to include rather than tokenize youth in policy development. Jacobs and George highlighted particular challenges of engaging with youth with intersecting identities. Here we unpack future considerations to inform equitable policies grounded in the perspectives of youth, focusing on our areas of study with youth with disabilities and young children.</p>", "<p> Future work that focuses on studying youth representation in the policy development process could be more inclusive by gathering a diverse range of youth perspectives.By not including the perspectives of a diverse range of youth in policy development, decision-makers are inadvertently contributing to societal exclusion of youth from historically under-represented groups. Youth with disabilities have a right to access health services and may need greater services as a result of living with a health condition or impairment in a low-resourced setting.<sup>##UREF##3##6##,##UREF##4##7##</sup> They should be included in health policy decisions that impact their daily lives and right to health. One solution is drawing from the field of disability studies to enhance the inclusion of youth with disabilities’ perspectives using culturally attuned and inclusive methods. Best practice includes adapting and including an array of multi-method inclusive, accessible, adaptable, and non-ableist tools (eg, photo elicitation, cartoon captioning, vignettes, sentence starters, drawing) to enable different ways of expression.<sup>##REF##36048816##8##</sup> It is important to include the perspectives of a diverse range of youth, including youth with disabilities, when developing policies applicable to all children (eg, school and housing). When the rights of youth with disabilities are siloed into disability policy, decision makers are not recognizing them as holistic individuals with diverse needs that cross-cut all sectors.</p>", "<p> Including diverse perspectives of youth also includes understanding how to include younger children (ie, less than 10 years of age) using approaches that are tailored to younger children’s needs and social position. The perspectives of younger children have not always been included in decision making processes despite the existing evidence about the unique perspective that their inclusion provides.<sup>##REF##35659206##4##</sup> Literature from childhood studies offers a breadth of approaches that attend to power structures for engaging younger children, from ethnography to arts-based approaches.<sup>##UREF##5##9##,##UREF##6##10##</sup> Meaningful participation can take many forms including such as the use of reflective guides to attend to representation, voice, interpretation, biases, representation, and equity.<sup>##REF##35659206##4##</sup> No matter the strategies used, the aim is always to listen to younger children without tokenizing them or treating them as passive subjects to study.</p>", "<p> Further work could reflect on if another schematic of the P7 Model would better capture the intended connections across domains versus the current centering of Purpose. We wonder if the domain of Power would be most important to inform the design of youth participatory processes in policy development. With Purpose centered, the current study’s focus on adults’ perspectives in the work is apparent. The study primarily engaged with people in positions of power and authority, with less youth interviewed (a total of 3 out of 30 participants) and fewer quoted.However,adults are not good proxies for young people’s perceptions. The work could also be strengthened by acknowledging how the work benefitted adult researchers and being reflexive about how adult responses were prioritized.<sup>##UREF##5##9##</sup> Further, in the reflexivity section, the unique power differential between the researchers and youth participants was recognized to a lesser degree. Greater recognition of power differentials would provide an opportunity to critically examine what was said by youth but never followed up on, what issues and by whom got put in the foreground of policy discussions, what and whose ideas were marginalized, and for whom did the policy formation process benefit most.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This work is supported in part by an American Occupational Therapy Foundation (AOTF) Implementation Research Grant (<bold>Error! Hyperlink reference not valid.</bold>) received by JN and JH. JH’s work on this article was also funded, in part, by the National Cancer Institute, grant number U01CA27503. The funders had no role in the decision to publish or in the preparation of the manuscript.</p>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nReflective Guide for Children’s Meaningful Inclusion.</p></statement></fig>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"ijhpm-12-7974-g001\" position=\"float\"/>" ]	[]	[{"label": ["2"], "person-group": ["\n"], "surname": ["Njelesani", "Hunleth"], "given-names": ["J", "J"], "article-title": ["Youth participatory research evidence to inform health policy: a systematic review protocol"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["8"], "fpage": ["e036522"], "pub-id": ["10.1136/bmjopen-2019-036522"]}, {"label": ["3"], "person-group": ["\n"], "surname": ["Spray"], "given-names": ["J"], "article-title": ["The value of anthropology in child health policy"], "source": ["Anthropol Action"], "year": ["2018"], "volume": ["25"], "issue": ["1"], "fpage": ["29"], "lpage": ["40"], "pub-id": ["10.3167/aia.2018.250104"]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Cahill", "Dadvand"], "given-names": ["H", "B"], "article-title": ["Re-conceptualising youth participation: a framework to inform action"], "source": ["Child Youth Serv Rev"], "year": ["2018"], "volume": ["95"], "fpage": ["243"], "lpage": ["253"], "pub-id": ["10.1016/j.childyouth.2018.11.001"]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Njelesani", "Cameron", "Gibson", "Nixon", "Polatajko"], "given-names": ["J", "D", "BE", "S", "H"], "article-title": ["A critical occupational approach: offering insights on the sport-for-development playing field"], "source": ["Sport Soc"], "year": ["2014"], "volume": ["17"], "issue": ["6"], "fpage": ["790"], "lpage": ["807"], "pub-id": ["10.1080/17430437.2014.882907"]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Njelesani", "Sedgwick", "Davis", "Polatajko"], "given-names": ["J", "A", "JA", "HJ"], "article-title": ["The influence of context: a naturalistic study of Ugandan children\u2019s doings in outdoor spaces"], "source": ["OccupTher Int"], "year": ["2011"], "volume": ["18"], "issue": ["3"], "fpage": ["124"], "lpage": ["132"], "pub-id": ["10.1002/oti.310"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Hunleth"], "given-names": ["J"], "article-title": ["Beyond on or with: questioning power dynamics and knowledge production in \u2018child-oriented\u2019 research methodology"], "source": ["Childhood"], "year": ["2011"], "volume": ["18"], "issue": ["1"], "fpage": ["81"], "lpage": ["93"], "pub-id": ["10.1177/0907568210371234"]}, {"label": ["10"], "mixed-citation": [" Clark CD. In a Younger Voice: Doing Child-Centered Qualitative Research. New York: Oxford University Press;. "]}]	{ "acronym": [], "definition": [] }	10	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 8; 12:7974	oa_package/3f/ed/PMC10590227.tar.gz
PMC10590229	0	[]	[]	[]	[]	[]	[ "<p>Increased political commitment and financial input to primary care have led to a growing role of performance measurement. Rasooly et al studied the implementation of performance measurement for primary care for people with diabetes in China. This is an important topic that has received little attention from previous literature. In light of the findings from the article, this paper argues for rethinking the current use of performance measurement. It also suggests potential ways to improve primary care performance measurement, in order to avoid some of the pitfalls of top-down performance measurement and to create an enabling environment for primary care strengthening.</p>", "<p>\n<bold>Citation:</bold> Xu J. Rethinking performance measurement of primary care in China: Comment on \"Quality and performance measurement in primary diabetes care: a qualitative study in urban China.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7825. doi:10.34172/ijhpm.2023.7825</p>" ]	[ "<p> Well-functioning primary care is widely considered the corner stone of a high-performing health system. Along with increased political commitment and financial input to primary care, various tools to measure the performance of primary care has been developed by national and international agencies to facilitate establishment of accountability.<sup>##UREF##0##1##, ####REF##29226448##2##, ##UREF##1##3##, ##REF##29042348##4##, ##UREF##2##5####2##5##</sup> Some of these tools were also applied in payment for primary care facilities, ie, “pay-for-performance.” However, the results of performance measurement (particularly as a basis for paying healthcare providers) were mixed.<sup>##REF##33373774##6##</sup> In 2009, China launched a comprehensive health system reform that positioned primary care strengthening among its top priorities. A range of performance indicators for primary care have been used, with many tied to salary for primary care providers. In light of a recent paper<sup>##REF##35942954##7##</sup> published in the <italic toggle=\"yes\">International Journal of Health Policy and Management</italic> and the findings from others, we discuss the way forward for using primary care measurement in China.</p>", "<title>Growing Role of Performance Measurement in China</title>", "<p> The comprehensive health system reform in China led to rapidly growing public investment in primary care in the country. Through the establishment of Basic Public Health Service Scheme,<sup>##REF##31227480##8##</sup> an increasing amount of spending went into a range of public health services provided by primary care facilities including diabetes management, health management for elderly, maternal and child health, health records and so on. The Urban-Rural Basic Social Health Insurance Scheme also increased reimbursement for primary care services. Reimbursement rates for outpatient visits by patients with diabetes and a range of other non-communicable diseases (NCDs) at primary care facilities were substantially increased (from about 50% to about 80%). This increased public expenditure led to the valid question about “value for money.” Besides, an ambitious scheme of family doctor contract services was also introduced to improve the coordination and continuity of care. In response to the expanding spending and reform among others, the role of performance measurement has also substantially grown. Due to the importance of hypertension and diabetes as key mitigable risk factors for cardiovascular disease (CVDs) — the top cause of mortality and morbidity in China, management for hypertension and diabetes feature prominently in these performance measures.</p>", "<p> Performance measurement takes place at multiple levels. At its maximum, there may be as many as 7 levels of monitoring and evaluation — namely, from individual health worker, teams of family medicine, primary care facilities, to local county/district, municipal, provincial, and national levels. Indeed, a typical scene in a rural township health center (or an urban community health center) is a big board glued to the wall of the director’s office. On the board is a large table including a range of performance indicators that cover both outpatient services and basic public health service functions including management of hypertension and diabetes patients among others. The table is well aligned if not exactly the same with the national guideline for performance evaluation.</p>", "<title>Strengths and Limitations of a Top-Down Approach</title>", "<p> Performance on key indicators is evaluated and ranked at each level of measurement, giving rise to both hierarchical and peer pressure to excel or to keep up with others. Moreover, pay-for-performance is also established for such services. In other words, both financial incentive and peer-pressure contributed to a powerful structure that turned funding and resources into activities of NCDs management. This top-down structure channels the centrally defined targets all the way to the level of primary care in each township and village, expanding service coverage rapidly across the country. Significant progress has been reported in improvement in care for hypertension and diabetes,<sup>##REF##28985269##9##,##REF##35602141##10##</sup> as well as reduced patient expenditure.<sup>##REF##26555238##11##</sup> However, such progress was confronted by the continuous growth in mortality attributable to CVDs, as well as the widening gaps between urban and rural CVDs mortality rates,<sup>##UREF##3##12##</sup> suggesting that there is still much room for improvement in the quality of NCDs management.</p>", "<p> The study by Rasooly et al<sup>##REF##35942954##7##</sup> shed lights on the implementation story behind the numbers. The hierarchical structure of performance measurement accompanied with frequent monitoring and evaluation has contributed to the implementation of the reform. The clear targets have also facilitated clarification of the work of frontline health workers and even help create a sense of collaboration both within primary care facilities and between primary care doctors and hospital specialists. In short, the use of stringent performance measure not only helps make frontline providers answerable to the multilevel hierarchy but also provides room for local collaboration.</p>", "<p> On the other hand, the study revealed limitations in the current use of performance measurement. First, there has been little room for bottom-up feedback from frontline practitioners and middle-level managers during planning of the performance targets. Second, as the gaps in patients’ trust of primary care doctors persists, leading to continued bypassing of primary care by patients who often opt to seek care directly from hospitals. Third, the rigid performance indicators also have done little to reflect the patients’ actual needs for health and wellbeing and may lead to replacement of internal motivation for doctors to address the need of patients. Fourth, important gaps in performance measurement for primary care services, including lack of use of guideline recommended effective measures due to absence of public finance to cover fees for the tests. Fifth, the authors also identified fraudulent reporting despite mechanisms for verification. This lack of effective verification coupled with the incentive to excel in performance is likely not restricted to the local area. Worryingly, fraudulent reporting may lead to systemic over-reporting of performance, pushing further for unrealistic and inflated targets, cherry-picking of patients easier to manage, and concealing of real service gaps.</p>", "<title>Way Forward</title>", "<p> Newton-Lewis et al<sup>##UREF##4##13##</sup> have pointed out that the complex and dynamic nature of health systems makes outcome of health services difficult to control. The predominantly directory use of performance measurement widely seen in low- and middle-income countries should be shifted towards more enabling approaches. As Newton-Lewis et al<sup>##UREF##4##13##</sup> highlighted, system-level environment and organizational culture play important roles in determining the appropriate balance between directive and enabling approaches. Building on their analysis, this paper suggests the following ways to avoid some of the pitfalls of performance measurement and to create an enabling environment for primary care strengthening.</p>", "<p> First, accurate measurement for performance is needed. As Rasooly et al<sup>##REF##35942954##7##</sup> suggests, increasingly accurate and cost-effective use of more advanced test (such as hemoglobin A1C for diabetic patients) may be an important way to improve performance measurement.</p>", "<p> Second, information technology should facilitate verification of performance and identification of fraud. Rapidly developing in China are regional health information systems that cover nearly all of patients’ data related to health service utilization and health insurance claims. As a result, linking patients’ health records may make it convenient to tell a patient’s actual health and outcomes of NCDs management. Facial recognition has also been used for patients with hypertension and/or diabetes during follow-up visits provided by primary care providers. It helps make sure that local health workers actually perform follow-up visits and blood pressure measurement of and glycemia test.</p>", "<p> Third, for such measurement to be effective, it will likely require additional payment. Either increased input or reallocation of current fund will be needed for performance verification, information system, and using better indicators (including additional tests).</p>", "<p> Fourth, performance indicators for downstream outcomes may be used. For example, key indicators for primary care such as avoidable hospitalizations may need to be introduced at local and regional levels.</p>", "<p> Fifth, local stakeholders should be engaged in deciding both performance targets and their uses, so that performance measurement is realistic and meaningful. While new ways of measurement may squeeze out some frauds, they cannot eliminate room for gaming. Moreover, some of these technical solutions may not seem appropriate or feasible in certain areas. For local providers and bureaucrats to genuinely collaborate to improve primary care, they need to find such targets legitimate. Real challenges such as patients’ bypassing and lack of trust in primary care should be recognized as structural constraints for performance improvement. Using performance measurement along with efforts to empower and strengthen primary care service capacity may leverage the local potential to develop people-centered, high-quality care.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that he has no competing interests.</p>", "<title>Funding</title>", "<p> Jin Xu’s work is supported with the major research project “Building of and Database-construction for A Global Community of Health for All” (Grant No. 21ZDA130) sponsored by the National Social Science Fund of China. However, the funder played no role in the paper.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["1"], "mixed-citation": [" Expert Panel on Effective Ways of Investing in Health (EXPH). Opinion on Tools and Methodologies for Assessing the Performance of Primary Care. EXPH; 2017. "]}, {"label": ["3"], "mixed-citation": [" Primary Heath Care Division of China\u2019s National Health Commission. Guiding Opinion on Strengthening Performance Evaluation of Primary Care Facility. 2020. "], "uri": ["http://www.nhc.gov.cn/jws/s7882/202008/0ad3357cf1c747e0af8e5e145698d571.shtml"]}, {"label": ["5"], "mixed-citation": [" World Health Organization (WHO), United Nations Children\u2019s Fund (\u200eUNICEF)\u200e. Primary Health Care Measurement Framework and Indicators: Monitoring Health Systems Through a Primary Health Care Lens. Geneva: WHO, UNICEF; 2022. "]}, {"label": ["12"], "mixed-citation": [" National Center for Cardiovascular Diseases. Annual Report on Cardiovascular Health and Diseases in China (2021). Beijing: Science Press; 2022. "]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Newton-Lewis", "Munar", "Chanturidze"], "given-names": ["T", "W", "T"], "article-title": ["Performance management in complex adaptive systems: a conceptual framework for health systems"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["7"], "fpage": ["e005582"], "pub-id": ["10.1136/bmjgh-2021-005582"]}]	{ "acronym": [], "definition": [] }	13	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 15; 12:7825	oa_package/a3/dd/PMC10590229.tar.gz
PMC10590230	0	[ "<title>Background</title>", "<p> Major system change (MSC) is often enacted by local providers and commissioners in England and elsewhere as a way of addressing multiple challenges in the health and social care system, including financial pressures, workforce deficits and clinical outcomes.<sup>##UREF##0##1##</sup> It seems highly likely that such programmes will remain a ‘go to’ option for local policy makers, with long term operational issues combining with the effects of the COVID-19 pandemic to create huge pressures for health and social care organisations.<sup>##REF##35850953##2##</sup></p>", "<p> These initiatives are regularly presented as rational processes, informed by open consultation, to devise optimal, logical solutions to problems experienced by organisations such as acute hospitals.<sup>##REF##21719140##3##</sup> Despite this, there is a growing body of academic work which questions this ‘taken for granted nature of service change’<sup>##REF##31541570##4##</sup> (p. 1216). These critical perspectives draw attention towards crucial but neglected factors that influence the way such processes take place, including ‘local meanings, cultures and identities; leadership, co-optation and control; and framing, evidencing and strategies’<sup>##REF##31099047##5##</sup> (p. 1222). Out of these studies, a strong theme has emerged regarding the role of power in driving how MSCs are framed, how they unfold, and their outcomes.</p>", "<p> Studying the role of power in the context of MSC creates several overlapping methodological and ethical dilemmas and challenges for researchers in this area. The way Perry et al balance these dilemmas with respect to their research into MSC provides several lessons and points for consideration, which we explore in this commentary. This relates specifically to <italic toggle=\"yes\">where to direct focus </italic>in terms of participation in the research, and whether or not the researcher should view their role as <italic toggle=\"yes\">helping </italic>the service change proceed.</p>" ]	[]	[]	[]	[]	[ "<p>To study major system change (MSC) in healthcare, it is crucial to consider the influence of <italic toggle=\"yes\">power</italic>. Despite this, dominant perspectives on MSC in healthcare present these as relatively neutral processes, where reconfigurations are logical solutions to clearly defined problems. Perry and colleagues’ paper adds to a growing body of research which challenges the presentation of MSC as neutral, managerial processes, instead identifying how power dynamics lie at the heart of why service change happens, how it unfolds, and its outcomes. However, the introduction of power considerations raises several overlapping methodological and ethical dilemmas for researchers, and questions regarding research design and dissemination. In this commentary, we use the insights generated by Perry et al to further explore these issues.</p>", "<p>\n<bold>Citation:</bold> Smith CQ, Williams I. The pervasiveness of power: dilemmas for researchers of major system change in healthcare: Comment on \"‘Attending to history’ in major system change in healthcare in England: specialist cancer surgery service reconfiguration.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7639. doi:10.34172/ijhpm.2023.7639</p>" ]	[ "<title>Understanding Major System Change</title>", "<p> MSC in healthcare can have major implications for the wellbeing of staff,<sup>##REF##35471103##6##</sup> patients and the public, can swallow up substantial resources, and is often a source of conflict and disagreement between groups involved.<sup>##REF##33636017##7##</sup> Those seeking to study such processes must first negotiate access, invariably with those who are leading the changes. Inevitably, as with much qualitative research involving elite participants, these actors may seek to represent the official organisational position.<sup>##UREF##1##8##,##UREF##2##9##</sup> Indeed, they are likely to be inclined towards a positive view of their programmes of change as evidence-based, necessary and targeted towards clinical need.<sup>##REF##25461877##10##</sup> However, such claims are ‘highly contested in the research community’<sup>##REF##25461877##10##</sup> (p. 196). For instance, in their systematic review of the methods used in economic evaluations of specialised healthcare services, Bhattarai et al find a lack of standardised evidence for the benefits of MSC. They warn this ‘may mislead decision-makers towards making wrong decisions on centralisation’<sup>##UREF##3##11##</sup> (p. 1). The benefits of such changes are therefore not always as clear as sometimes presented in public plans and documents, and there may be strong competing views particularly from those groups not immediately involved in leading the change. Establishing a plurality of perspectives – particularly ones that are traditionally marginalised – can therefore be important for studies seeking to establish a ‘fully rounded’ view of MSCs and how these ‘play out’ in practice. This, in turn, promises to elucidate important power dynamics, and how these influence the ways that different groups see and act in relation to reconfigurations.</p>", "<p> Perry and colleagues’<sup>##REF##35297232##12##</sup> research provides a timely example of the benefits of establishing wide participation in MSC studies, particularly when exploring the role different understandings of history play in how groups engage in the reconfiguration. Their recruitment and data collection, taking place over a period of three years, draws testimonies from a range of professionals sitting on the various groups and committees involved in the service change. It also includes approximately 160 hours of participant observation, and analysis of 300 documents. This variety of sources and voices allows them to generate insights on conflict and disagreement within the service change, and thus more insights on the operation of power in this context. For example, the article gives significant attention to issues of framing and discursive power, particularly how ‘a tightly managed process’ (p. 2840) allowed for more contentious issues to be somewhat hidden from view. This critical analysis is enabled by the scope of the study which takes in multiple stakeholder perspectives, examining the historical deadlock between opposing professional groups and organisations involved in the change. This in turn allows for an account which goes beyond ‘simple rules’ to show how complex power dynamics involved in the process are as much a driver as any calculations and projections of the anticipated benefits.</p>", "<p> As noted, Perry et al add an important historical dimension to a burgeoning ethnographic literature. Ethnographic research into healthcare improvement more generally can reveal the influence of power relations and systems,<sup>##REF##34865630##13##</sup> and therefore helps elucidate a political dimension of MSC in healthcare that is not immediately evident otherwise. For example, in their study of the engagement carried out as part of a regional transformation plan in the National Health Service (NHS) in England, Carter and Graham explore the ‘micro-politics’ of patient and public involvement. They draw attention to how techniques such as ‘agenda framing,’ lack of transparency and ‘the exclusion of counter-narratives’ all worked to help align the activity of representation groups to the ‘radical transformation of the NHS’<sup>##UREF##4##14##</sup> (p. 724). The process by which this was reached largely worked to obscure from view the ‘disparate views’ of members of the patient and public involvement group, as ‘consensus became a form of governmentality’<sup>##UREF##4##14##</sup> (p. 723). Research like this again draws attention to the importance of not taking managerial accounts of the benefits of service change, and the processes involved, at face value. The presence of such disparate perspectives also brings into focus the difficulties researchers face in adjudicating between opposing accounts of the process and outcomes of MSC.</p>", "<title>Ethical Challenges</title>", "<p> Such challenges, while navigable, can pose deeper dilemmas for researchers in the stance they take towards service change and, specifically, the extent to which they should focus on generating knowledge to <italic toggle=\"yes\">help </italic>managers implement service change. In Weberian terms,<sup>##UREF##5##15##</sup> this can be framed as the extent to which academic research should seek to find solutions to issues that are practically pertinent to the <italic toggle=\"yes\">value relevance frameworks</italic> of policy makers (the questions they see as important as defined by the ends they strive for) – or whether they exist to also critique these ends themselves. With respect to service change, there are two main standpoints a researcher might take:</p>", "<p>Support – This is characteristic of the dominant ‘instrumental evaluative’ perspective outlined by Jones et al, wherein research ‘presupposes the need for change and is concerned with judging the ‘success’ of changes that have been introduced in terms of clinical or economic outcomes’<sup>##REF##31099047##5##</sup> (p. 1221). </p>", "<p>Critique – Such perspectives can take two overlapping forms. The first entails a focus on how local policy makers strategically use knowledge to achieve their ends and make service change happen. This includes Foucauldian perspectives which scrutinise the practices of government used to legitimise large scale upheavals<sup>##REF##31009877##16##</sup> and the rhetorical strategies of framing used to implement change in the face of community resistance, thus undermining democratic participation.<sup>##REF##25461877##10##</sup> The second involves making sure views outside of dominant managerial perspectives — in terms of both staffing groups<sup>##REF##35471103##6##</sup> and patient and public<sup>##UREF##6##17##</sup> — are given voice. </p>", "<p> Many applied researchers adopt a somewhat ambivalent middle ground between these two standpoints. This is understandable given the difficulty of determining <italic toggle=\"yes\">prior to implementation </italic>whether or not a change will improve outcomes, and the imperative for research to demonstrate relevance to practical policy problems.<sup>##REF##12869343##18##</sup> Such ambivalence is present in Perry and colleagues’<sup>##REF##35297232##12##</sup> paper, which at points adopts the standpoint of support, at others critique. For example, in the key messages of the article, the authors state:</p>", "<p> “<italic toggle=\"yes\">This study examines how, by being knowledgeable and aware of the history of previous attempts to change the way health services are provided, those organising change can make them happen”</italic> (p. 2829).</p>", "<p> This statement leans towards a standpoint of ‘support’ in its concern to identify strategies that will enable successful implementation of these contested change processes. Elsewhere in the paper, Perry et al examine the ‘political nature of the changes being planned’<sup>##REF##35297232##12##</sup> (p. 2839). This includes the way the structure of the service change process acts as a form of ‘discursive power’ that is used to frame and channel thinking towards a course of action that diverges from the desired outcomes of some stakeholders. Of course, such observations throw into question the extent to which the outcomes of the change are themselves desirable. In this case, Perry et al note the established recommendations for reconfiguration of obstetrics and gynaecology specialist cancer surgery services as a means of reducing variation, increasing patient volumes and improving outcomes. They also note evidence for the benefits for patient outcomes of concentration of specialist services <italic toggle=\"yes\">in some contexts</italic>. However, the disputed benefits of MSC more generally raise difficult questions for researchers regarding the extent to which their work should generate recommendations as to how managers can <italic toggle=\"yes\">make them happen. </italic>Regrettably, there are no simple rules researchers can follow to get this right but, in our experience, they should be a constant point of reflection for those studying major systems change in healthcare. Therefore, Perry and colleagues’<sup>##REF##35297232##12##</sup> research successfully demonstrates the value of in-depth qualitative research into MSC in uncovering hidden power dynamics. At the same time, it also facilitates reflection on the difficult ethical challenge researchers face in how to position <italic toggle=\"yes\">themselves</italic> to these dynamics, to which there are no easy answers.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["1"], "mixed-citation": [" Bate A. Reconfiguration of NHS Services (England). House of Commons Library; 2017. "]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Harvey"], "given-names": ["WS"], "article-title": ["Methodological approaches for interviewing elites"], "source": ["Geogr Compass"], "year": ["2010"], "volume": ["4"], "issue": ["3"], "fpage": ["193"], "lpage": ["205"], "pub-id": ["10.1111/j.1749-8198.2009.00313.x"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Solarino", "Aguinis"], "given-names": ["AM", "H"], "article-title": ["Challenges and best-practice recommendations for designing and conducting interviews with elite informants"], "source": ["J Manag Stud"], "year": ["2021"], "volume": ["58"], "issue": ["3"], "fpage": ["649"], "lpage": ["672"], "pub-id": ["10.1111/joms.12620"]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Bhattarai", "McMeekin", "Price", "Vale"], "given-names": ["N", "P", "C", "L"], "article-title": ["Economic evaluations on centralisation of specialised healthcare services: a systematic review of methods"], "source": ["BMJ Open"], "year": ["2016"], "volume": ["6"], "issue": ["5"], "fpage": ["e011214"], "pub-id": ["10.1136/bmjopen-2016-011214"]}, {"label": ["14"], "person-group": ["\n"], "surname": ["Carter", "Martin"], "given-names": ["P", "G"], "article-title": ["Engagement of patients and the public in NHS sustainability and transformation: an ethnographic study"], "source": ["Crit Soc Policy"], "year": ["2018"], "volume": ["38"], "issue": ["4"], "fpage": ["707"], "lpage": ["727"], "pub-id": ["10.1177/0261018317749387"]}, {"label": ["15"], "person-group": ["\n"], "surname": ["Hammersley"], "given-names": ["M"], "article-title": ["On the role of values in social research: Weber vindicated?"], "source": ["Sociol Res Online"], "year": ["2017"], "volume": ["22"], "issue": ["1"], "fpage": ["130"], "lpage": ["141"], "pub-id": ["10.5153/sro.4197"]}, {"label": ["17"], "mixed-citation": [" Steward E. Publics and Their Health Systems: Rethinking Participation. Basingstoke: Palgrave Macmillan; 2016. "]}]	{ "acronym": [], "definition": [] }	18	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 22; 12:7639	oa_package/26/4b/PMC10590230.tar.gz
PMC10590231	0	[ "<title>Background</title>", "<p> Centralized drug procurement (CDP) cooperatively combines the resources of drug purchasing authorities to improve efficiency and create greater purchasing power, which has been widely used by many countries and international organizations as a pharmaceutical pricing policy to achieve affordability and accessibility of pharmaceutical products to patients and healthcare systems.<sup>##UREF##0##1##,##REF##22835922##2##</sup></p>", "<p> China applied the national-level CDP since the end of 2018, which is also known as “National Volume-based Procurement (NVBP)” and promoted by the National Healthcare Security Administration (NHSA).<sup>##UREF##1##3##</sup> The Joint Procurement Office was established to organize the tendering process and acts on behalf of all local drug procurement agencies and healthcare institutions.<sup>##UREF##2##4##</sup> For each drug covered by NVBP (defined by International Nonproprietary Name [INN], administration route and specification), the agreed-upon procurement volume is provided, which is estimated as a percentage of the previous annual usage volumes of healthcare institutions. Compared to previous provincial-level drug procurement without agreed-upon procurement volume, NVBP is more conducive to creating economies of scale. To be eligible for NVBP bidding, generic drugs must pass the bioequivalence testing to verify they are equivalent to their brand-name counterparts, which was previously not strictly required. In the procurement cycle, healthcare institutions are obligated to purchase the bid-winning drugs in quantities that at least meet the agreed-upon procurement volumes, while healthcare institutions also have the option to purchase non-winning drugs with the same INN from other manufacturers. Therefore, it is anticipated that NVBP will not only lead to a reduction in drug prices and save procurement expenditures, but will also improve quality of generic drugs and guide healthcare institutions’ drug purchasing and usage behavior, et al.<sup>##UREF##1##3##,##UREF##3##5##</sup> The first pilot NVBP was initiated in 11 cities across China in 2019, covering 25 drugs. The predetermined percentages for estimating the agreed-upon procurement volume ranged between 60%-70%. In the pilot NVBP, the manufacturer that offered the lowest bidding price of each drug was granted exclusive sale authority within the one-year procurement cycle, and 23 out of 25 bid-winning drugs were generic.</p>", "<p> Many previous studies have shown that CDP can effectively lower the prices and procurement expenditures of bid-winning drugs, including CDP conducted by international organizations such as Eastern Caribbean Drug Service,<sup>##REF##10172681##6##</sup> Global Fund to Fight AIDS, Tuberculosis and Malaria,<sup>##REF##28052986##7##,##REF##19649366##8##</sup> or countries such as France,<sup>##UREF##4##9##</sup> India,<sup>##REF##28607278##10##</sup> Brazil,<sup>##REF##24189152##11##,##REF##20107694##12##</sup> Colombia,<sup>##REF##31857910##13##</sup> as well as NVBP in China.<sup>##UREF##2##4##</sup> Some of these studies suggested that the impacts may vary across time or pharmacological areas, but reliable evidence is scarce, since most of the research periods were shorter than one complete procurement cycle, or did not distinguish or only focused on one specific pharmacological area. In addition, China has highly fragmented drug manufacturing sectors,<sup>##REF##27080345##14##</sup> for many bid-winning drugs, there are non-winning drugs with the same INN produced by many other manufactures. Moreover, the NVBP only covers limited numbers of drugs, there are lots of alternative drugs not covered by NVBP in the same pharmacological areas. The transaction process of these drugs is less transparent than the bid-winning drugs, which may provide financial incentives for healthcare institutions to purchasing them. Previous studies have observed decrease in procurement volume of non-winning drugs after NVBP, along with the increase for bid-winning drugs.<sup>##UREF##5##15##, ####REF##34760861##16##, ##REF##34823516##17####34823516##17##</sup> However, the policy effect on the alternative drugs not covered by NVBP is still unclear, with limited studies reporting inconsistent results for drugs in different pharmacological areas such as antibiotic, antihypertensive and antiviral drugs.<sup>##REF##34760861##16##, ####REF##34823516##17##, ##REF##34238290##18####34238290##18##</sup></p>", "<p> Tianjin is one of the first 11 cities piloting NVBP in China, and also one of the four municipalities (provincial cities) in China. After the Joint Procurement Office announced the bid-winning manufactures and prices for 25 drugs covered by the pilot NVBP, Tianjin officially implemented the pilot NVBP at April 1, 2019 and started the first 1-year procurement cycle (Figure S1, ##SUPPL##0##Supplementary file 1##), with all public healthcare institutions participated. The second procurement cycle of the pilot NVBP in Tianjin started at April 25, 2020, following the guidance of local medical insurance bureau. During the second procurement cycle, the bid-winning prices further dropped nearly for all drugs, and three out of 25 drugs’ bid-winning manufactures changed (Table S1). The second procurement cycle was set to 1 or 2 years for different bid-winning drugs.</p>", "<p> This study aimed to evaluate the impact of the pilot NVBP on the procurement price, volume, and expenditure for the drugs covered by the policy, and the drugs not covered but may affected by the policy, taking Tianjin as an example. Differences among procurement cycles and pharmacological categories were also investigated.</p>" ]	[ "<title>Methods</title>", "<title> Setting</title>", "<p> The pilot NVBP policy covered 11 cities including 4 municipalities and 7 sub-provincial cities. In the current study, the impact of the pilot NVBP was investigated in the municipality of Tianjin, which is located in Northern China and covers an area of 11 966 km<sup>2</sup> with 16 districts.<sup>##UREF##6##19##</sup> In 2019, Tianjin accommodated 15.62 million population with a per-capita gross domestic product of CNY 90 371, 127.48% of the national average gross domestic product level.<sup>##UREF##6##19##,##UREF##7##20##</sup> There were 5962 healthcare institutions in Tianjin in 2019, among which 441 were hospitals and 5 348 were healthcare institutions at the basic level.<sup>##UREF##6##19##</sup></p>", "<title> Data Source and Sample Selection</title>", "<p> Data were obtained from Tianjin Medical Purchasing Center upon on the approval from Tianjin Municipal Medical Insurance Bureau for research purposes. The extracted data contain monthly aggregated drug purchase records of healthcare institutions in Tianjin, from January 2018 through December 2020, which included drug’s generic name, brand name, form, specification, package size, manufacture, drug approval number, procurement unit, price per unit, procurement volume, procurement expenditure, procurement date (month-year), and name of the buyer (healthcare institution). The extracted data comprised approximately 970 thousand records, covering 383 INN of the NVBP-covered drugs and alternative drugs (as defined in the subsequent text) in the NVBP policies implemented in Tianjin from 2018 to 2020 (Figure S1).</p>", "<p> Two interventions, the pilot NVBP initiated on April 1, 2019, in Tianjin, and the start of its second procurement cycle on April 25, 2020, divided the 36 months study period into 3 segments (##FIG##0##Figure 1##): before the pilot NVBP (T<sub>0</sub>: January 2018 to February 2019), during the first procurement cycle (T<sub>1</sub>: April 2019 to March 2020), and during the second procurement cycle (T<sub>2</sub>: May 2020 to December 2020). Data for March 2019 was excluded because some healthcare institutions purchased the bid-winning drugs at the bid-winning prices in this month before the formal launch of the pilot NVBP. Data for April 2020 were also excluded since the records in the first and second procurement cycles cannot be separated in the monthly aggregated data.</p>", "<p> The study samples were the bid-winning drugs in the pilot NVBP and their corresponding alternative drugs. The information of the bid-winning drugs was listed in Table S1. The drugs with the same INN and administration route as the bid-winning drugs were referred as “NVBP-covered drugs,” which included both the bid-winning drugs and non-winning drugs. Alternative drugs refer to the drugs that are clinically substitutable for bid-winning drugs, which were certified by NHSA in the officially issued document “Monitoring Plan Work of National Centralized Drug Procurement and Use” (Table S2). As shown in ##FIG##1##Figure 2##, alternative drugs were classified into three layers, wherein the tier-one alternative drugs were those have the same INNs or similar molecular structures as the bid-winning drugs, the tier-two alternative drugs mainly were those in the same chemical subgroups as the bid-winning drugs, and the tier-three alternative drugs mainly were those treating the same diseases as the bid-winning drugs. However, not all drugs meeting the above criteria were included and classified, taking into account the regulatory consideration and clinical perspective. Therefore, the tier-one alternative drugs exhibit the highest substitutability for the bid-winning drugs, followed by the tier-two and tier-three alternative drugs.</p>", "<p> During the study period, study samples that may have been affected by confounding policies were additionally excluded from this study such as alternative drugs (except the non-winning drugs) with the same INN as the bid-winning drugs in the pilot or second or third NVBP, to ensure that the measured effects of NVBP on alternative drugs were not confounded by its effects on the bid-winning drugs, as well as the antineoplastic alternative drugs that were newly added to the National Reimbursement Drug List through pricing negotiation.</p>", "<title> Measurement</title>", "<p> Study outcomes of interest were the changes in procurement price, volume, and expenditure of samples. Procurement expenditure was reported in monetary value. Procurement volume was measured as the number of defined daily doses (DDDs) in order to compare drugs with different forms. DDD refers to the average maintenance dose per day for a drug used for its main indication in adults. DDD was uniquely assigned per route of administration within an anatomical therapeutic chemical (ATC) code when the information is directly available on the World Health Organization (WHO) website.<sup>##UREF##8##21##</sup> Otherwise, DDD was calculated based on drugs’ instructions following the WHO’s principle for DDD assignment.<sup>##UREF##8##21##</sup> The cost of defined daily dose (DDDc), a proxy indicator for procurement price, was computed as “procurement expenditure/DDDs.” The DDDc of both the bid-winning and non-winning drugs were not reported in this study as some of them were not purchased in some months, resulting in the inability to calculate their DDDc values.</p>", "<title> Statistical Analysis</title>", "<p> Monthly procurement price (DDDc), volume (DDDs), and expenditure were calculated in the study period. The mean values were calculated and compared during the common months (May to December) before and after the two interventions. Single-group interrupted time series (ITS) analyses with two interventions were conducted to evaluate the impact of the pilot NVBP on DDDc, DDDs, and expenditure, in the first and second procurement cycles. Segment regression models were used to measure the level change (change at the first month following the intervention) and trend change (monthly change) after the interventions with level and trend before the interventions controlled:</p>", "<p> Where <italic toggle=\"yes\">Y</italic><sub>t</sub> indicates the outcome of interest measured at time <italic toggle=\"yes\">t</italic>. <italic toggle=\"yes\">Time</italic><sub>t</sub> is a continuous variable indicating the months from the start of study period at time <italic toggle=\"yes\">t</italic>. <italic toggle=\"yes\">I</italic><sub>tj</sub> and <italic toggle=\"yes\">I</italic><sub>tk</sub> are dummy variables indicating the relationship between time <italic toggle=\"yes\">t</italic> and the interventions (the start of the first and second procurement cycles of the pilot NVBP). <italic toggle=\"yes\">I</italic><sub>tj</sub> and <italic toggle=\"yes\">I</italic><sub>tk</sub> are set to 1 after the interventions, respectively, and 0 in the pre-intervention period. <italic toggle=\"yes\">D</italic><sub>i</sub> are three dummy variables that refer to the month of the Spring Festival in 2018, 2019, and 2020 to control the influence of Spring Festival on drug consuming behavior. <italic toggle=\"yes\">ε</italic><sub>t</sub> is an estimate of the random error. Therefore, coefficient <italic toggle=\"yes\">β</italic><sub>2</sub> represents the level change and <italic toggle=\"yes\">β</italic><sub>3</sub> represents the trend change of the chosen outcomes during the first procurement cycles of the pilot NVBP, while the effects in the second procurement cycle are indicated by <italic toggle=\"yes\">β</italic><sub>4</sub> and <italic toggle=\"yes\">β</italic><sub>5</sub> similarly. Autocorrelation was assessed using plots of autocorrelation and partial-autocorrelation function as well as Durbin-Watson test. The autocorrelation form of the autoregressive–moving-average ARMA (p, q) model for the stationary series were determined. Then the significant autoregressive parameters (p, q) were included in regression models for autocorrelation adjustment.<sup>##REF##12174032##22##, ####REF##27283160##23##, ##UREF##9##24####9##24##</sup> The definitions of the bid-winning drugs in the regression models were consistent with those in Table S1.</p>", "<p> The relative changes in outcomes at the sixth month after the interventions were calculated by comparing predicted outcomes in the presence and absence of the interventions, which combined the level and trend changes.<sup>##REF##12174032##22##,##UREF##10##25##</sup></p>", "<p> Subgroup analyses were performed to explore whether the overall impact was consistent in drugs in different pharmacological groups. Twelve pharmacological subgroups were created according to ATC-3 codes and indications of winning products: namely antihypertensives, lipid-modifying drugs, psycholeptics, psychoanaleptics, antiepileptics, antineoplastics, antivirals, antibacterials, antithrombotics, drugs for obstructive airway diseases, antidiarrheics, and anti-inflammatory/antirheumatic drugs (Table S3).</p>", "<p> STATA 15.0 was used for data preparation and R 3.6.1 was used for regression analysis. The significance level was set as two-sided α < 0.05.</p>" ]	[ "<title>Results</title>", "<title> Changes in Procurement Price ( DDDc )</title>", "<p> A total of 25 NVBP-covered drugs, and 73 alternative drugs with different INN from the NVBP-covered drugs were included in the analysis (Tables S1 and S2). Descriptive analyses showed the monthly average DDDc of NVBP-covered drugs from May to December 2018, 2019, and 2020 were CNY6.42, CNY2.58, and CNY1.88 per DDD, respectively, demonstrating a decreasing trend. While the corresponding descriptive DDDc for other tier-one, tier-two, and tier-three alternative drugs all revealed the contrary trends (Table S4).</p>", "<p> The results from the ITS analyses showed that, before the pilot NVBP, there was no clear significant trend in NVBP-covered drugs’ DDDc (<italic toggle=\"yes\">P</italic> = .053), while the DDDc of the other tier-one (β<sub>1</sub> = 0.014, <italic toggle=\"yes\">P</italic> < .001), tier-two (β<sub>1</sub> = 0.014, <italic toggle=\"yes\">P</italic> < .001), and tier-three (β<sub>1</sub> = 0.020, <italic toggle=\"yes\">P</italic> < .001) alternative drugs increased gently by months (Table, ##FIG##2##Figure 3-A/B##). Influenced by the pilot NVBP, during the first procurement cycle, the DDDc of NVBP-covered drugs dropped immediately (β<sub>2</sub> = -3.878, <italic toggle=\"yes\">P</italic> < .001) and kept decreasing over months (β<sub>3</sub> = -0.068, <italic toggle=\"yes\">P</italic> = .001), which resulted in a 61.55% decrease after half a year. During the second procurement cycle, slight decrease (β<sub>4</sub> = -0.356, <italic toggle=\"yes\">P</italic> = .049) of NVBP-covered drugs’ DDDc was further observed. For alternative drugs, the increasing trend of DDDc of tier-two alternatives slowed down after the pilot NVBP (β<sub>3</sub> = -0.029, <italic toggle=\"yes\">P</italic> = .017), but no other significant change was detected.</p>", "<p> Among the 12 pharmacological subgroups, the magnitude of price reduction of the NVBP-covered drugs varied, which was greater in the lipid-modifying, antihypertensive, antidiarrheic, antiviral subgroups but smaller in the nervous system subgroup (Table S5). For example, the DDDc of the lipid-modifying NVBP-covered drugs dropped immediately upon the initiation of the first (β<sub>2</sub> = -5.009, <italic toggle=\"yes\">P</italic> < .001) and second (β<sub>4</sub> = -0.776, <italic toggle=\"yes\">P</italic> < .001) procurement cycles after the pilot NVBP, which resulted in 76.29% and 48.54% reduction in the sixth month after the two interventions, respectively. However, the changes were -24.60% and 0.00% for the psychoanaleptic subgroup (Figure S2, ##SUPPL##1##Supplementary file 2##). For alternative drugs, unexpected DDDc increases were found in the second procurement cycle for the tier-two alternative drugs in the antidiarrheic (β<sub>5</sub> = 0.380, P<.001; relative change after half a year: 251.23%) and the anti-inflammatory (β<sub>4</sub> = 1.359, <italic toggle=\"yes\">P</italic> = .003; relative change after half a year: 42.85%) subgroups (##FIG##3##Figure 4B##, Figure S3, Table S5 of ##SUPPL##2##Supplementary file 3##), owing to healthcare institutions beginning to purchase more expensive products with specific INN (Berberine, Ketorolac tromethamine) from new suppliers during this procurement cycle.</p>", "<title> Changes in Procurement Volume (DDDs)</title>", "<p> Descriptive analyses showed that (Table S4), before the pilot NVBP, non-winning drugs comprised a large part of the total procurement volumes of the NVBP-covered drugs, much higher than the bid-winning drugs (non-winning versus bid-winning: 89.41% versus 10.59% from May to December 2018). Conversely, the bid-winning drugs became dominant after the policy (non-winning versus bid-winning: 19.23% versus 80.77% from May to December 2019; 13.87% versus 86.13% from May to December 2020).</p>", "<p> According to the ITS analyses, the DDDs of bid-winning drugs increased dramatically and instantly after the pilot NVBP in the first procurement cycle (β<sub>2</sub> = 1.92×10<sup>7</sup>, <italic toggle=\"yes\">P</italic> < .001; relative change after half a year: 1036.91%) and kept rising during the second procurement cycle (β<sub>5</sub> = 7.17×10<sup>5</sup>, <italic toggle=\"yes\">P</italic> = .046; relative change after half a year: 20.41%). Meanwhile, the procurement volume of non-winning generic and original drugs both decreased during the first procurement cycle (relative change after half a year: -82.71% versus -76.04%). For NVBP-covered drugs, the increase of DDDs (β<sub>1</sub> = 5.62×10<sup>5</sup>, <italic toggle=\"yes\">P</italic> < .001) slowed down and remained stable after the pilot NVBP (β<sub>3</sub> = -5.61×10<sup>5</sup>, <italic toggle=\"yes\">P</italic> = .003). No significant increase in the other tire-one, tier-two and tier-three alternatives was observed after the policy (Table, ##FIG##2##Figure 3-C/D##).</p>", "<p> Although no significant increase was found for the overall DDDs of NVBP-covered drugs, the DDDs of NVBP-covered drugs in the subgroups of lipid-modifying and antivirals drugs rose significantly after that the pilot NVBP, possibly indicating the release of medication demand (Table S6, ##SUPPL##3##Supplementary file 4##). Conversely, NVBP-covered drugs for obstructive airway diseases were observed with both level (β<sub>2</sub> = -1.85×10<sup>5</sup>, <italic toggle=\"yes\">P</italic> = .001) and trend (β<sub>3</sub> = -3.10×10<sup>4</sup>, <italic toggle=\"yes\">P</italic> < .001) decline in DDDs after the pilot NVBP, which could be partially explained by the influence of COVID-19. For the psychoanaleptic subgroup, there was also a decrease in NVBP-covered drugs’ DDDs after the pilot NVBP, with no significant change in bid-winning drugs’ DDDs. The reason is possibly that NVBP-covered drugs in this subgroup had the minimal price reduction as mentioned above. For non-winning original and generic drugs in subgroups, the antineoplastic non-winning original drugs were the exceptions, as no significant decrease in DDDs was observed during the two procurement cycles after the pilot NVBP (β<sub>2</sub> = 405, <italic toggle=\"yes\">P</italic> = .708; β<sub>3</sub> = -197, <italic toggle=\"yes\">P</italic> = .169; β<sub>4</sub> = 1.60×10<sup>3</sup>, <italic toggle=\"yes\">P</italic> = .176; β<sub>5</sub> = 148, <italic toggle=\"yes\">P</italic> = .482) (Figure S4).</p>", "<p> Notably, there were significant increases in the procurement volume of alternative drugs in the antihypertensive, lipid-modifying, psychoanaleptic, antiepileptic, antiviral, antibacterial, antidiarrheic, and anti-inflammatory/antirheumatic subgroups (##FIG##3##Figure 4-C/D##, Figure S5). This suggested the undesirable “spillover” effect of the policy, which may result from the additional financial incentives provided to healthcare institutions to purchase alternative drugs, as their transaction process may be less transparent. Moreover, the increase in procurement volume and price of the antidiarrheic tier-two alternatives (β<sub>4</sub> = 2.30×10<sup>5</sup>, <italic toggle=\"yes\">P</italic> < .001; β<sub>5</sub> = -225, <italic toggle=\"yes\">P</italic> = .795) indicated healthcare institutions not only purchased more alternative drugs but also preferred alternative products with higher prices (Table S6). Furthermore, there was no clear correlation discovered between the increase in alternative drugs’ procurement volume and pharmacological characteristics (subgroup types) or tiers of substitutability for the bid-winning drugs.</p>", "<title> Changes in Procurement Expenditure</title>", "<p> Similar as the descriptive results about DDDs (Table S4), non-winning drugs contributed most of NVBP-covered drugs’ procurement expenditure before the pilot NVBP (non-winning versus bid-winning: 86.12% versus 13.88% in May to December 2018), but after the policy, bid-winning drugs’ procurement expenditure dramatically increased, accounting for more than half of the total (non-winning versus bid-winning: 47.87% versus 52.13% from May to December 2019; 41.91% versus 58.09% from May to December 2020).</p>", "<p> After the pilot NVBP, during the first procurement cycle, the procurement expenditure of NVBP-covered drugs decreased significantly (β<sub>2</sub> = -7.29×10<sup>7</sup>, <italic toggle=\"yes\">P</italic> < .001; β<sub>3</sub> = -5.62×10<sup>6</sup>, <italic toggle=\"yes\">P</italic> < .001; relative change after half a year: -62.6%), revealing the cost-saving effects of the NVBP, while this trend moderated in the second procurement cycle. However, this cost-saving effect may be weakened as the procurement expenditure of the alternative drugs significantly increased (Table, ##FIG##2##Figure 3-E/F##), during the second procurement cycle after the pilot NVBP (relative change after half a year: other tier-one: 4.38%, tier-two: 10.28%, tier-three: 8.86%).</p>", "<p> The cost-saving effects of the pilot NVBP on NVBP-covered drugs has been found in most subgroups and with varying degrees, except the antineoplastic subgroup (Table S7 of ##SUPPL##4##Supplementary file 5##, Figure S6). Among the 12 subgroups, most of the bid-winning drugs’ procurement expenditure increased slightly, aside from the psychoanaleptics and the anti-inflammatory/antirheumatic subgroups since their procurement volume did not increase significantly as other subgroups.</p>", "<p> Similar to the findings from the procurement volume, during the second procurement cycle, in the subgroups of antidiarrheic, antibacterial, lipid-modifying and antiviral drugs, the procurement expenditure of their alternative drugs increased along with the volumes as mentioned above (Table S7, Figure S7).</p>" ]	[ "<title>Discussion</title>", "<p> The current study find that the pilot NVBP implemented in Tianjin lowered the procurement price of NVBP-covered drugs, improved the market concentration by promoting the substitution of bid-winning drugs for non-winning drugs, and was cost-saving, in both the first and second procurement cycle. However, in some pharmacological subgroups, the procurement volume and expenditure of alternative drugs grew during the second procurement cycle, which may diminish the overall benefits of the policy.</p>", "<p> Experience from many international organizations and other countries have demonstrated that CDP can effectively reduce drug prices,<sup>##REF##10172681##6##, ####REF##28052986##7##, ##REF##19649366##8##, ##UREF##4##9##, ##REF##28607278##10##, ##REF##24189152##11##, ##REF##20107694##12##, ##REF##31857910##13####31857910##13##</sup> with reductions ranging from -52% to -2.1%.<sup>##REF##10172681##6##,##UREF##4##9##</sup> China’s NVBP policy has shown a greater potential for lowering drug price, which may benefit from the greater purchasing power created by China’s enormous market size. In this study, the procurement prices of the NVBP-covered drugs decreased by 61.55% during the first procurement cycle of the pilot NVBP and did not rebound in the second procurement cycle. This price reduction effects of the pilot NVBP have also been observed by previous studies conducted in Shenzhen, the other pilot city.<sup>##REF##34760861##16##,##REF##34823516##17##,##REF##34663282##26##</sup> Moreover, Yuan have found the price reductions of bid-winning drugs varied from 21% to 96% after the pilot NVBP, when comparing their bid-winning prices with the their lowest price in the pilot cities one year before the policy.<sup>##UREF##2##4##</sup></p>", "<p> The procurement volume increased for bid-winning drugs, while decreased for non-winning drugs, which was consistent with the findings from previous studies on China’s NVBP,<sup>##UREF##5##15##, ####REF##34760861##16##, ##REF##34823516##17####34823516##17##,##REF##33334027##27##</sup> but few studies on the CDP conducted in other countries have paid attention to this research question. As mentioned before, China has highly fragmented drug manufacturing sectors,<sup>##REF##27080345##14##</sup> thus it is not uncommon for many manufactures to produce drugs with the same INN. The NVBP policy marked a turning point, and by augmenting the market share of the bid-winning drugs, it improved market concentration. Moreover, considering 23 out of 25 bid-winning drugs in the pilot NVBP were generics, this policy tremendously promoted the generic substitution, which is known as an effective way to improve drug affordability and accessibility.<sup>##UREF##2##4##,##UREF##5##15##,##REF##33374493##28##</sup></p>", "<p> Significant increases in the NVBP-covered drugs’ procurement volume were observed in antiviral and lipid-modifying subgroups. Taking antiviral subgroup as an example, six months after the pilot NVBP, the DDDs of NVBP-covered drugs (Entecavir, Tenofovir disoproxil) increased by 40.70%, which, however, was lower than the descriptive pre- and post-policy growth rate (95.60%) reported in the study based on another pilot city, Shenzhen.<sup>##REF##34760861##16##</sup> Aside from the difference in study location and study period, the difference in the growth rate could be partially explained as the relative change (40.70%) in this study was calculated based on ITS regression model so that the pre-intervention trend of DDDs was controlled. Previous studies indicated that only 11% of patients with hepatitis B disease received standardized antiviral treatment in China in 2016, due to the poor drug affordability.<sup>##REF##34760861##16##,##UREF##11##29##,##REF##29599078##30##</sup> After the pilot NVBP, the DDDc of antiviral NVBP-covered drugs (Entecavir and Tenofovir disoproxil) dropped by 76.33% within six months, providing an opportunity to release patients’ demand for them.</p>", "<p> In 7 out of 12 pharmacological subgroups, the procurement volume and expenditure of alternative drugs (tier-two or tier-three) increased significantly after the pilot NVBP, mainly during the second procurement cycle. Research on the CDP conducted in other countries rarely focuses on the alternative drugs, while above undesired “spillover” effect was also detected by previous studies in Shenzhen, China after the pilot NVBP, for antibacterial drugs, but not for antihypertensive or antiviral drugs.<sup>##REF##34760861##16##, ####REF##34823516##17##, ##REF##34238290##18####34238290##18##</sup> A possible explanation could be the extra financial incentives for healthcare institutions to purchase alternative drugs that have less transparent transaction process. To be more specific, in NVBP, bid-winning drugs’ manufactures no longer need to conduct market research, negotiate with individual healthcare institutions, or promote their products with competition from other manufactures.<sup>##REF##28052986##7##,##REF##27080345##14##,##REF##34721029##31##</sup> However, these process might still be necessary for promoting the alternative drugs, and the related administration and transaction cost may partly been transformed into the financial incentives to healthcare institutions. Alternative drugs in the antidiarrheic and the anti-inflammatory/antirheumatic subgroups, berberine and ketorolac tromethamine, were interesting examples. During the second procurement cycle after the pilot NVBP, healthcare institutions began to purchase these drugs from new manufactures with the unit sale price up to 6 times higher than before, and their procurement volume also increased significantly by month. It was worth noting that the majority of these undesirable “spillover” effects on alternative drugs were observed in the second procurement cycle after the policy. This might be attributed to the fact that, after the first procurement cycle, healthcare institutions got familiar with the NVBP rules and might become more manipulative when seeking financial incentives.</p>", "<p> Although the procurement volume of bid-winning drugs increased dramatically after the pilot NVBP, more than CNY 550 million was saved for purchasing NVBP-covered drugs within 6 months after the NVBP in Tianjin based on the ITS results. According to official reports, the accumulated cost saving from NVBP over the past 3 years reached a total of CNY 260 billion nationwide.</p>", "<p> This study provides new evidence that expands public’s understanding of the impacts of the NVBP, especially about its effects on alternative drugs, and the diverse effects across different procurement cycles and pharmacological categories. The study design is rigorous thus the possible effects of the other policies are largely eliminated.</p>", "<p> This study also has several limitations. First, upon meticulously reviewing the policies and events occurred over the three-year study period, it was found that uncontrollable confounding factors still persisted, potentially introducing bias to the results, which included the policy to reduce the tax and price of antineoplastic drugs that carried out in Tianjin in December 2018, the update of the Chinese guideline of prevention and treatment for chronic hepatitis B in December 2019,<sup>##UREF##11##29##</sup> and the outbreak of COVID-19, as well as the periodic price adjustment conducted by procurement platform in Tianjin at the end of 2019. These confounding effects can be observed in some pharmacological subgroups, mainly in antineoplastic and antiviral subgroups and drugs for obstructive airway diseases, suggesting careful interpretations of findings were needed. Nevertheless, for the main analysis and the rest of subgroups, the findings were consistent and robust. Second, single-group ITS analysis was conducted rather than ITS analysis with a control group because of the limited data accessibility to non-pilot cities. Third, the alternative drugs were defined in accordance with the recommendations of the NHSA, taking into account chemical characteristics of drugs, and regulatory and clinical perspectives. However, not all drugs treating the same diseases were included, and it is recommended to conduct further exploration on the definition of alternative drugs in relation to different purposes. Forth, the generalizability of the study results is restricted as the impact of NVBP was only explored in single provincial city, although Tianjin was one of the cities piloting the NVBP firstly in China. Moreover, further investigation into the impact of NVBP on drug utilization, clinical benefit, and economic burden, using individual-level data, is warranted.</p>" ]	[ "<title>Conclusion</title>", "<p> The pilot NVBP policy in China is effective in reducing the procurement price, promoting generic substitution, and saving procurement expenditure. However, the increase in procurement price, volume and expenditure of the alternative drugs across various pharmacological categories reveals the significance of regulating healthcare institutions’ drug purchasing behavior, particularly for drugs that not covered by NVBP but are substitutable for bid-winning drugs in clinical practice.</p>" ]	[ "<p>\n<bold>Background:</bold> National Volume-Based Procurement (NVBP) program has been carried out in China to lower drug prices and reduce patients’ medication burden. This study aims to evaluate its impact on drug purchasing in Tianjin city, one of the first 11 cities piloting NVBP in China.\n</p>", "<p><bold>Methods:</bold> Using monthly drug procurement data from Tianjin Medical Purchasing Center between 2018 and 2020, this study identified bid-winning drugs and their alternative drugs in the pilot NVBP, and evaluated the policy impacts on their procurement price (cost of defined daily dose, DDDc), volume (the number of defined daily dose, DDDs), and expenditure, during the first (initiated at April 1, 2019) and second (initiated at April 25, 2020) procurement cycles of pilot NVBP, applying interrupted time series (ITS) analysis. Included drugs were classified into 12 pharmacological subgroups for further analysis.\n</p>", "<p><bold>Results:</bold> Decrease in DDDc of NVBP-covered drugs (bid-winning and non-winning drugs) were observed in the first (level change: -CNY 3.878/DDD, <italic toggle=\"yes\">P</italic><.001; trend change: -CNY 0.068/DDD, <italic toggle=\"yes\">P</italic>=.001; relative change: -61.55%) and second (level change: -CNY 0.356/DDD, <italic toggle=\"yes\">P</italic>=.049) procurement cycles of pilot NVBP, while no significant change was observed for the DDDc of alternative drugs, except for the increase in antidiarrheic and anti-inflammatory/antirheumatic subgroups as more expensive drugs were purchased from new suppliers in the second procurement cycle. The DDDs of bid-winning drugs significantly increased, while decreased for the non-winning original and generic drugs. Procurement expenditure was saved for NVBP-covered drugs (level change: -CNY 7.29×107, <italic toggle=\"yes\">P</italic><.001; trend change: -CNY 5.62×106, <italic toggle=\"yes\">P</italic><.001; relative change: -62.60%). However, during the second procurement cycle, procurement volume and expenditure of alternative drugs increased significantly in 7 out of 12 subgroups.\n</p>", "<p><bold>Conclusion:</bold> The pilot NVBP policy in China reduced procurement price, promoted generic substitution, and saved procurement expenditure. However, the increase in procurement price, volume and expenditure of alternative drugs may reveal the significance of regulating healthcare institutions’ drug purchasing behavior.</p>", "<p>\n<bold>Citation:</bold> Zhao B, Wu J. Impact of China’s national volume-based procurement on drug procurement price, volume, and expenditure: an interrupted time series analysis in Tianjin. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7724. doi:10.34172/ijhpm.2023.7724</p>" ]	[ "<title>Ethical issues</title>", "<p> This study used secondary drug procurement data from Tianjin Medical Purchasing Center. As such, ethical approval was not required.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This work was supported by the Tianjin Medical Purchasing Center of Tianjin Municipal Medical Insurance Bureau in China through a commissioned research project (grant number: Not applicable). The funder provided the data used of the current study, and the funder had no role in study design, data analysis, preparation and review of the manuscript.</p>", "<title>Data availability statement</title>", "<p> The data that support the findings of this study are available from Tianjin Medical Purchasing Center of Tianjin Municipal Medical Insurance Bureau but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Tianjin Municipal Medical Insurance Bureau.</p>", "<title>Disclaimers</title>", "<p> The views expressed in this article are for the authors and not the position of the institutions of affiliation or the funder.</p>", "<title>\nSupplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nClassification of Study Samples. Abbreviation: NVBP, National Volume-Based Procurement.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nClassification of Study Samples. Abbreviation: NVBP, National Volume-Based Procurement.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nProcurement Price, Volume, and Expenditure Before and After the Pilot NVBP. Abbreviations: NVBP, National Volume-Based Procurement, DDDs, defined daily doses; DDDc, cost of defined daily dose. Note: 1. Shaded areas represented that data in these month were excluded in this study. Vertical dashed lines represented the initiation of the first/second procurement cycle. 2. Solid lines were fitted based on actual values. Dotted lines simulated the counterfactual scenario where the intervention was not implemented.</p></statement></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4</label><statement><p>\nExamples of Subgroup Analyses: Procurement Price, Volume, and Expenditure of the Alternative Drugs from the Lipid-modifying and Antidiarrheic Subgroups, Before and After the Pilot NVBP. Abbreviations: NVBP, National Volume-Based Procurement; DDDs, defined daily doses; DDDc, cost of defined daily dose. Note: 1. The entire findings of the subgroup analyses were available in the supplementary files. 2. Shaded areas represented that data in these month were excluded in this study. Vertical dashed lines represented the initiation of the first/second procurement cycle. 3. Solid lines were fitted based on actual values. Dotted lines simulated the counterfactual scenario where the intervention was not implemented.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table</label><caption><title>Effect of the Pilot NVBP on Procurement Price, Volume and Expenditure (Results From ITS Analysis)\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Samples</bold>\n</th><th colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Before the Pilot NVBP</bold>\n</th><th colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>In the First Procurement Cycle</bold>\n</th><th colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>In the Second Procurement Cycle</bold>\n</th></tr><tr><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Intercept (β</bold><sub>0</sub><bold>)</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Trend (β</bold><sub>1</sub><bold>)</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Level Change (β</bold><sub>2</sub><bold>)</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Trend Change (β</bold><sub>3</sub><bold>)</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Relative Change</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Level Change (β</bold><sub>4</sub><bold>)</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Trend Change (β</bold><sub>5</sub><bold>)</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Relative Change</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"9\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">Procurement price (DDDc, unit: CNY/DDD)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NVBP-covered drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">6.297 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.024 (<italic toggle=\"yes\">P</italic> = .053)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-3.878 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.068 (<italic toggle=\"yes\">P</italic> = .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-61.55%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.356 (<italic toggle=\"yes\">P</italic> = .049)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.036 (<italic toggle=\"yes\">P</italic> = .265)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Other tier-one alternative drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.290 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.014 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.023 (<italic toggle=\"yes\">P </italic>= .507)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.005 (<italic toggle=\"yes\">P</italic> = .229)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.021 (<italic toggle=\"yes\">P</italic> = .607)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.003 (<italic toggle=\"yes\">P</italic> = .698)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tier-two alternative drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2.836 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.020 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.085 (<italic toggle=\"yes\">P</italic> = .355)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.029 (<italic toggle=\"yes\">P</italic> = .017)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-4.47%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.100 (<italic toggle=\"yes\">P</italic> = .338)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.000 (P = .981)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tier-three alternative drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.809 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.014 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.079 (<italic toggle=\"yes\">P</italic> = .342)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.018 (<italic toggle=\"yes\">P</italic> = .094)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.010 (<italic toggle=\"yes\">P</italic> = .915)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.030 (<italic toggle=\"yes\">P</italic> = .094)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"9\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">Procurement volume (DDDs, unit: DDD)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Bid-winning drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 457 695 (<italic toggle=\"yes\">P</italic> = .293)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">75 920 (<italic toggle=\"yes\">P</italic> = .641)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">19 227 545 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-130 468 (<italic toggle=\"yes\">P </italic>= .581)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 036.92%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">841 095 (<italic toggle=\"yes\">P</italic> = .651)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">716 613 (<italic toggle=\"yes\">P</italic> = .046)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">20.41%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Non-winning original drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4 404 130 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">189 335 (<italic toggle=\"yes\">P </italic>< .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-5 067 460 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-173 241 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-76.04%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-705 547 (<italic toggle=\"yes\">P</italic> = .066)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">30 941 (<italic toggle=\"yes\">P</italic> = .645)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Non-winning generic drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9 873 582 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">242 106 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-9 993 115 (<italic toggle=\"yes\">P </italic>< .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-351 970 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-82.71%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-730 794 (<italic toggle=\"yes\">P</italic> = .167)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">175 232 (<italic toggle=\"yes\">P</italic> = .070)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NVBP-covered drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">15 185 318 (P < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">562 253 (<italic toggle=\"yes\">P </italic>< .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2 912 482 (<italic toggle=\"yes\">P</italic> = .009)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-561 213 (<italic toggle=\"yes\">P</italic> = .003)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-3.75%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-1 793 140 (<italic toggle=\"yes\">P</italic> = .204)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">726 322 (<italic toggle=\"yes\">P</italic> = .010)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">6.27%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Other tier-one alternative drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3 206 890 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">43 717 (<italic toggle=\"yes\">P</italic> = .205)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-346 253 (<italic toggle=\"yes\">P</italic> = .375)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">33 423 (<italic toggle=\"yes\">P</italic> = .508)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-1 005 911 (<italic toggle=\"yes\">P</italic> = .022)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">110 241 (<italic toggle=\"yes\">P</italic> = .150)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tier-two alternative drugs </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7 637 906 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">322 449 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-801 254 (<italic toggle=\"yes\">P</italic> = .107)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-35 572 (<italic toggle=\"yes\">P</italic> = .635)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-2 096 439 (<italic toggle=\"yes\">P</italic> = .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">221 127 (<italic toggle=\"yes\">P</italic> = .050)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-8.45%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tier-three alternative drugs </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9 581 230 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">371 433 (<italic toggle=\"yes\">P </italic>= .007)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-1 246 402 (<italic toggle=\"yes\">P</italic> = .396)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">15 421 (<italic toggle=\"yes\">P</italic> = .935)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-2 840 424 (<italic toggle=\"yes\">P</italic> = .078)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">486 478 (<italic toggle=\"yes\">P</italic> = .094)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"9\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">Procurement expenditure (CNY)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Bid-winning products</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">12 328 187 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">625 959 (<italic toggle=\"yes\">P</italic> = .069)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">16 274 624 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-1 198 426 (<italic toggle=\"yes\">P</italic> = .021)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">106.64%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-3 372 521 (<italic toggle=\"yes\">P</italic> = .410)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 343 625 (<italic toggle=\"yes\">P</italic> = .077)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Non-winning original products</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">35 376 145 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 323 516 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-37 476 183 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-1 623 159 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-77.70%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-3 817 359 (<italic toggle=\"yes\">P</italic> = .197)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">508 739 (<italic toggle=\"yes\">P</italic> = .337)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Non-winning generic products</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">51 340 780 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 648 704 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-54 456 900 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-2 469 395 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-82.16%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-4 978 258 (<italic toggle=\"yes\">P</italic> = .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 246 476 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">48.15%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NVBP-covered drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">99 214 277 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3 562 972 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-72 905 028 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-5 624 416 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-62.60%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-12 866 086 (<italic toggle=\"yes\">P</italic> = .037)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3 918 726 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">27.36%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Other tier-one alternative drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">10 136 873 (<italic toggle=\"yes\">P </italic>< .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3 557 345 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-1 490 314 (<italic toggle=\"yes\">P</italic> = .092)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">135 120 (<italic toggle=\"yes\">P</italic> = .298)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-3 944 823 (<italic toggle=\"yes\">P</italic> = .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">394 900 (<italic toggle=\"yes\">P</italic> = .042)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.38%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tier-two alternative drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">22 136 025 (<italic toggle=\"yes\">P </italic>< .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 116 878 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">488 512 (<italic toggle=\"yes\">P</italic> = .872)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-580 384 (<italic toggle=\"yes\">P</italic> = .149)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-4 293 581 (<italic toggle=\"yes\">P</italic> = .194)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 230 507 (<italic toggle=\"yes\">P</italic> = .044)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">10.28%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tier-three alternative drugs</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">16 070 538 (<italic toggle=\"yes\">P</italic> < .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 023 580 (<italic toggle=\"yes\">P</italic> = .001)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-1 656 692 (<italic toggle=\"yes\">P</italic> = .585)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-422 418 (<italic toggle=\"yes\">P</italic> = .288)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00%</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-5 045 630 (<italic toggle=\"yes\">P</italic> = .129)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1 774 530 (<italic toggle=\"yes\">P</italic> = .005)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">8.86%</td></tr></tbody></table></table-wrap>" ]	[ "<disp-formula id=\"DF1\">\n<mml:math id=\"m1\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:msub><mml:mi>Y</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:mi>T</mml:mi><mml:mi>i</mml:mi><mml:mi>m</mml:mi><mml:msub><mml:mi>e</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:msub><mml:mi>I</mml:mi><mml:mrow><mml:mi>t</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>3</mml:mn></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:mi>T</mml:mi><mml:mi>i</mml:mi><mml:mi>m</mml:mi><mml:msub><mml:mi>e</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:msub><mml:mi>I</mml:mi><mml:mrow><mml:mi>t</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>4</mml:mn></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:msub><mml:mi>I</mml:mi><mml:mrow><mml:mi>t</mml:mi><mml:mi>k</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>5</mml:mn></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:mi>T</mml:mi><mml:mi>i</mml:mi><mml:mi>m</mml:mi><mml:msub><mml:mi>e</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:msub><mml:mi>I</mml:mi><mml:mrow><mml:mi>t</mml:mi><mml:mi>k</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mstyle displaystyle=\"true\"><mml:msubsup><mml:mo>∑</mml:mo><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mn>3</mml:mn></mml:msubsup><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mn>5</mml:mn><mml:mo>+</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:msub><mml:mi>D</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>ε</mml:mi><mml:mi>t</mml:mi></mml:msub></mml:mrow></mml:mstyle></mml:mrow></mml:math>\n</disp-formula>" ]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>By creating economies of scale and improving efficiency, the National Volume-Based Procurement (NVBP) in China effectively reduced procurement price and saved procurement expenditure. </p></list-item><list-item><p>However, the increases in procurement price, volume, and expenditure of alternative drugs that are not covered by the policy but are clinically substitutable for the bid-winning drugs indicated that healthcare institutions might have a tendency to seek extra finical incentives, which might diminish the overall benefits of NVBP. </p></list-item><list-item><p>The experience of China’s NVBP underscores the importance of deliberate systematic thinking in the design and implementation of centralized drug procurement (CDP), which calls for taking into the broader implications of the policy beyond its primary targets. </p></list-item><list-item><p>It is crucial to consider the diversity and substitutable relationship among drugs within the same pharmacological or therapeutic areas, when designing a CDP policy. </p></list-item><list-item><p>Establishing a long-term, sustainable, and systematic system to regulate the procurement of the bid-winning and alternative drugs, complemented by efficient financial incentive steering measures, seem necessary. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> Through lowering drug procurement prices and promoting generic substitution, the National Volume-Based Procurement (NVBP) policy has improved the affordability and accessibility of drugs across various pharmacological areas for patients, and these policy effects have demonstrated sustainability over time. However, the increase in procurement price, volume, and expenditure of alternative drugs may diminish the policy benefits, leading to unnecessary frequent transitions between the bid-winning drugs and alternative drugs for patients or increases in economic burden. Moreover, as the policy progressed, this problem became increasingly prevalent, potentially affecting more patients. Appropriate approaches should be designed to guide and regulate healthcare institutions’ procurement behavior, ensuring the provision of needed and cost-effective drugs to patients.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 1. Supplementary Figures and Tables About the Timeline of Policies, Details of the Study Samples, and Results of Descriptive Analysis (Figure S1, Table S1 to S4).\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 2. Supplementary Figures of Subgroup Analysis Results (Figure S2-S7).\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 3. Supplementary Table of the Subgroup Analysis Results for Procurement Price (Table S5).\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl4\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 4. Supplementary Table of the Subgroup Analysis Results for Procurement Volume (Table S6).\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl5\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 5. Supplementary Table of the Subgroup Analysis Results for Procurement Expenditure (Table S7).\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: NVBP, National Volume-Based Procurement; ITS, interrupted time series; DDDs, defined daily doses; DDDc, cost of defined daily dose.</p><p>\n<italic toggle=\"yes\">Note</italic>: 1. NVBP-covered drugs included both the bid-winning and non-winning drugs. 2. Relative change in this table refers to relative change at the sixth month after the intervention.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7724-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7724-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7724-g003\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7724-g004\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7724-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7724-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7724-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7724-s004.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7724-s005.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" World Health Organization. WHO Guideline on Country Pharmaceutical Pricing Policies. 2020. "], "uri": ["https://apps.who.int/iris/bitstream/handle/10665/335692/9789240011878-eng.pdf"]}, {"label": ["3"], "mixed-citation": [" The General Office of the State Council. Notice on Issuing National Centralized Drug Procurement and Using Pilot. 2019. "], "uri": ["http://www.gov.cn/zhengce/content/2019-01/17/content_5358604.htm"]}, {"label": ["4"], "person-group": ["\n"], "surname": ["Yuan", "Lu", "Xiong", "Jiang"], "given-names": ["J", "ZK", "X", "B"], "article-title": ["Lowering drug prices and enhancing pharmaceutical affordability: an analysis of the national volume-based procurement (NVBP) effect in China"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["9"], "fpage": ["e005519"], "pub-id": ["10.1136/bmjgh-2021-005519"]}, {"label": ["5"], "mixed-citation": [" The General Office of the State Council. Opinions on Promoting the Regular and Institutionalized Development of National Centralized Drug Procurement. 2021. "], "uri": ["http://www.gov.cn/zhengce/content/2019-01/17/content_5358604.htm"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Toulemon"], "given-names": ["L"], "article-title": ["The effect of group purchasing on prices hospitals pay for medicines"], "source": ["Health Econ"], "year": ["2018"], "volume": ["27"], "issue": ["9"], "fpage": ["1380"], "lpage": ["1393"], "pub-id": ["10.1002/hec.3788"]}, {"label": ["15"], "mixed-citation": [" Wang J, Yang Y, Xu L, et al. The impact of National Centralized Drug Procurement policy on the use of policy-related original and generic drugs in public medical institutions in China: a difference-in-difference analysis based on national database. medRxiv [Preprint]. June 28, 2021. "], "uri": ["https://www.medrxiv.org/content/10.1101/2021.06.21.21256568v1.full"]}, {"label": ["19"], "mixed-citation": [" Tianjin Bureau of Statistics & Survey Office of National Bureau of Statistics Tianjin. Tianjin Statistical Yearbook 2020. 2020. "], "uri": ["https://stats.tj.gov.cn/nianjian/2020nj/zk/indexch.htm"]}, {"label": ["20"], "mixed-citation": [" National Bureau of Statistics of China. China Statistical Yearbook 2020. 2020. "], "uri": ["http://www.stats.gov.cn/tjsj/ndsj/2020/indexch.htm"]}, {"label": ["21"], "mixed-citation": [" WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2022. 2022. "], "uri": ["https://www.whocc.no/atc_ddd_index/"]}, {"label": ["24"], "person-group": ["\n"], "surname": ["Hategeka", "Ruton", "Karamouzian", "Lynd", "Law"], "given-names": ["C", "H", "M", "LD", "MR"], "article-title": ["Use of interrupted time series methods in the evaluation of health system quality improvement interventions: a methodological systematic review"], "source": ["BMJ Glob Health"], "year": ["2020"], "volume": ["5"], "issue": ["10"], "fpage": ["e003567"], "pub-id": ["10.1136/bmjgh-2020-003567"]}, {"label": ["25"], "person-group": ["\n"], "surname": ["Teixeira Rodrigues", "Roque", "Pi\u00f1eiro-Lamas", "Falc\u00e3o", "Figueiras", "Herdeiro"], "given-names": ["A", "F", "M", "A", "A", "MT"], "article-title": ["Effectiveness of an intervention to improve antibiotic-prescribing behaviour in primary care: a controlled, interrupted time-series study"], "source": ["J AntimicrobChemother"], "year": ["2019"], "volume": ["74"], "issue": ["9"], "fpage": ["2788"], "lpage": ["2796"], "pub-id": ["10.1093/jac/dkz244"]}, {"label": ["29"], "mixed-citation": [" Chinese Society of Hepatology in Chinese Medical Association, Chinese Society of Infectious Diseases in Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B: a 2019 update [Chinese]. Chinese Journal of Liver Disease. 2019;11(4):5-27.\n"], "pub-id": ["10.3969/j.issn.1674-7380.2019.04.002"]}]	{ "acronym": [], "definition": [] }	31	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 20; 12:7724	oa_package/9f/f8/PMC10590231.tar.gz
PMC10590232	0	[]	[]	[]	[]	[]	[ "<p>At its core, political economy analysis involves examination of the relationship between the state and the market. A number of country case studies have emerged in recent years that aim to identify political economy factors facilitating or impeding health sector reforms towards universal coverage. In this commentary, we expand Nannini and colleagues’ analysis to elaborate on how political economy analyses can better inform policy design towards more successful reforms in low- and middle-income countries (LMICs) by drawing more heavily on improved research design and theory. We suggest three ways that political economy studies could make deeper claims by historicizing analyses, going comparative and/or by grounding findings more deeply in theory.</p>", "<p>\n<bold>Citation:</bold> Fox AM. Advancing empirics and theory for a deeper political economy analysis: Comment on \"Health coverage and financial protection in Uganda: a political economy perspective.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7537. doi:10.34172/ijhpm.2023.7537</p>" ]	[ "<p> When and why do countries adopt health financing reforms that ensure that access to health services is based on need rather than ability to pay? Nannini et al<sup>##REF##34634869##1##</sup> undertake a study of the political economy of universal health coverage (UHC) reform in Uganda and find that the current political situation is not yet conducive for implementing a UHC system with widespread financial protection. They identify several challenges specific to the case of Uganda, including the following: (1) Unions oppose payroll deductions from workers’ pay as a financing mechanism; (2) The “pre-payment” mechanism requiring contributions from members contradicts the notion that care should be “free” leading to reduced popularity of the proposed reform; (3) A growing private health sector fears competition between social health insurance and commercial schemes; and (4) Low confidence in government capacity. These are important insights and each are quite consistent with both theoretical expectation and other case studies of health reforms towards UHC in low- and middle-income countries (LMICs).<sup>##UREF##0##2##</sup></p>", "<p> A number of single case-studies of applied political economy analyses such as Nannini and colleagues’ have arisen in recent years in global health that are aimed either at some exercise of prediction (ie, is a country likely to adopt a given reform?) or explanation (ie, why a country did or did not adopt a particular reform at a specific moment?).<sup>##REF##31563946##3##, ####UREF##1##4##, ##REF##34849898##5##, ##REF##35346208##6####35346208##6##</sup> A recent systematic review by Rizvi et al<sup>##REF##31904858##7##</sup> identified at least 55 papers on the political economy of health reform, most of which were individual case studies. These studies have offered useful insights about the particulars of specific cases of reform. However, this commentary argues that the time has come to move beyond description to advance a more rigorous application of empirics and theory in political economy studies of health reform in LMICs to improve our ability to generalize beyond specific cases and make broader claims and applied recommendations.</p>", "<p> Three specific ways that political economy studies of health reform in LMICs could make deeper claims include the following:</p>", "<p>Historicize analyses </p>", "<p>Go comparative </p>", "<p>Test competing theories and/or ground findings more deeply in theory </p>", "<title>Historicize Analyzes</title>", "<p> Historical institutionalism is an approach to political economy analysis that emphasizes how timing, sequences and path dependence affect the development of institutions over the long term and shape future policy paths.<sup>##UREF##2##8##</sup> In other words, by setting countries down a particular path, past policies are one of the strongest predictors of future policies. For instance, in a US context, policies adopted in the 1950s that encouraged the proliferation of private, employer-sponsored health insurance has created expectations about how healthcare should be provided and a powerful industry supporting its continuation as a private good. These types of self-reinforcing trends are known as “policy feedback” effects.<sup>##UREF##3##9##</sup> Research on policy feedback finds that not only does politics shape policy choices, but also that past policy choices shape future politics. This occurs because new policies create constituencies who benefit from a particular policy and whose political consciousness is shaped by their experiences with existing policies and programs. For instance, social security policies that are targeted at older adults bestow particularistic benefits upon this group, which elevates their consciousness and motivation as a powerful political constituency.<sup>##REF##22232420##10##</sup> Likewise, by examining the evolution of health sector reforms over nearly 60 years, Harris and Libardi Maia<sup>##REF##34555293##11##</sup> find that path-dependent processes that entrenched the private sector in Brazil have pushed Brazil and Thailand in divergent reform directions despite a similar effort/interest in building universal coverage. These are the types of insights that can be obtained by historicizing analyses.</p>", "<p> By contrast, recent studies claiming to apply political economy analysis tend to focus largely on the present moment. Nannini et al<sup>##REF##34634869##1##</sup> are no exception, focusing largely on the last two decades. Based on this analysis, they conclude that “the current political situation is not yet conducive for implementing a UHC system with widespread financial protection: dominant interests and ideologies do not create a net incentive to implement a comprehensive scheme for this purpose.” However, an analysis based solely on the present moment, or recent past, begs the question of how this moment compares to those that have come before. Is the present moment especially unconducive when compared against prior moments? Historizing accounts can provide insights into how and why present institutions have evolved in the way they have – and how these institutional arrangements might influence present and future reform prospects. Additionally, political economy theory and empirical analysis suggests that the conditions conducive to reform often emerge and converge rapidly,<sup>##UREF##4##12##</sup> rendering the present moment potentially a poor predictor of future policy openness without additional context over a longer time horizon.</p>", "<p> Though there is no recipe for how long is appropriate to look back, by employing different “periodization” strategies to test the effects of institutional changes or exogenous shocks,<sup>##UREF##5##13##</sup> studies employing political economy analysis can better identify relevant time frames for analysis. For example, by placing their analysis in the historical trajectory of Zimbabwe’s health reforms since the country’s independence in the 1980s, Mhazo and Mapongo<sup>##REF##35346208##6##</sup> find that the political opportunity structures for reform in Zimbabwe have changed in recent decades, with the window for reform shrinking. While Mhazo and Mapongo<sup>##REF##35346208##6##</sup> come to a similar conclusion as Nannini et al,<sup>##REF##34634869##1##</sup> their longer time horizon offers more confidence that this moment is less conducive than those that have come before. Similarly, Nannini et al<sup>##REF##34634869##1##</sup> could have looked to the nature of the National Resistance Movement regime, or previous regimes, in Uganda and what they have meant for Uganda’s health sector over time.</p>", "<p> From a practical perspective, how might historicizing analyses matter? By historicizing key policies, researchers can better identify available pathways for reform and policymakers can avoid policy choices that are likely to create institutional arrangements that will be difficult to diverge from in the future. For instance, Nannini and colleagues’<sup>##REF##34634869##1##</sup> finding that unions oppose payroll deduction from workers’ pay is understandable when cast in light of existing institutional arrangements that have evolved to benefit particular classes of workers – ie, those in the formal sector with union protections. Contestations over fringe benefits are quite common under corporatist arrangements that require tripartite negotiations among labor, state and industry.<sup>##UREF##6##14##</sup> However, in a context of low formal sector employment, rather than this institutional arrangement presenting an opportunity for more comprehensive reform, labor unions representing formal-sector workers may also fear how new national programs might steal funds from or otherwise dilute their own existing state (social security) programs for formal sector workers.<sup>##UREF##0##2##</sup></p>", "<title>Go Comparative</title>", "<p> A second approach to advancing potential lesson drawing is to use small-N case comparisons to draw inferences. Small-N comparative case studies can be powerful tools that can simulate larger N quantitative designs by attempting to reduce “endogeneity” through the process of case selection to isolate major explanatory factors. A well-done comparative case study not only makes the case for a particular causal explanation, but also tries to systematically rule out alternative explanations. Comparative case studies thereby aim to move from description to explanation.<sup>##UREF##7##15##</sup> However, well-done comparative case studies are rare in global health. This is likely due to multiple reasons including the difficulty of identifying appropriate case comparisons, low incentives for researchers to devote the necessary time and resources to develop deep knowledge of multiple cases, the fact that a lot of research arises from short-term consultancies, and lack of training in these methods, among others.</p>", "<p> For instance, Nannini and colleagues’ findings that unionized workers tend to oppose extending national health insurance via mechanisms that would impose a payroll tax could be examined across a larger set of cases to determine whether this is a more generalized source of resistance to insurance-based reform in LMICs or is more specific to Uganda. In fact, recent studies and reviews of literature have tended to find support for the notion that unions will tend to oppose coverage expansions that are financed through payroll taxes that tend to fall heavier on formal sector workers.<sup>##UREF##0##2##</sup> If union opposition is theorized to be a major barrier to reform, cases could be selected to compare countries with different outcomes to examine how opposition from unions was overcome. Or countries could be matched based on their union strength or bargaining mechanisms to assess whether outcomes vary based on this factor. A recent 11-country study of countries at different stages of UHC identified useful lessons for countries moving towards coverage expansions.<sup>##REF##26299185##16##</sup> Another example of a successful comparative case study that simultaneously integrates history and comparative design includes Wong’s book, ‘<italic toggle=\"yes\">Healthy Democracies,</italic>’ which employs a most similar systems design to identify the role that democratization in Taiwan and South Korea played in changing the incentive structures of vote-seeking policymakers in favor of popular social policies – ie, UHC.<sup>##UREF##8##17##</sup> Similarly, in his 2017 book, ‘<italic toggle=\"yes\">Achieving Access,</italic>’ Harris compares efforts to institutionalize universal healthcare and expand access to AIDS drugs in three major industrializing countries: Thailand, Brazil, and South Africa.<sup>##UREF##9##18##</sup> He finds that democratization empowered elite professional associations to advocate for universal healthcare and AIDS treatment. Well formulated comparative designs such as this enhance the internal validity and inferences that can be drawn from small-N studies and follow a similar causal logic to larger-N studies.<sup>##UREF##7##15##</sup></p>", "<p> By going comparative, researchers can seek to answer such questions as where have UHC reforms been successful, where have they failed, and where have they simply not been tried? Which explanations for low agenda status of UHC recur across different settings? Which factors affecting UHC expansions appear to be more general versus case specific? Where has the private sector been successfully kept at bay? What are the roles of regime type, social movements, professional associations or political leadership in UHC expansions?</p>", "<title>Test Competing Theories and/or Ground Findings More Deeply in Theory</title>", "<p> Research on the political economy of health reform in global health tends to be theory-light. Frameworks are frequently developed and applied in a rote manner with hypotheses never clearly specified. Inductive approaches are utilized to examine emergent factors that mattered in a specific case, but broader theories or expectations are rarely formed that could be extended to other cases. Yet, contributions to broader theory is what separates academic research from policy reports that recount events but whose implications fail to extend beyond the particular case at hand. To enhance the generalizability of findings, political economy analyses of health reform can test competing theories or compare case specific elements against expectations derived from theory. Of note, these ‘empirical tests’ need not be quantitative in nature. Rather, they may involve a variety of qualitative approaches, which can help illuminate causal mechanisms.<sup>##UREF##5##13##,##UREF##7##15##</sup></p>", "<p> Political economy studies of health reform that better incorporate theory and more explicitly test different theoretical mechanisms have identified several explanations for when and why major redistributive programs might emerge (see eg, Hall<sup>##UREF##10##19##</sup> for a summary of major explanations). These include interest-based explanations, which suggest that groups or individuals have economic “interests” that undergird their behavior in predictable ways and that individuals/groups will behave in a rational manner to enhance their influence and power.<sup>##UREF##10##19##</sup> Interest-based explanations might predict that countries with a strong private sector and powerful public sector unions might oppose payroll based reforms that would work against their immediate economic interests. Institutions-based explanations do not necessarily dispute interest-based accounts, but note that interests are “structured” or channeled in certain predictable ways by the “institutional” arrangements they confront in different national contexts. For instance, institutions-based explanations might look at how democratization changes the relative power of different interest groups and their ability to influence health reform as a number of studies have.<sup>##UREF##8##17##,##UREF##9##18##</sup> Explanations that emphasize the power of ideas, by contrast, put primacy on the ways that ideas shape policy debates independent of the material interest that undergird them. Ideas-based explanations might look to whether there are influential social movements that frame healthcare as a human right or whether public opinion is strongly supportive of or against specific reforms. Likewise, explanations emphasizing a combination of ideology and organizational strength, such as power-resources theory,<sup>##UREF##6##14##</sup> have suggested that left parties will tend to champion reforms as a consequence of the linkages between left parties and labor unions though recent studies have recognized this may not work the same way in an LMIC context where party ideology does not neatly fit a left-right continuum.<sup>##UREF##0##2##,##UREF##11##20##</sup></p>", "<p> In the absence of theory testing, studies risk concluding that ‘everything matters’ or ‘it depends,’ which may not be very helpful in advancing policy or practice. In the absence of theory testing, what stable recommendations can we make to policy reformers that their proposed reforms will be likely to succeed?</p>", "<p> An example of the successful application of theory to a single case might be Croke et al,<sup>##REF##31563946##3##</sup> who showed that popular opinion against moving from a national health service model to a national health insurance model was a major factor undermining health reform towards UHC in Malaysia. Likewise, Harris<sup>##UREF##0##2##</sup> finds that left leaders in LMICs will tend to oppose insurance-based models, which are seen as more “neoliberal” than health-service based models. These studies support Nannini and colleagues<sup>##REF##34634869##1##</sup> finding that insurance-based reforms in Uganda has been undermined by the notion of “pre-payment” via an earmarked payroll tax, which contradicts the government’s commitment to “free” healthcare. According to Nannini et al, moving to an insurance-based model is seen as both compromising the public popularity of UHC and the political calculus associated with its extension. This finding could be understood as an “ideas”-based explanation, grounded in notions of public opinion and policy responsiveness.</p>", "<p> These approaches to deepening political economy analysis of health reform are not mutually exclusive. Comparative studies may look historically to identify relevant cases or examine change over time within cases. Historical institutional and comparative studies should incorporate theory to develop their hypotheses or “priors” about expectations. These approaches can also help identify whether and how theories developed in high-income country contexts are directly applicable to present-day LMIC contexts or if expectations need to be modified/updated.<sup>##UREF##11##20##</sup></p>", "<p> In summary, the growing number of quality case studies of the political economy of UHC in LMICs is a welcome development. We applaud the growing recognition that health reform is a political and not merely a technical process. However, we believe the breadth of insights derived from political economy studies of UHC in LMICs could be strengthened through attention to improved methodological and theoretical approaches to political economy analysis.</p>", "<title>Acknowledgements</title>", "<p> I would like to thank Dr. Michael Reich for his helpful feedback and suggestions on the Comment as well as the three anonymous reviewers whose input helped improve the final version.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that she has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "person-group": ["\n"], "surname": ["Harris"], "given-names": ["J"], "article-title": ["The politics of expanding healthcare access to the poor and informal sectors"], "source": ["Sociol Forum"], "year": ["2019"], "volume": ["34"], "issue": ["4"], "fpage": ["818"], "lpage": ["837"], "pub-id": ["10.1111/socf.12551"]}, {"label": ["4"], "person-group": ["\n"], "surname": ["Chemouni"], "given-names": ["B"], "article-title": ["The political path to universal health coverage: power, ideas and community-based health insurance in Rwanda"], "source": ["World Dev"], "year": ["2018"], "volume": ["106"], "fpage": ["87"], "lpage": ["98"], "pub-id": ["10.1016/j.worlddev.2018.01.023"]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Thelen"], "given-names": ["K"], "article-title": ["Historical institutionalism in comparative politics"], "source": ["Annu Rev Polit Sci"], "year": ["1999"], "volume": ["2"], "issue": ["1"], "fpage": ["369"], "lpage": ["404"], "pub-id": ["10.1146/annurev.polisci.2.1.369"]}, {"label": ["9"], "mixed-citation": [" Pierson P. Politics in Time: History, Institutions, and Social Analysis. Princeton University Press; 2004. "]}, {"label": ["12"], "mixed-citation": [" Tuohy CH. Accidental Logics: The Dynamics of Change in the Health Care Arena in the United States, Britain, and Canada. Oxford University Press; 1999. "]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Lieberman"], "given-names": ["ES"], "article-title": ["Causal inference in historical institutional analysis: a specification of periodization strategies"], "source": ["Comp Polit Stud"], "year": ["2001"], "volume": ["34"], "issue": ["9"], "fpage": ["1011"], "lpage": ["1035"], "pub-id": ["10.1177/0010414001034009003"]}, {"label": ["14"], "person-group": ["\n"], "surname": ["Korpi"], "given-names": ["W"], "article-title": ["Power resources and employer-centered approaches in explanations of welfare states and varieties of capitalism: protagonists, consenters, and antagonists"], "source": ["World Polit"], "year": ["2006"], "volume": ["58"], "issue": ["2"], "fpage": ["167"], "lpage": ["206"], "pub-id": ["10.1353/wp.2006.0026"]}, {"label": ["15"], "mixed-citation": [" King G, Keohane RO, Verba S. Designing Social Inquiry: Scientific Inference in Qualitative Research. Princeton University Press; 1994. "]}, {"label": ["17"], "mixed-citation": [" Wong J. Healthy Democracies: Welfare Politics in Taiwan and South Korea. Cornell University Press; 2004. "]}, {"label": ["18"], "mixed-citation": [" Harris J. Achieving Access: Professional Movements and the Politics of Health Universalism. Cornell University Press; 2017. "]}, {"label": ["19"], "mixed-citation": [" Hall PA. The role of interests, institutions, and ideas in the comparative political economy of the industrialized nations. In: Lichbach MI, Zuckerman AS. Comparative Politics: Rationality, Culture, and Structure. Cambridge University Press. 1997:174-207. "]}, {"label": ["20"], "person-group": ["\n"], "surname": ["Farber", "Harris"], "given-names": ["R", "J"], "article-title": ["American medical sociology and health problems in the global south"], "source": ["Sociol Perspect"], "year": ["2022"], "volume": ["65"], "issue": ["5"], "fpage": ["848"], "lpage": ["868"], "pub-id": ["10.1177/07311214211067763"]}]	{ "acronym": [], "definition": [] }	20	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 10; 12:7537	oa_package/7a/74/PMC10590232.tar.gz
PMC10590233	0	[ "<title>Introduction</title>", "<p> COVID-19 pandemic has affected everyone, and especially the people with disabilities (PwD). Access to healthcare support for PwD received widespread attention, and related research has been undertaken worldwide, including Europe,<sup>##REF##32383576##1##</sup> the United States,<sup>##UREF##0##2##</sup> China,<sup>##REF##32085843##3##</sup> South Africa,<sup>##REF##32934920##4##</sup> Iran,<sup>##UREF##1##5##</sup> England and Australia,<sup>##REF##33341397##6##</sup> and others.<sup>##REF##32463287##7##,##REF##34246591##8##</sup> Within Australia, the pandemic impaired the implementation of the National Disability Insurance Scheme (NDIS) which allocates funds to eligible participants for purchase of services. During the pandemic, many providers of services withdrew from the market,<sup>##UREF##2##9##</sup> making access to services for the participants difficult while restrictions placed on mobility of the public compounded this problem.<sup>##REF##33362318##10##</sup> These problems were exacerbated by impaired in-person services such as medical consultations,<sup>##REF##34081819##11##</sup> limited access to telehealth services,<sup>##REF##33426739##12##</sup> and insufficient knowledge of the impact of coronavirus young PwD and their families.<sup>##UREF##3##13##</sup></p>", "<p> Learning the impact of such national emergency is important for policy-makers of the Federal Government and the NDIS. While there has been some qualitative research on the effects of the pandemic on PwD,<sup>##REF##33821041##14##</sup> little is known about the magnitude of its impact on PwD’s utilisation of their allocated budget.<sup>##UREF##4##15##</sup> This study analyses data published by the NDIS, together with the COVID-19 data, to explore the impact of the pandemic on NDIS participants’ expenditure and utilisation of funds. To this end, a quasi-experimental approach is used to compare the expenditure of the participants who were in pandemic-affected regions and time periods with those who were not. The results are reported through a range of descriptive statistics, followed by regression analysis to decipher the role of COVID-19 and restriction policies in affecting the participants’ utilisation of funds. Our analysis assists in answering three primary research questions:</p>", "<p>Question 1: What was the quantum of under-expenditure by NDIS participants during the pandemic? </p>", "<p>Question 2: What were the main drivers for the under-utilisation of the funds? </p>", "<p>Question 3: How did these drivers influence the utilisation of funds by the participants? </p>", "<p> New lessons learnt from the analysis includes the lagged effect of the pandemic on expenditure of NDIS participants, as well as the detrimental impact on the utilisation of funds from the restrictions placed on their mobility. All these findings point to potential policy interventions to mitigate some of the adverse consequences of similar nationwide emergencies.</p>" ]	[ "<title>Methods</title>", "<p> We leveraged quantitative methods spanning descriptive and regression analysis to assess the impact of COVID-19 on utilisation of funds allocated to the NDIS participants. The descriptive analysis presented information from national, state-, and regional level by merging NDIS data with COVID-19 data. The regression analysis was then conducted to identify the factors that had driven participants’ utilisation of funds during the pandemic. The overall structure of the research framework is shown in ##FIG##0##Figure 1## where the situation and research questions are presented in the dashed boxes and the actions undertaken enclosed in solid lines. The specific methods are described in detail in the following sections.</p>", "<title> Methods in Descriptive Analysis </title>", "<p> The national level descriptive analysis aims to offer an overview of NDIS participants’ quarterly budget, expenditure, and utilisation rate across time, and present the variance of these figures. By analysing against the spread of the COVID-19 in Australia, this analysis highlighted the impact of the pandemic on the expenditure of funds from the NDIS.</p>", "<p> The state-level analysis compared the expenditure and utilisation rate of NDIS participants between the periods that were affected by the pandemic versus those that were not, and across regions/jurisdictions for the overlapping quarters when infection rates were very different between them. In this analysis, the states of VIC, NSW, and QLD were selected because they have the largest numbers of NDIS participants, experienced the largest numbers of COVID-19 cases, and have the largest population of all six States in Australia.<sup>##UREF##17##36##</sup> Furthermore, QLD and VIC are located on the eastern seaboard flanking NSW. Residents from NSW were able to move freely across the borders (as for the rest of Australia), except for the periods when hard lockdowns were placed during the outbreaks. Based on the comparison, we calculated a counterfactual expenditure for the state that was worst affected by the pandemic compared to its neighbour States. Specifically, we created the counterfactual budget and expenditure curves for the worst impacted State (such as VIC) by averaging the quarterly budget and quarterly expenditure in the other States. Formally, we assumed the ratio between quarterly expenditure and budget in VIC is equal to that in its neighbour States. That is:</p>", "<p> where refers to the counterfactual quarterly expenditure in the absence of the pandemic; <italic toggle=\"yes\">B</italic><sub>VIC</sub> denotes the actual quarterly budget in VIC; <italic toggle=\"yes\">E</italic><sub>Ave</sub> and <italic toggle=\"yes\">B</italic><sub>Ave</sub> are the average of the expenditure in the neighbour states and that of budget respectively; <italic toggle=\"yes\">E</italic><sub>i</sub> and <italic toggle=\"yes\">B</italic><sub>i</sub> refer to the quarterly expenditure and budget in state <italic toggle=\"yes\">i</italic>respectively, and <italic toggle=\"yes\">n</italic> denotes the total number of states. In this way, we can calculate the counterfactual level of quarterly expenditure for VIC using the following equation.</p>", "<p> The difference-in-differences (DID) technique was used in regional level descriptive analysis to estimate the effect of lockdowns by comparing the changes in expenditure over time between the NDIS participants of different characteristics. Specifically, we firstly partitioned the NDIS data of VIC into urban VIC and rural VIC based on the geographic matching between the local government areas and local health districts provided by the VIC Department of Health and Human Services.<sup>##UREF##18##37##</sup> The purpose of this data segmentation is to allow assessment of impact of lockdowns on the level of NDIS participants’ access to services because the urban areas hold deeper markets providing healthcare services compared to the rural areas. In addition, the lockdown policies in urban VIC were more stringent compared to those in rural regions, which provides another factor for comparison. Secondly, these two segments were further divided into four by NDIS participants’ living conditions, ie, whether they are in SIL or in SDA. This segmentation assists in evaluating the impact of lockdowns on the mobility of participants, assuming that participants in SIL hold higher level of mobility than SDA participants in general, and essential healthcare services (such as access to carers) were permitted for both cohorts. Consequently, the NDIS participants in VIC were grouped into four cohorts, including Urban-SIL, Urban-SDA, Rural-SIL and Rural-SDA. A comparison between the changes in the expenditure of these four cohorts during lockdowns shed light on whether the lockdowns impacted participants’ expenditure via impairing their mobility or access to services.</p>", "<title> Methods in Regression Analysis </title>", "<p> Regression analysis was conducted to answer the second and third research questions. Linear regression estimates the probability of an event occurrence by fitting data to linear predictor functions which model the relationship between two or more independent variables and the one dependent variable.<sup>##UREF##19##38##</sup> The linear regression algorithm was chosen because it is one of the classic and well-established machine learning techniques, especially its ability to display the statistical relationship between each of the predictors and the outcome. The general form of the linear regression model is:</p>", "<p> where <italic toggle=\"yes\">X</italic> is the independent variable matrix in size of <italic toggle=\"yes\">m ×</italic> (<italic toggle=\"yes\">n + 1</italic>), assuming a dataset with <italic toggle=\"yes\">m</italic> observations and <italic toggle=\"yes\">n</italic> variables; <italic toggle=\"yes\">Y</italic> is the dependent variable vector of <italic toggle=\"yes\">m × 1</italic>; <italic toggle=\"yes\">ϵ</italic> is the error vector of <italic toggle=\"yes\">m × 1</italic>; and <italic toggle=\"yes\">β</italic> represents the parameter estimate from the ordinary least squares (OLS) regression. In this paper, linear regression was used to estimate the utilisation rate of NDIS participants on the state-level information, where the explanatory variables were drawn from a cross-sectional data created by merging the NDIS, COVID-19, lockdown policy, and State Final Demand (SFD) data. The selection and explanation of variables for the regression model is presented in the Datasets and Pre-processing section. Problem of heteroscedasticity was addressed using weighted least squares method, where the OLS estimate (<italic toggle=\"yes\">β</italic>) was updated to weighted least squares estimate ():</p>", "<p> where <italic toggle=\"yes\">W</italic> is a matrix containing the weights , where represents variance of the errors in the OLS regression. To obtain <italic toggle=\"yes\">σ</italic><sub>i</sub>, we performed another OLS regression using the absolute residuals to estimate a standard deviation function against the fitted values. The resulting fitted values of this regression are used as estimates of <italic toggle=\"yes\">σ</italic><sub>i</sub>.</p>" ]	[ "<title>Results of Descriptive Analysis</title>", "<title> National Level</title>", "<p>\n##FIG##1##Figure 2## shows the quarterly budget, expenditure and gap (in dollars) of the NDIS, as well as the average (Ave) utilisation rate (in percent). The gap here refers to the margin between the budget and expenditure.</p>", "<p> The overall budget allocated to the NDIS participants has increased over time. Similarly, the levels of expenditure by the participants also increased over the 9 quarters. The average utilisation rate increased from 2019/Q3 to the next quarter, held up for the subsequent three quarters, dipped significantly from 2020/Q3 to the nadir of 57% in 2021/Q1 before rebounding over the next quarter. In addition, average utilisation rate is above 59% in Q1, Q2, and Q3 before dropping to a low of 55% in Q1 of 2021. Recall that Australia was affected by the COVID-19 pandemic in Q1, Q2, and Q3 of 2020, and then spent the subsequent three quarters with minimal number of cases detected, followed by another wave from the end of Q2 of 2021. The episodes of the outbreaks are broadly aligned with the variation in the utilisation rate, which suggests that the pandemic may have been responsible for the changes in utilisation rate. However, it also suggests that the pandemic may have caused a carryover effect over the utilisation rate. Factors other than the pandemic may have been in play thus the DID method is used to create counterfactual levels of expenditure in the absence of the COVID-19.</p>", "<title> State Level</title>", "<p>\n##FIG##2##Figure 3## illustrates that the budget of NDIS increased over all quarters in all three states. However, an abnormal drop is noticeable in the expenditure for VIC from the third quarter to the last quarter of 2020. This dip is noticeably absent in NSW and QLD; rather the shapes of their curves are close to being parallel suggesting that utilisation rates are similar across the three jurisdictions. We read the dip in Expenditure for VIC as being the impact of the pandemic. Recall that VIC was affected the most compared to the other states in Q1, Q2 and Q3 of 2020. Especially in 2020/Q3, VIC was responsible for most of the COVID-19 cases in Australia yet there were not many cases in the other States. By comparing the expenditure curves between NSW, QLD, and VIC, we deduce that the pandemic slowed down the rise in spending funds across the nation, indicating the carryover effect of the COVID-19 noted earlier.</p>", "<p> While the state-level expenditure of VIC had barely grown from 2020/Q2 ($67.78 million) to 2021/Q1 ($69.75 million), the corresponding increases for NSW and QLD from $86.35 million to $94.15 million and $64.84 million to $72.95 million, respectively, were significant. Therefore, we use the equation (3) for VIC and found that a margin of $31.2 million between the counterfactual expenditure and the actual expenditure from 2020/Q2 to 2021/Q2 for VIC. In other words, COVID-19 pandemic lowered expenditure for VIC by $31.2 million which is around 8.85% of the total expenditure and 5.51% of the total budget in these quarters.</p>", "<title> Regional Level</title>", "<p>\n##FIG##3##Figure 4## shows the expenditure of the four participants cohorts in VIC during the COVID-19 lockdowns, where the vertical axis measures the sum of expenditure within each cohort. A colour-coded indicator was developed based on the Timeline of Every VIC Lockdown (Dates & Restrictions)<sup>##UREF##22##42##</sup> to associate the quarterly expenditure with the lockdown stringency in urban and rural VIC. Although there were six lockdown episodes imposed in VIC to the end of 2021, only five could be aligned to the available NDIS data due to the limited data availability. Depth of colour denotes the intensity of the restrictions during the lockdowns: darker colour indicates more stringent lockdown restrictions, and lighter colour means less intense restrictions. The intensity is presented based on the semantic description of the lockdown restrictions and the rules included in the restrictions. For instance, Stage 4 lockdown is more stringent than Stage 3; restriction on movement of a maximum 5 km from home is stricter than that of 25 km; and a lockdown with curfews in place is more stringent than otherwise. No colour means there was no restriction.</p>", "<p> Observations can be drawn by associating the lockdown timeline with the quarterly expenditure in ##FIG##3##Figure 4##. Specifically, the intensity of the lockdowns had a bearing on the levels of, and variations in, the expenditure, particularly in terms of the margin of decrease after a strict lockdown. This finding is reflected by comparing between urban and rural VIC: lockdowns in urban and rural areas started at Stage 3 intensity from the beginning of Q2 of 2020 but restrictions in rural regions were gradually relaxed from Q3 while urban VIC was placed under Stage 4 (ie, more stringent) restrictions. Consequently, urban areas that had gone through stringent lockdowns witnessed larger falls in expenditure and utilisation rate compared to rural regions.</p>", "<p> In addition, it is noticeable that the SIL cohorts (Urban-SIL and Rural-SIL) show much larger variance than the other two cohorts in SDA. This means that the pandemic affected expenditure of the SIL (ie, the higher mobility group) participants more than their SDA-counterparts. In addition, recall that urban VIC went through more stringent restrictions compared to rural areas, yet the expenditure of Urban-SDA does not show strong fluctuations across quarters. Note that the Urban-SDA cohort experienced the same lockdown restrictions as the Urban-SIL. If the lockdowns weighed down the expenditure of participants in urban VIC to the same degree via impairing the access to services and participants’ mobility, the cohort of Urban-SDA should have shown a similar variance to the Urban-SIL. This difference leads to the proposition that the decrease in NDIS participants’ expenditure was largely associated with the crimped mobility of people compared to the impaired access to services.</p>" ]	[ "<title>Discussion</title>", "<p> The findings of our descriptive and regression analysis demonstrated the magnitude of the impact of COVID-19 on the utilisation of funds by NDIS participants. A drop in NDIS participants’ expenditure during the pandemic was revealed using data of VIC, and it was evident that the drop was largely associated with limited mobility of people imposed by lockdowns compared to impaired access to services. By analysing the influencing factors, our regression analysis also highlighted that the spread of COVID-19 and policy-induced restrictions had placed joint impact on participants’ utilisation of funds lagged by one quarter.</p>", "<p> It is not surprising that expenditure of the NDIS participants was affected by the COVID-19. Impact of the pandemic to PwD, such as lacking food or basic healthcare services,<sup>##REF##34200979##45##,##UREF##25##46##</sup> has been well-documented.<sup>##UREF##4##15##</sup> This situation may have been prevented since the NDIS budget allocated to the participants increased during the pandemic. The new knowledge contributed to the literature lies in the magnitude of the drop in the expenditure of NDIS participants due to the pandemic. Approximately A$31.2 million were unspent by the participants residing in the state of VIC, which was about 8.85% of the state level total expenditure in five quarters, and the contraction lasted for up to two quarters. These measures provide the NDIS policy-makers with a guidance for budge planning in preparation for nation-wide emergencies of a similar nature in the future. In particular, the carryover effect indicates an estimate for how long it would take for PwD to return to the pre-pandemic levels of spending after a restrictive lockdown policy.</p>", "<p> Another lesson learnt is that the lockdowns in VIC had a bearing on the NDIS participants’ expenditure by crimping their mobility. This result is important for NDIS policy-makers as it points to the need to allow disability assistance in moving to the source of a service, and particularly so when the service itself cannot be brought to the consumer. The case of specialist medical services is a case in point: while such services may be delivered inside a specialist care accommodation, the same may not be possible for individuals living independently. Consequently, the latter group would require assistance with transportation during a lockdown. This aligns with the results of our regression analysis where participants living independently (SIL) and using their budget for daily consumables and transportation (Core support) are more sensitive in adjusting their utilization of budget during the pandemic. This is valuable for policy-makers to consider exclusive policies for PwD, particularly those who have travelling and self-supporting (including family support) capacity, when stringent lockdown is necessary to deal with national or state-level crisis. Without this special consideration, the risk of deteriorating health conditions for PwD, particularly those relying on regular consumables, therapies, and movement, will increase.<sup>##UREF##26##47##</sup></p>", "<p> Furthermore, our regression analysis revealed the statistical significance and impact of the broad policy-induced restrictions on the utilisation rate of the NDIS participants lagged by one quarter. Stringent lockdowns, together with the prevailing COVID-19 situation (such as increasing number of infected and hospitalised cases), had a strong impact on the lagged response of utilisation rate. Overall, the NDIS participants spent more of their budget when facing stringent indoor restrictions. This aligns with the findings of existing literature that PwD needs extra daily goods, medication, and increased expenditure associated with COVID-19 (such as antiseptic products, face masks and rapid tests) when they can only rely on limited visits during the pandemic.<sup>##REF##34200979##45##,##REF##32746851##48##</sup> New knowledge discovered was that the utilisation rate in the subsequent quarter was negatively impacted by stringent restrictions on outdoor gathering and interstate travelling. This result provides support to the “saving-up” hypothesis which posit that PwD would plan to spend less of their allocated budget on unnecessary purchases when anticipating tough times to come.<sup>##UREF##27##49##,##REF##32904300##50##</sup></p>" ]	[ "<title>Conclusion</title>", "<p> There is consensus in the literature that COVID-19 has adversely affected PwD in a range of aspects. The data published by the NDIS provides the opportunity to explore the impact of the pandemic on the scheme participants’ utilisation of funds. We overlay the NDIS data on episodes of the COVID-19 outbreaks to quantify the impact of the outbreaks on expenditure and utilisation rate of the funds allocated to the NDIS participants during the pandemic.</p>", "<p> The quarterly scheme of NDIS data was aligned with the COVID-19 outbreaks, including the periods when lockdowns were imposed. A DID method was employed to calculate the impact of the pandemic on the levels of spending of the NDIS participants. Differences between jurisdictions within Australia that were severely affected by the outbreaks compared to those who were not, that across regions within VIC, and over time were compared to create the counterfactual levels of expenditure in the absence of COVID-19. These estimates were based on available data on utilisation of the funds allocated to the individual participants — 103 030 in total records. An initial estimate revealed that the pandemic was accompanied by a drop in expenditure of approximately 9%, relative to what would have been expected in the absence of COVID-19, and such drop in expenditure lasted up to two quarters after each outbreak. In addition, we investigated the potential causes for the drop in expenditure and found that the limited mobility imposed through policies was a key reason. A follow-up regression analysis confirmed the impact of COVID-19 and policy-induced restrictions on the budget utilisation rate of the NDIS participants lagged by one quarter.</p>", "<p> These findings are of relevance to contemporary policy-making. First, PwD have been adversely affected by the COVID-19 pandemic — a result that is of little surprise, but the magnitude of this impact as presented here is new to the literature. Second, restricting mobility can be as harmful as the pandemic itself in terms of access to services by PwD. Consequently, management plans that factor in the limited mobility of PwD during disasters can ameliorate some of the difficulties faced by a vulnerable group in the community.</p>", "<p> Finally, while we have taken utmost care in estimating the impact of COVID-19 pandemic on expenditure by NDIS participants, our analysis is far from being definitive. The quantitative estimates of ours using large data sets can be complemented with detailed and individual level surveys of NDIS participants to gain their perspective on the extent to which COVID-19 affected them. Therefore, a follow-up qualitative study would be beneficial by comparing expenditure of the participants and other cohorts, meanwhile investigating their experiences on the impact of the lockdowns on their expenditure plans. Future qualitative research can also compare the experiences of NDIS participants who live dependently and independently, have gone through tight and loose lockdown policies.</p>" ]	[ "<p>\n<bold>Background:</bold> COVID-19 pandemic has affected everyone, especially people with disabilities (PwD). While there has been qualitative research on the impact of the pandemic on PwD in Australia, little quantitative evidence has been produced on the magnitude of this impact.\n</p>", "<p><bold>Methods:</bold> A range of descriptive analytic methods are employed on the data merged from the National Disability Insurance Scheme (NDIS) and COVID-19 data on national, state, and regional levels to compare the expenditure of the NDIS participants who are in pandemic-affected regions and time periods with those that are not. Regression analysis is also performed to estimate the participants’ utilisation of funds using explanatory variables drawn from the NDIS, COVID-19, and lockdown policy information.\n</p>", "<p><bold>Results:</bold> Our analysis reveals that: (1) the pandemic reduced expenditure of the NDIS participants by approximately A$ 31.2 million, equal to 8.85% of the total expenditure over five quarters for the state of Victoria (VIC) alone; (2) the contractions in expenditure lasted for up to two quarters during the pandemic; (3) the reductions in expenditure were largely associated with the limited mobility imposed via lockdowns compared to the impaired access to services; and (4) the spread of COVID-19 that led to restrictions on mobility of people had a bearing on utilisation of funds by NDIS participants in the subsequent quarter.\n</p>", "<p><bold>Conclusion:</bold> COVID-19 has affected the expenditure of the PwD in Australia. We overlaid the NDIS data on the COVID-19 outbreaks to estimate the impact of the pandemic on expenditure and utilisation rate of the funds allocated to the NDIS participants. Our findings point to potential policy interventions to mitigate some of the adverse consequences of similar nationwide emergencies.</p>", "<p>\n<bold>Citation:</bold> Zhang Y, Chand S. Impact of COVID-19 on utilisation of funds by people with disabilities: lessons drawn from the Australian National Disability Insurance Scheme. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7663. doi:10.34172/ijhpm.2023.7663</p>" ]	[ "<title>Background</title>", "<title> Australian National Disability Insurance Scheme</title>", "<p> The Australian NDIS was designed to shift Australian disability services from government block-funding model to personalised insurance model, resulting in both an increase in the quantum of funds made available and greater choice and control over services accessed by participants of the NDIS.<sup>##UREF##5##16##</sup> Similar personalised insurance scheme is also employed in other countries, such as the National Health Service in the United Kingdom,<sup>##UREF##6##17##</sup> Social Security Disability Insurance in the United States,<sup>##REF##34366496##18##</sup> and Disability Insurance program in the Netherlands.<sup>##REF##30366230##19##</sup></p>", "<p> The NDIS is jointly funded by Australian Commonwealth and State and Territory Governments, with its implementation commenced in 2013.<sup>##UREF##7##20##</sup> It has more than 500 000 participants covered with an annual budget of A$35.8 billion for 2022-2023.<sup>##UREF##8##21##</sup> Through NDIS, eligible PwD develop plans based on their individual situation and specific needs, and receive a budget with which to purchase services and supports required to meet their needs and achieve plan goals. A wide range of disability types are covered by the scheme, including disabilities from birth as well as those due to disease, injury or accident. Participants of the scheme have two options in terms of their living arrangements, namely supported independent living (SIL) and specialist disability accommodation (SDA). Participants in SIL can choose to live independently while those in SDA usually require extensive in-house support. All participants are afforded three types of support with funding allocated for core services, capacity building, and capital investments.<sup>##UREF##9##22##</sup> Since initiation, the NDIS has made significant progress in improving access to the services and support for the participants,<sup>##UREF##10##23##</sup> however the implementation of the scheme was impaired by the COVID-19 pandemic.</p>", "<title> COVID-19 in Australia and Responses</title>", "<p> The first outbreak of COVID-19 in Australia was recorded in March 2020, with cases reported in Sydney and Melbourne. By June 2020, the state of Victoria (VIC) saw the second wave where most of the cases were locally acquired. During this outbreak, infections were reported within aged care facilities and among PwD and healthcare workers.<sup>##REF##32855153##24##,##UREF##11##25##</sup> Starting from late June 2021, Australia saw the third wave of infections, with the source of transmission being in the state of New South Wales (NSW). The infections spread to VIC in early August and reached Queensland (QLD) by October. The number of confirmed cases climbed quickly, surpassing that from the previous outbreaks by September 2021 even though vaccinations were largely applied. Meanwhile, outbreaks within aged care facilities and among staff employed there increased in both NSW and VIC.<sup>##REF##34866321##26##</sup></p>", "<p> In response, individual State and Territory governments put in place policies and procedures to contain the spread of the infections. New regulations were introduced after the second outbreak through a revised management plan to protect PwD. In July 2020, the National Disability Services urged all disability service providers to adopt the advice of the Department of Health and Human Services on infection control, including wearing of face masks in workplaces. In August, new COVID-19 infection control procedures were developed to prevent disability workers from spreading the virus in multiple disability facilities and individual homes.<sup>##UREF##12##27##</sup> Within the NDIS, service providers were encouraged to create their own plans in response to the pandemic.<sup>##REF##33341397##6##</sup> Consequently, most service providers cutback on their operations with the last few suspending their operations altogether at the height of the pandemic.<sup>##UREF##13##28##</sup> This then led to severe shortages of some services, lengthening waiting lists for the curtailed services.</p>", "<p> Protocols of test, isolate, and treatment were employed extensively to contain the spread of COVID-19 virus. Additionally, intermittent lockdowns were placed, restricting the mobility of people in regions where the outbreaks were severe. For instance, VIC Government introduced unprecedented public restrictions in June 2020 including impositions of multiple periods of lockdowns limiting movement of the residents within set geography and travel times. These impositions curtailed the spread of the virus but also disrupted access to services for the PwD. Later in July and August, VIC ratcheted up the restrictions by imposing curfews, closed schools and most retail outlets, and allowed movement just for essential work and exercise.</p>", "<title> Impact of COVID-19 on People With Disabilities</title>", "<p> Existing literature has reported the impact of COVID-19 on the PwD. The Center for Disease Control and Prevention, for example, analysed impact of COVID-19 infections and revealed that older adults, racial and ethnic minority groups, and those with underlying chronic health conditions were severely impacted compared to the rest of the population.<sup>##REF##32379729##29##</sup> These findings are aligned with previous research outcome which showed that people with underlying neurological conditions were at a higher risk of dying from seasonal influenza and other respiratory-based diseases.<sup>##REF##22931899##30##</sup> In addition, a recent analysis of national mortality data for deaths attributed to pneumonia prior to the COVID-19 outbreak indicated a 2 to 6 times higher death rate due to pneumonia among people with intellectual and developmental disabilities compared to those without these disabilities.<sup>##UREF##14##31##</sup> Similarly, a comparative analysis between rural and urban areas in the United States revealed that pandemic growth in rural areas was mostly driven by outbreaks within institutional settings such as prisons, meat and poultry processing plants, and nursing homes while those in urban areas were more widespread.<sup>##REF##33328335##32##</sup></p>", "<p> Little is known on the magnitude of impact of COVID-19 on PwD in Australia. Researchers have relied on targeted surveys to collect information on the experiences of students with disabilities during COVID-19,<sup>##UREF##15##33##</sup> satisfaction of the NDIS participants with the services and supports provided during the pandemic,<sup>##UREF##2##9##</sup> experiences with remotely delivered NDIS consultations,<sup>##UREF##16##34##</sup> COVID-19 outbreaks among PwD living in residential care facilities,<sup>##REF##34866321##26##</sup> and implied risk of severe health outcomes within PwD given their higher rates of chronic morbidities.<sup>##REF##32298251##35##</sup> However, none of the existing studies produces quantitative estimates of the impact of COVID-19 on the expenditure of PwD.</p>", "<p> Knowing the impact of COVID-19 pandemic is important for policy-making. The magnitude of such an impact has a direct bearing on the Federal Budget given the size of the outlay. Demonstrating the decreased spending of PwD can indicate that they were unable to purchase the services and supports they needed during the pandemic, pointing to market failure and unmet need for support among PwD. This can advise policies to reduce poverty during the pandemic and expedite recovery in the aftermath.<sup>##UREF##4##15##</sup> In addition, an understanding of the factors that drove expenditure of NDIS participants can provide insights to policy-makers of the NDIS on the trade-off between broad benefits and risks of potential side effects. Therefore, this study aims to explore impact of the COVID-19 on the NDIS participants’ expenditure and utilisation of funds using data as evidence.</p>", "<title>Datasets and Pre-processing</title>", "<title> National Disability Insurance Scheme Data</title>", "<p> The NDIS data has been published quarterly from June 2019 on the official NDIS website.<sup>##UREF##20##39##</sup> In this study, data of 9 quarters was used, that is, from the third quarter of 2019 to the third quarter of 2021. There are 103 030 observations after removing duplicate records. The attributes used for analysis contain:</p>", "<p>Quarter: Quarter of the data record. </p>", "<p>State: Australian State or Territory where the participant resides. </p>", "<p>Region: Service district where the participant resides. </p>", "<p>SIL or SDA (<italic toggle=\"yes\">SoS</italic>): Whether the participant is in Supported Independent Living (<italic toggle=\"yes\">SIL</italic>) or in Specialist Disability Accommodation (<italic toggle=\"yes\">SDA</italic>). Note that the participants are either in SIL or SDA. </p>", "<p>Support class (<italic toggle=\"yes\">Sup</italic>): The support classes under which the recorded participant receives funds, including Core (<italic toggle=\"yes\">Cor</italic>), Capacity Building (<italic toggle=\"yes\">Cab</italic>), and Capital (<italic toggle=\"yes\">Cap</italic>) support. </p>", "<p>Age band (<italic toggle=\"yes\">Ag</italic>): The range of age where the recorded participant is at. The original 9 age bands were collated into three categories: <italic toggle=\"yes\">Ag</italic> ≤ 18, <italic toggle=\"yes\">Ag</italic> (19-54], and <italic toggle=\"yes\">Ag</italic> > 54. </p>", "<p>Participant count (<italic toggle=\"yes\">Pc</italic>): number of participants in the service district. </p>", "<p>Budget (<italic toggle=\"yes\">Bu</italic>): Amount of funds in dollars approved for the participant’s plan in the recorded quarter. </p>", "<p>Utilisation rate (<italic toggle=\"yes\">Ur</italic>): Percentage of funds that the participant has used in the recorded quarter. </p>", "<p> The first six attributes contain categorical values whereas the last three are numerical. Expenditure of NDIS participants (<italic toggle=\"yes\">Exp</italic>) was generated by multiplying the <italic toggle=\"yes\">Bu</italic> and <italic toggle=\"yes\">Ur</italic>.</p>", "<title> COVID-19 Entry Data and Policy-Induced Restriction Data</title>", "<p> To assess the impact of the COVID-19 on expenditure of the NDIS participants, the NDIS data was merged with COVID-19 related data. This includes (1) COVID-19 entry data that was aggregated by Covid19data.com.au and downloaded via a GitHub repository,<sup>##UREF##21##40##</sup> and (2) policy-induced restriction data (referred to as policy data hereafter).</p>", "<p> As for the COVID-19 entry data, we collated two explanatory variables, namely number of daily confirmed cases (<italic toggle=\"yes\">CC</italic>) and cases in hospital (<italic toggle=\"yes\">CH</italic>) in quarters to align with the quarterly format of the NDIS data.</p>", "<p> In addition, data on the restrictiveness of policies was collected from two sources, namely restriction policies released by the NSW, VIC, and QLD government websites and the Oxford COVID-19 Government Response Tracker (OxCGRT) via a GitHub repository.<sup>##REF##33686204##41##</sup> These restrictions reflect the stringency of the pandemic-induced regulations, which were later considered as factors that drove the utilisation of funds by NDIS participants.</p>", "<p> To collate explanatory variables from the policy data of state government websites, we manually reviewed all the published policy updates and retrieved the specific content in every update regarding two key restrictions during the pandemic:</p>", "<p>Indoor gathering limit (<italic toggle=\"yes\">L</italic><sub>in</sub>): The maximum number of individuals who were allowed to gather indoor. </p>", "<p>Outdoor gathering limit (<italic toggle=\"yes\">L</italic><sub>out</sub>): The maximum number of individuals who were allowed to gather outdoor. </p>", "<p> We converted the numerical values specified in the restrictions into categorical variables based on pre-defined criteria. Specifically, we firstly defined an average restriction value for quarterly restriction based on the following equation:</p>", "<p> where <italic toggle=\"yes\">Rst</italic><sub>q</sub> refers to the average restriction in quarter <italic toggle=\"yes\">q</italic>, <italic toggle=\"yes\">Rst</italic><sub>i</sub> denotes the restriction in period <italic toggle=\"yes\">i</italic>, <italic toggle=\"yes\">D</italic><sub>i</sub> is the number of days in the period <italic toggle=\"yes\">i</italic>, and <italic toggle=\"yes\">n</italic><sub>q</sub> means the number of time periods in quarter <italic toggle=\"yes\">q</italic>. For instance, assume Q1 restricted indoor gatherings to a maximum of 2 people per day for 50 days, 5 people for 30 days, and 10 for 10 days, then the average restriction value for Q1, <italic toggle=\"yes\">Rst</italic><sub>Q1</sub> = (50 × 2 + 30 × 5 + 10 × 10)/90 = 3.89 visitors per day. Subsequently, we defined criteria to convert the <italic toggle=\"yes\">Rst</italic><sub>q</sub> into categorical format:</p>", "<p>For indoor gathering limit, we defined three categories, namely, maximum 10 people can gather and “no gathering is allowed” (<italic toggle=\"yes\">L</italic><sub>in</sub> ≤ 10); limits from 10 to 20 people (<italic toggle=\"yes\">L</italic><sub>in</sub> (10, 20]); and limits above 20 people, including “no limit for indoor gatherings” (<italic toggle=\"yes\">L</italic><sub>in</sub> > 20). </p>", "<p>For outdoor gathering limit, we defined three categories, namely, maximum 20 people can gather and “no gathering is allowed” (<italic toggle=\"yes\">L</italic><sub>out</sub> ≤ 20); limits from 20 to 100 people (<italic toggle=\"yes\">L</italic><sub>out</sub> (20, 100]); and limits above 100 people including “no limit for outdoor gatherings” (<italic toggle=\"yes\">L</italic><sub>out</sub> > 100). </p>", "<p> Furthermore, we used a stringency index from the OxCGRT as another variable for restriction:</p>", "<p>Restrictions on internal movement (<italic toggle=\"yes\">L</italic><sub>mov</sub>): Record restrictions on internal movement between cities/regions. The index <italic toggle=\"yes\">L</italic><sub>mov</sub> is a categorical variable where three categories are recorded, namely Class 1, 2, and 3, representing different level of restriction stringency, where Class 3 is the most stringent. </p>", "<p> Note that the reason for selecting only <italic toggle=\"yes\">L</italic><sub>mov</sub> from the OxCGRT is due to the focus of this study and to reduce bias by human factor. Specifically, since this study aims to explore the impact of restriction policies on the spending of the NDIS participants, those OxCGRT indices that are not related to restrictions are excluded. In addition, the OxCGRT collated restriction policies across a wide range of countries, hence the same spectrum of restrictions was applied to all the countries even though some restrictions were not imposed in Australia, such as the OxCGRT index “C5M_Close public transport.” As a result, some indices were deduced by human interpretation using the same policy. For instance, the “C1M_School closing” and “C2M_Workplace closing” indices were often deduced from the same policy which did not specify whether schools or workplaces must be shut down. We also found high correlation between <italic toggle=\"yes\">L</italic><sub>in</sub> and “C3M_Cancel public events,” and between <italic toggle=\"yes\">L</italic><sub>out</sub> and “C4M_Restrictions on gatherings.” Therefore, this study only used restriction indices including <italic toggle=\"yes\">L</italic><sub>in</sub>, <italic toggle=\"yes\">L</italic><sub>out</sub>, and <italic toggle=\"yes\">L</italic><sub>mov</sub> which were all specifically stated in the polices.</p>", "<title> Merged Data and Pre-Processing</title>", "<p> The COVID-19 entry data and policy data were merged to the NDIS data using time (Quarter) and location (State and Territory) as key attributes. In addition, the quarterly Australian SFD information was also integrated. It indicates the total value of goods and services that are traded in a state by end-consumers for consumption or investment. It was included as an explanatory variable (<italic toggle=\"yes\">SFD</italic>) to test whether the state-level economic activity had an influence on the utilisation rate of the NDIS participants. While the budget funded to the NDIS is a small part of SFD, the Pearson correlation coefficient between <italic toggle=\"yes\">Ur</italic> and <italic toggle=\"yes\">SFD</italic> is low (coefficient of -0.002) thus reducing the possibility of reverse causation.</p>", "<p> In the descriptive analysis, the NDIS participants’ budget, utilisation rate and expenditure on the total 103 030 observations in three jurisdiction levels and across time were presented. This allows for segmentation of the data into subgroups for comparisons.</p>", "<p> In addition, the regression analysis used 11 attributes (<italic toggle=\"yes\">SoS, Ag, Sup, Pc, CC, CH, L</italic><sub>in</sub>, <italic toggle=\"yes\">L</italic><sub>out</sub>, <italic toggle=\"yes\">L</italic><sub>mov</sub>, and SFD) as explanatory variables to estimate the participants’ utilisation rate (<italic toggle=\"yes\">Ur</italic>). Four steps of pre-processing were conducted to prepare for the analysis:</p>", "<p>Aggregation: The overall data was aggregated by state, quarter, and the categorical NDIS variables (<italic toggle=\"yes\">SoS, Ag, </italic>and<italic toggle=\"yes\"> Sup</italic>). The <italic toggle=\"yes\">Pc</italic> was averaged, the <italic toggle=\"yes\">CC</italic> and <italic toggle=\"yes\">CH</italic> were summarized during the aggregation, and the remaining variables were joined. Meanwhile the three categorical variables were dummy coded. A total of 315 observations were generated after aggregation. </p>", "<p>Normalisation: The <italic toggle=\"yes\">Pc</italic> in each observation was divided by the state-level total participant count, making it <italic toggle=\"yes\">Pc</italic><sub>r</sub>. The <italic toggle=\"yes\">CC</italic> and <italic toggle=\"yes\">CH</italic> were converted to relative perspective by diving the state-level population, making them <italic toggle=\"yes\">CC</italic><sub>r</sub> and <italic toggle=\"yes\">CH</italic><sub>r</sub>. </p>", "<p>Transformation: The response variable (<italic toggle=\"yes\">Ur</italic>) was logarithm transformed into <italic toggle=\"yes\">log</italic>(<italic toggle=\"yes\">Ur</italic>), meanwhile quantile transformation was performed on <italic toggle=\"yes\">Pc</italic><sub>r</sub>, <italic toggle=\"yes\">CC</italic><sub>r</sub>,<italic toggle=\"yes\"> and CH</italic><sub>r</sub>, making them <italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">Pcr</italic>), <italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">CCr</italic>), and <italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">CHr</italic>). </p>", "<p>Correlation and collinearity tests: Pearson correlation and variance inflation factor measures were employed on the explanatory variables, and the results of the tests are listed in Table S1 at ##SUPPL##0##Supplementary file 1##. </p>", "<title>Results of Regression Analysis</title>", "<p> Regression analysis was performed on the merged data after pre-processing. In addition, we regressed the lagged response variable (by one quarter) using the same explanatory variables since a potential carryover effect was demonstrated in the descriptive analysis. Note that only the COVID-19 data and policy data were lagged by one quarter to estimate the utilisation rate of next quarter.</p>", "<p> The coefficients and related statistics of both regression results are reported in Table. The variables are grouped by the datasets from where they were collected. For instance, variables from 1 to 3 are from the policy data; variable 4 and 5 are from the COVID-19 data; and variables 6 to 9 belong to the COVID-19 data.</p>", "<p> We discuss our findings from the regression analysis next:</p>", "<p>The lagged model fits the data better, suggesting that the effects of COVID-19 extended for a quarter. Besides, the Breusch–Pagan test indicates that the second model is appropriate. In addition, the <italic toggle=\"yes\">P</italic> values of the restriction variables in the regression on lagged response are all statistically significant at 0.05 level, whereas those on the unlagged response are not significant. These statistics point to a one-quarter carryover effect of the pandemic and restrictions on the NDIS participants’ utilisation of their budget. </p>", "<p>Focusing on the regressing results on the lagged response, we find that the stringent indoor restriction during lockdowns has a negative impact on the participants’ utilisation rate in the subsequent quarter. In contrast, the strict outdoor and interstate travel polices show a positive impact. This finding suggests that when visiting homes is restricted, the participants tend to use less of their budget in the subsequent quarter. Regarding the outdoor activity and interstate travel restrictions, the participants are estimated to plan for higher expenditure if they have more freedom in the next quarter for outdoor gathering and traveling. In addition, the quarterly confirmed cases is estimated to have a positive impact on the next quarter utilisation rate, whereas the hospitalised cases shows a negative impact, with a relatively smaller coefficient indicating its weak impact on the utilisation rate. </p>", "<p>Among the variables from NDIS data, the variables of core services (support for daily living activities) used by participants and independently living (SIL) condition have shown strong positive impact to the utilisation rate. This suggests that the participants with higher mobility and spending their budget on daily necessities (such as consumables and transportation) increased their utilisation during the pandemic. In contrast, those living in specialist accommodation and relying on the budget for higher-cost assistance (such as home modification) or capacity building (such as finding a job) were prone to reduce their utilisation in this period. This corroborates the claim that mobility of the participants matters for their utilisation. Only the young age is not statistically significant, which may be the result of data aggregation distributing the participants in different age bands evenly across states and quarters. Finally, the SFD is not statistically significant suggesting that the broad measure of demand in the jurisdiction had negligible impact on the NDIS participants utilisation of budget. </p>", "<title>Ethical issues</title>", "<p> The authors declare that the data used in this research is secondary data and thus not involving any ethical issues.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nResearch Framework. Abbreviations: NDIS, National Disability Insurance Scheme; VIC, Victoria; NSW, New South Wales; QLD, Queensland; DID, difference-in-differences; SFD, State Final Demand.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nNational Level Quarterly Budget, Expenditure and Gap as Shown by the Bar Chart, and Average Utilisation Rate as Shown by the Line Chart.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nComparison Between the Quarterly Budget and Expenditure in New South Wales, Queensland, and Victoria. Abbreviations: VIC, Victoria; NSW, New South Wales; QLD, Queensland.</p></statement></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4</label><statement><p>\nQuarterly Expenditure of the Four Participant Cohorts Grouped by Urban/Rural and SIL/SDA Associated With Lockdown Stringency. Abbreviations: SIL, supported independent living; SDA, specialist disability accommodation.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table</label><caption><title>The Coefficients and Related Statistic Report of the Variables in Regressing the Average Utilisation Unlagged and Lagged by One Quarter\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>ID</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Variables</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Coefficient</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Standard Error</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>t-Statistic</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P </bold>\n</italic>\n<bold>Value</bold>\n</td></tr><tr><td colspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Unlagged Results</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">L</italic>\n<sub>in</sub> ≤ 10</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">-0.1280</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.118</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">-1.083</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.280</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">L</italic>\n<sub>out</sub> ≤ 20</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.0534</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.117</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.457</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.648</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">L</italic>\n<sub>mov</sub> = Class3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.0189</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.056</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.334</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.739</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">CC</italic><sub>r</sub>)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.0507</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.011</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.491</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">CH</italic><sub>r</sub>)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.0081</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.007</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-1.097</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.273</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Sup = Cor</italic>\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.0928</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.053</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">20.722</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">SoS = SIL</italic>\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.6726</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.084</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7.992</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Ag</italic> ≤ 18</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.0856</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.089</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.965</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.335</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">Pc</italic><sub>r</sub>)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.2082</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.034</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6.111</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">SFD</italic>\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.0367</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.017</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-2.098</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.037</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">(intercept)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-0.6216</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.059</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-10.511</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr><td colspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Lagged Results (By One Quarter)</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">L</italic>\n<sup></sup>\n<sub>in</sub> ≤ 10</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.2829</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.114</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">2.475</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.014</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">L</italic>\n<sup></sup>\n<sub>out</sub> ≤ 20</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.2273</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.056</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-4.074</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">L</italic>\n<sup></sup>\n<sub>mov</sub> = Class3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.1503</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.053</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-2.832</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.005</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">CC</italic><sup></sup><sub>r</sub>)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.2126</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.042</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5.052</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">CH</italic><sup>*</sup><sub>r</sub>)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.0317</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.010</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-3.132</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.002</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Sup = Cor</italic>\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.4967</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.029</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">51.562</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">SoS = SIL</italic>\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.7235</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.089</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8.108</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Ag</italic> ≤ 18</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.0718</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.091</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.786</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.433</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Q</italic>(<italic toggle=\"yes\">Pc</italic><sub>r</sub>)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.1882</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.034</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5.462</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.000</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">SFD</italic>\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.0119</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.014</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.847</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.398</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">(intercept)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-0.6280</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.064</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-9.808</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">.000</td></tr></tbody></table></table-wrap>" ]	[ "<disp-formula id=\"DF1\">\n<label>(1)</label>\n<mml:math id=\"m1\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>E</mml:mi><mml:mrow><mml:mi>V</mml:mi><mml:mi>I</mml:mi><mml:mi>C</mml:mi></mml:mrow><mml:mo></mml:mo></mml:msubsup></mml:mrow><mml:mrow><mml:msub><mml:mi>B</mml:mi><mml:mrow><mml:mi>V</mml:mi><mml:mi>I</mml:mi><mml:mi>C</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfrac><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mi>E</mml:mi><mml:mrow><mml:mi>A</mml:mi><mml:mi>v</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>B</mml:mi><mml:mrow><mml:mi>A</mml:mi><mml:mi>v</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfrac></mml:mrow></mml:math>\n</disp-formula>", "<disp-formula id=\"DF2\">\n<label>(2)</label>\n<mml:math id=\"m2\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:msub><mml:mi>E</mml:mi><mml:mrow><mml:mi>A</mml:mi><mml:mi>v</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mstyle displaystyle=\"true\"><mml:mo>∑</mml:mo><mml:mrow><mml:msub><mml:mrow/><mml:mrow><mml:mi>i</mml:mi><mml:mo>∈</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mi>E</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow></mml:mstyle></mml:mrow><mml:mi>n</mml:mi></mml:mfrac><mml:mo>,</mml:mo><mml:mtext> </mml:mtext><mml:msub><mml:mi>B</mml:mi><mml:mrow><mml:mi>A</mml:mi><mml:mi>v</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mstyle displaystyle=\"true\"><mml:mo>∑</mml:mo><mml:mrow><mml:msub><mml:mrow/><mml:mrow><mml:mi>i</mml:mi><mml:mo>∈</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mi>B</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow></mml:mstyle></mml:mrow><mml:mi>n</mml:mi></mml:mfrac></mml:mrow></mml:math>\n</disp-formula>", "<inline-formula id=\"DF7\">\n<mml:math id=\"m7\" display=\"inline\" overflow=\"scroll\"><mml:mrow><mml:msubsup><mml:mi>E</mml:mi><mml:mrow><mml:mi>V</mml:mi><mml:mi>I</mml:mi><mml:mi>C</mml:mi></mml:mrow><mml:mo></mml:mo></mml:msubsup></mml:mrow></mml:math>\n</inline-formula>", "<disp-formula id=\"DF3\">\n<label>(3)</label>\n<mml:math id=\"m3\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:msub><mml:mi>E</mml:mi><mml:mrow><mml:mi>V</mml:mi><mml:mi>I</mml:mi><mml:mi>C</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>B</mml:mi><mml:mrow><mml:mi>V</mml:mi><mml:mi>I</mml:mi><mml:mi>C</mml:mi></mml:mrow></mml:msub><mml:mo>.</mml:mo><mml:mstyle displaystyle=\"true\"><mml:mo>∑</mml:mo><mml:mrow><mml:msub><mml:mrow/><mml:mrow><mml:mi>i</mml:mi><mml:mo>∈</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msub><mml:mi>E</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>B</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow></mml:mfrac></mml:mrow></mml:mstyle></mml:mrow></mml:math>\n</disp-formula>", "<disp-formula id=\"DF4\">\n<label>(4)</label>\n<mml:math id=\"m4\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mi>Y</mml:mi><mml:mo>=</mml:mo><mml:mi>X</mml:mi><mml:mo>.</mml:mo><mml:mi>β</mml:mi><mml:mo>+</mml:mo><mml:mi>ϵ</mml:mi></mml:mrow></mml:math>\n</disp-formula>", "<inline-formula id=\"DF8\">\n<mml:math id=\"m8\" display=\"inline\" overflow=\"scroll\"><mml:mover accent=\"true\"><mml:mi>β</mml:mi><mml:mo>^</mml:mo></mml:mover></mml:math>\n</inline-formula>", "<disp-formula id=\"DF5\">\n<label>(5)</label>\n<mml:math id=\"m5\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mover accent=\"true\"><mml:mi>β</mml:mi><mml:mo>^</mml:mo></mml:mover><mml:mo>=</mml:mo><mml:mi>arg</mml:mi><mml:mtext> </mml:mtext><mml:munder><mml:mrow><mml:mi>min</mml:mi></mml:mrow><mml:mi>β</mml:mi></mml:munder><mml:mstyle displaystyle=\"true\"><mml:msubsup><mml:mo>∑</mml:mo><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mi>n</mml:mi></mml:msubsup><mml:mrow><mml:msubsup><mml:mi>ϵ</mml:mi><mml:mi>i</mml:mi><mml:mrow><mml:msup><mml:mo>*</mml:mo><mml:mn>2</mml:mn></mml:msup></mml:mrow></mml:msubsup><mml:mo>=</mml:mo><mml:msup><mml:mrow><mml:mfenced><mml:mrow><mml:msup><mml:mi>X</mml:mi><mml:mi>T</mml:mi></mml:msup><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:mi>W</mml:mi><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:mi>X</mml:mi></mml:mrow></mml:mfenced></mml:mrow><mml:mrow><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:msup><mml:mi>X</mml:mi><mml:mi>T</mml:mi></mml:msup><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:mi>W</mml:mi><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:mi>Y</mml:mi></mml:mrow></mml:mstyle></mml:mrow></mml:math>\n</disp-formula>", "<inline-formula id=\"DF9\">\n<mml:math id=\"m9\" display=\"inline\" overflow=\"scroll\"><mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>/</mml:mo><mml:msubsup><mml:mi>σ</mml:mi><mml:mi>i</mml:mi><mml:mn>2</mml:mn></mml:msubsup></mml:mrow></mml:math>\n</inline-formula>", "<inline-formula id=\"DF10\">\n<mml:math id=\"m10\" display=\"inline\" overflow=\"scroll\"><mml:mrow><mml:msubsup><mml:mi>σ</mml:mi><mml:mi>i</mml:mi><mml:mn>2</mml:mn></mml:msubsup></mml:mrow></mml:math>\n</inline-formula>", "<disp-formula id=\"DF6\">\n<label>(6)</label>\n<mml:math id=\"m6\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mi>R</mml:mi><mml:mi>s</mml:mi><mml:msub><mml:mi>t</mml:mi><mml:mi>q</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mstyle displaystyle=\"true\"><mml:msubsup><mml:mo>∑</mml:mo><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:msub><mml:mi>n</mml:mi><mml:mi>q</mml:mi></mml:msub></mml:mrow></mml:msubsup><mml:mrow><mml:mi>R</mml:mi><mml:mi>s</mml:mi><mml:msub><mml:mi>t</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>.</mml:mo><mml:mtext> </mml:mtext><mml:msub><mml:mi>D</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow></mml:mstyle></mml:mrow><mml:mrow><mml:mn>90</mml:mn></mml:mrow></mml:mfrac></mml:mrow></mml:math>\n</disp-formula>" ]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><p> Based on the results of our study, the following practical recommendations for policy-makers are made:</p><list list-type=\"bullet\"><list-item><p>The National Disability Insurance Scheme (NDIS) could prepare and publicise policies to underwrite access to services for people with disabilities (PwD) such that they are able to purchase necessary services during national emergencies such as COVID-19 pandemic. </p></list-item><list-item><p>These policies need to remain in effect for at least two quarters after the start of such emergencies. </p></list-item><list-item><p>Under national emergencies, the NDIS may prioritise assistance to some participant cohorts, such as those who had higher mobility and those spending their funding on daily necessities (such as consumables and transportation). </p></list-item><list-item><p>PwD may be granted exemption to the restrictions placed on mobility of people during emergencies, and such exemptions may be targeted to allow access to specific services. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> The COVID-19 has severely affected people with disabilities (PwD) in Australia from accessing services funded through the National Disability Insurance Scheme (NDIS). Based on extensive analysis of available data, we show that: (<italic toggle=\"yes\">i</italic>) funds were under-spent by NDIS participants during the pandemic; (<italic toggle=\"yes\">ii</italic>) such under-spending was more significant among specific participants, such as those living independently or using funds on daily necessities; and (<italic toggle=\"yes\">iii</italic>) spread of COVID-19 and mobility restrictions jointly contributed to the under-spend. Consequently, management plans that factor in the limited mobility during national disasters can ameliorate some of the difficulties faced by PwD in the community.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1 contains Table S1.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Note:</p><p> The * on the variables in the second result means that they were lagged response of <italic toggle=\"yes\">Ur</italic>.</p><p> The <italic toggle=\"yes\">R</italic><sup>##UREF##0##2##</sup> for the regression model on unlagged response is 0.742, and that on lagged response is 0.942.</p><p> The <italic toggle=\"yes\">P</italic> value of Breusch-Pagan test<sup>##UREF##23##43##</sup> for the regression model on lagged response is 0.2783, rejecting the heteroscedasticity hypothesis. However, the test on unlagged response is 0.0181, indicating the existence of heteroscedasticity.</p><p> The endogeneity<sup>##UREF##24##44##</sup> is not expected in this regression because the selected variables are either COVID-19 statistics and restriction policies, or admin information of the NDIS participants, all of which are expected to be exogenous.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7663-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7663-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7663-g003\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7663-g004\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7663-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["2"], "person-group": ["\n"], "surname": ["Jeste", "Hyde", "Distefano"], "given-names": ["S", "C", "C"], "article-title": ["Changes in access to educational and healthcare services for individuals with intellectual and developmental disabilities during COVID-19 restrictions"], "source": ["J Intellect Disabil Res"], "year": ["2020"], "volume": ["64"], "issue": ["11"], "fpage": ["825"], "lpage": ["833"], "pub-id": ["10.1111/jir.12776"]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Jalali", "Shahabi", "Bagheri Lankarani", "Kamali", "Mojgani"], "given-names": ["M", "S", "K", "M", "P"], "article-title": ["COVID-19 and disabled people: perspectives from Iran"], "source": ["Disabil Soc"], "year": ["2020"], "volume": ["35"], "issue": ["5"], "fpage": ["844"], "lpage": ["847"], "pub-id": ["10.1080/09687599.2020.1754165"]}, {"label": ["9"], "mixed-citation": [" Morello R, Smith L, Lawford B, Hinman R, Bennell K. Participant Experiences with NDIS Services During COVID-19 pandemic (Part 1). Australia: Australian Government; 2021. "]}, {"label": ["13"], "mixed-citation": [" Dickinson H, Yates S. More Than Isolated: The Experience of Children and Young People with Disability and Their Families During the COVID-19 Pandemic. Canberra: UNSW Canberra; 2020. "]}, {"label": ["15"], "person-group": ["\n"], "surname": ["McGarity", "Morris"], "given-names": ["SV", "ZA"], "article-title": ["People with disabilities and COVID-19 economic impact payments"], "source": ["J Poverty"], "year": ["2023"], "volume": ["27"], "issue": ["2"], "fpage": ["185"], "lpage": ["196"], "pub-id": ["10.1080/10875549.2022.2080029"]}, {"label": ["16"], "person-group": ["\n"], "surname": ["Olney", "Dickinson"], "given-names": ["S", "H"], "article-title": ["Australia\u2019s new National Disability Insurance Scheme: implications for policy and practice"], "source": ["Policy Des Pract"], "year": ["2019"], "volume": ["2"], "issue": ["3"], "fpage": ["275"], "lpage": ["290"], "pub-id": ["10.1080/25741292.2019.1586083"]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Brennan", "Rice", "Traustad\u00f3ttir", "Anderberg"], "given-names": ["C", "J", "R", "P"], "article-title": ["How can states ensure access to personal assistance when service delivery is decentralized? A multi-level analysis of Iceland, Norway and Sweden"], "source": ["Scand J Disabil Res"], "year": ["2017"], "volume": ["19"], "issue": ["4"], "fpage": ["334"], "lpage": ["346"], "pub-id": ["10.1080/15017419.2016.1261737"]}, {"label": ["20"], "person-group": ["\n"], "surname": ["Thill"], "given-names": ["C"], "article-title": ["Listening for policy change: how the voices of disabled people shaped Australia\u2019s National Disability Insurance Scheme"], "source": ["Disabil Soc"], "year": ["2015"], "volume": ["30"], "issue": ["1"], "fpage": ["15"], "lpage": ["28"], "pub-id": ["10.1080/09687599.2014.987220"]}, {"label": ["21"], "mixed-citation": [" Kehoe J. Better-off Aged Care and NDIS Users Can Pay Their Own Way. Australian Financial Review; 2022. "], "uri": ["https://www.afr.com/policy/tax-and-super/better-off-aged-care-and-ndis-users-can-pay-their-own-way-20221114-p5by4g#:~:text=The%20NDIS%20is%20forecast%20to,government%20hospitals%20(%2427.3%20billion)"]}, {"label": ["22"], "mixed-citation": [" NDIS. Understanding the NDIS. 2023. "], "uri": ["https://www.ndis.gov.au/understanding"]}, {"label": ["23"], "person-group": ["\n"], "surname": ["Carey", "Malbon", "Olney", "Reeders"], "given-names": ["G", "E", "S", "D"], "article-title": ["The personalisation agenda: the case of the Australian National Disability Insurance Scheme"], "source": ["Int Rev Sociol"], "year": ["2018"], "volume": ["28"], "issue": ["1"], "fpage": ["20"], "lpage": ["34"], "pub-id": ["10.1080/03906701.2018.1425084"]}, {"label": ["25"], "mixed-citation": [" Carey G. The National Disability Insurance Scheme and COVID-19: a collision course. Med J Aust 2020;213(3):141-141.e1. "], "pub-id": ["10.5694/mja2.50690"]}, {"label": ["27"], "mixed-citation": [" Kavanagh A, Dimov S, Shields M, McAllister A, Dickinson H, Kavenagh M. Disability Support Workers: The Forgotten Workforce in COVID-19. Melbourne: The Univesity of Melbourne; 2020. "]}, {"label": ["28"], "mixed-citation": [" Kavanagh A. Protecting People with Disability During the Pandemic. Vol 29. Melbourne Disability Institute, University of Melbourne; 2020. "]}, {"label": ["31"], "mixed-citation": [" Landes SD, Stevens D, Turk MA. COVID-19 and Pneumonia: Increased Risk for Individuals with Intellectual and Developmental Disabilities During the Pandemic. 2020. "]}, {"label": ["33"], "mixed-citation": [" Dickinson H, Smith C, Yates S, Bertuol M. Not Even Remotely Fair: Experiences of Students with Disability During COVID-19. Canberra: UNSW Canberra; 2020. "]}, {"label": ["34"], "mixed-citation": [" Lawford B, Bennell KL, Hinman RS, Morello R, Oliver K, Spittle A. Participant Experiences with National Disability Insurance Scheme Funded Allied Healthcare Services During COVID-19. Melbourne: The University of Melbourne; 2021. "]}, {"label": ["36"], "mixed-citation": [" Australian Bureau of Statistics (ABS). National, State and Territory Population. Australia: ABS; 2021. "]}, {"label": ["37"], "mixed-citation": [" Victoria State Government. Victoria \u2013 Department of Human Services \u2013 Local Government Areas (LGAs). Victoria State Government; 2023. "]}, {"label": ["38"], "mixed-citation": [" Freedman DA. Statistical Models: Theory and Practice. Cambridge University Press; 2009. "]}, {"label": ["39"], "mixed-citation": [" NDIS. Data Downloads. 2023. "], "uri": ["https://data.ndis.gov.au/data-downloads"]}, {"label": ["40"], "mixed-citation": [" O\u2019Brien J. COVID-19 Data for Australia. "], "uri": ["https://github.com/M3IT/COVID-19_Data"]}, {"label": ["42"], "mixed-citation": [" Vicki. Timeline of Every Victoria Lockdown (Dates & Restrictions). Vol 2021. Big Australia Bucket List; 2021. "]}, {"label": ["43"], "person-group": ["\n"], "surname": ["Breusch", "Pagan"], "given-names": ["TS", "AR"], "article-title": ["A simple test for heteroscedasticity and random coefficient variation"], "source": ["Econometrica"], "year": ["1979"], "volume": ["47"], "issue": ["5"], "fpage": ["1287"], "lpage": ["1294"], "pub-id": ["10.2307/1911963"]}, {"label": ["44"], "mixed-citation": [" Antonakis J, Bendahan S, Jacquart P, Lalive R. Causality and endogeneity: problems and solutions. In: Day DV, ed. The Oxford Handbook of Leadership and Organizations. Oxford Library of Psychology; 2014. p. 93-117. "]}, {"label": ["46"], "person-group": ["\n"], "surname": ["Lee", "Kim"], "given-names": ["S", "J"], "article-title": ["A country report: impact of COVID-19 and inequity of health on South Korea\u2019s disabled community during a pandemic"], "source": ["Disabil Soc"], "year": ["2020"], "volume": ["35"], "issue": ["9"], "fpage": ["1514"], "lpage": ["1519"], "pub-id": ["10.1080/09687599.2020.1809352"]}, {"label": ["47"], "person-group": ["\n"], "surname": ["Mbazzi", "Nalugya", "Kawesa"], "given-names": ["FB", "R", "E"], "article-title": ["The impact of COVID-19 measures on children with disabilities and their families in Uganda"], "source": ["Disabil Soc"], "year": ["2022"], "volume": ["37"], "issue": ["7"], "fpage": ["1173"], "lpage": ["1196"], "pub-id": ["10.1080/09687599.2020.1867075"]}, {"label": ["49"], "person-group": ["\n"], "surname": ["Chand", "Zhang"], "given-names": ["S", "Y"], "article-title": ["Learning from machines to close the gap between funding and expenditure in the Australian National Disability Insurance Scheme"], "source": ["International Journal of Information Management Data Insights"], "year": ["2022"], "volume": ["2"], "issue": ["1"], "fpage": ["100077"], "pub-id": ["10.1016/j.jjimei.2022.100077"]}]	{ "acronym": [], "definition": [] }	50	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 9; 12:7663	oa_package/ab/d4/PMC10590233.tar.gz
PMC10590234	0	[ "<title>Background</title>", "<p> Medical residents are profoundly affected by burnout and depression. Depending on the definition, measurement and specialty, the estimated prevalence of depression and burnout for residents ranges from around 30%<sup>##REF##26647259##1##</sup> to 50%, respectively.<sup>##REF##31132791##2##,##REF##30820845##3##</sup> These conditions that undermine well-being have serious implications for resident productivity,<sup>##UREF##0##4##</sup> motivation and performance,<sup>##REF##11874308##5##</sup> as well as patient safety.<sup>##REF##29121895##6##</sup> Self-care and support seeking behavior of residents are thus important for patient outcomes, quality of care,<sup>##REF##27391946##7##</sup> and for residents themselves.<sup>##REF##32449867##8##</sup> The importance of resident well-being is reflected in the increase of attention in scholarly articles and the urgency in which national and local residency programs are implementing well-being interventions.<sup>##UREF##1##9##</sup> However, while some of these interventions have positive results, there are also signs that residents may not sufficiently utilize formal support.<sup>##REF##33857247##10##</sup></p>", "<p> Recent events and reports of intensifying work pressures puts a magnifying glass on the issue of resident well-being and support. For example, the recent COVID-19 crisis threatened residents’ well-being due to increased workload and significant challenges in their training, education, and responsibilities.<sup>##REF##34043931##11##</sup> In recognition of the burden and intensity of work that residents and other healthcare workers face, significant efforts are being made to provide well-being and formalized support programs for medical staff.<sup>##REF##34802325##12##</sup> As Lai et al,<sup>##REF##32202646##13##</sup> indicate, a sense of support can have a positive impacted on residents’ well-being. However, Zoorob et al,<sup>##REF##33857247##10##</sup> show that over 40% of surveyed residents who were offered formal support during the COVID-19 period did not find it useful or make use of it. However, the reasoning behind low support utilization remains unclear. This prompts us to consider the utility of formal support and if residents experience barriers to its use. Examining the utility of formalized support can lead to valuable insights for the way we give attention to well-being in a setting that is constrained by the balance between education and clinical care.</p>" ]	[ "<title>Methods</title>", "<p> In order to set the basis for future research, we conducted a small scale mixed-method study to identify whether residents indeed do not utilize formal psychological support and what potential underlying reasons might be for non-use. The data utilized for this study is part of a larger mixed-method study of how hospitals in a heavily hit region of the Netherlands adapted to and coped with the COVID-19 crisis that has been ongoing since September 2020.<sup>##REF##34802325##14##</sup> To ascertain support use, we conducted analysis of a survey which included a subsample of medical residents, and assessed the utilization of formalized support programs across five hospitals in the Netherlands.<sup>##REF##34802325##14##</sup> To examine potential antecedents of non-use, the first author conducted nine interviews with residents, and medical specialists between September 2020 and April 2021. More specifically, we conducted an interpretive analysis, reviewing responses of (five) medical residents and (four) medical specialists to questions that focused on impact of the crisis, available support, use of support and support mechanisms, well-being in general. We utilize emergent insights regarding the well-being and support seeking behaviors of residents to support our current theorizing and to call for future research into this issue.</p>" ]	[ "<title>Results</title>", "<title> Uptake of Formal Support</title>", "<p> From the interviews, medical specialists suggested that residents had taken on an enormous burden throughout the course of the crisis. Some participants emphasized the reality that residents were confronted with high emotional and mental burdens during frontline work, and in particular with patient death. The intensity of the work, the illness of the patients, and unfamiliar roles, wards, and tasks created additional burdens. However, while formal support was available for the interviewed participants (eg, via an internal psychosocial support team, support helplines, external professional psychologists on standby), the present data suggests that use of these interventions may have been low for this group,</p>", "<p> “<italic toggle=\"yes\">Yes, we always had, yes, one employee who actually came by every day to the A&E department: “is there someone who needs help?” or someone who just wanted to talk. But I have to say, I don’t know, I didn’t take advantage of it. I don’t think much of our group. But I think it was more for the other specialties” </italic>[Resident].</p>", "<p> Quantitative questionnaire data suggested that in the subsample of 24 residents, only 2 indicated that they used formal support during the first COVID-19 peak in the Netherlands (19 indicated they did not, 3 did not reply). Of the 19 residents who indicated that they did not make use of formal support, none even considered using it. Responses to other items related to support indicated that the residents in this subsample did receive informal support, mostly from their families, coworkers, supervisors, and in some cases dedicated professionals (eg, psychologists). As such, it seems using formal support is not common among residents.</p>", "<p> In addition, the residents in our qualitative sample downplayed the toll of the pandemic on themselves while still highlighting its negative reality for their colleagues, pointing to clear patterns in other groups who are not used to such intense work and patient death. Medical specialists on the other hand noted the impact of the pandemic on residents.</p>", "<p> “<italic toggle=\"yes\">We still need our residents because they do most of the work. But on the other hand, we need to let them breathe because they they can’t keep up anymore. So we changed the shifts completely and they now have, for example, four residents do the same work they used to do in the first wave with two residents, so we try to lower the impact and the stress levels. But still, it’s not enough. And we we are struggling with how to support them and make them feel safe” </italic>[Medical Specialist, Internist].</p>", "<p> In particular, some specialists pointed to recognition of signs of burnout and potentially long-term psychological tolls in the intensive care unit group. However, it was sometimes difficult to figure out how to best support them.</p>", "<title> Institutional Barriers to Formal Support </title>", "<p> Low utilization of support was attributed by one medical specialist as being related to the interdependency between residents and supervisors. Particularly for residents, their dependence upon their supervisors and the need to show they ‘can handle it’ may deter the utilization of support when support seeking is perceived as ‘weak.’</p>", "<p> “<italic toggle=\"yes\">…on one hand, I think it’s really good as a sign that you should talk about it and that the possibility is there. But on the other hand, I think a lot of the residents didn’t feel like sharing because they’re in this dependency of us as supervisors. And their whole residency depends on how they function as a doctor. So if you’re going to tell you’re struggling, it would be a symptom of a failing” </italic>[Medical Specialist Internist].</p>", "<p> This need to be seen as ‘tough’ was echoed by another specialist who indicated the utility of residents being tough enough to handle the sometimes brutal reality of a residency program.</p>", "<title> Peer Support and Modeling Behavior for Spontaneous Coping</title>", "<p> Despite the efforts to promote formal support utilization, for physicians the preferred mode of sharing experiences and seeking support was within the peer groups. Some participants pointed to self-care and seeking peer support as a form of best practice. In groups where senior staff made an effort to share experiences and start an open conversation, a psychologically safe environment may be created for residents to also engage in sharing experiences and seeking support in such groups.</p>", "<p> “<italic toggle=\"yes\">I think in the psychosocial support team they were asked to also help in providing with some emotional training [for residents] and to [help them] anticipate what type of situation they would come in to, how to handle this. And also how to help each other and talk about this if you needed. So there was attention also to this mental part of the workload…the head of the department of internal medicine was quite aware of this. So he also approached us in the beginning phase, please join, [so] he and I went to their daily meeting and he introduced us to the entire group, I think there was 60 people there, and said ‘ok these people can be of support and so forth and I think that it’s very important to talk about this if you want to.’ So I think giving this example of that this is normal to talk about how this is impacting your mental wellbeing, by the leaders in the department, that’s a very important thing. That was I think the strength here” </italic>[Head of psychosocial support team].</p>", "<p> The modeling by leading physicians may be seen as a crucial factor in setting a norm of help seeking behaviors.</p>" ]	[ "<title>Discussion</title>", "<p> Organizational support is a valuable asset for resident well-being, however as our data indicates, and has been noted in other emergent research, even during times of increased work pressures and burdens, residents exhibit low numbers of formal support utilization<sup>##REF##33857247##10##</sup> or may not perceive formalized interventions as beneficial for their well-being.<sup>##REF##34545767##15##</sup> Although the present sample is limited by a small sample size, our utilization of two sources of primary data across several hospitals allows us to bring forward important insights and provide a good basis for future research that incorporates a more robust sample. Our data suggest that informal peer-support may be utilized the most by residents, and thus may prove more effective than more formalized modalities. This aligns with other research that has shown peer support to be the most utilized and useful form of support for physicians.<sup>##REF##22106247##16##</sup> With resources being distributed towards formalized support programs, it is essential to consider whether these are the best suited, or most effective, types of support. In the following sections we consider ways forward, focusing on the importance of building peer support competences in medical training, and the role of management in building a culture of self-care and normalizing seeking support to better support the well-being of residents.</p>", "<title> Ways Forward</title>", "<title> Building Peer Support Competences</title>", "<p> In light of our finding that informal support may be more desired and utilized than formal programs, we suggest that it becomes increasingly important to learn peer-supporting behavior during medical training. That is, while compelling evidence exists that peer and informal social connections (eg, among residents) may be an essential factor in improving resident well-being,<sup>##REF##32040767##17##,##REF##27438155##18##</sup> there is little formal training of peer support in the medical curriculum.<sup>##REF##32232665##19##</sup> As such, there is an urgent need to give more attention to skills needed for such peer-support in the medical curriculum. Training residents in competences such as active listening, peer-support and emotional intelligence may facilitate the development of a climate of support and well-being<sup>##REF##32232665##19##</sup> more effectively than formal well-being interventions.</p>", "<title> The Role of Management </title>", "<p> Confirming earlier notions that residents do not actively seek support when experience stress at work,<sup>##REF##33870005##20##</sup> our study also highlights the important role of leaders in fostering a support seeking and safe culture. Increasing demands and work stress on residents in recent years has put a magnifying glass on already existing challenges within the medical field, including the challenge of retention<sup>##REF##33419774##21##</sup> and alarmingly high rates of burnout and depression among clinicians.<sup>##REF##26647259##1##</sup> It is therefore essential that organizations and leaders take an active role to consider and promote the cultural changes that need to occur to protect residents and safeguard their well-being.<sup>##REF##21715992##22##</sup> Open discussion and peer support is necessary to allow physicians to recognize moral distress<sup>##REF##33419774##21##</sup> and can support general well-being. However, there are signs that it is difficult for residents to make time for recovery or seek support in an already busy schedule and stigma of support seeking or expressing mental health concerns often keeps residents suffering in silence, fearful of negative repercussions.<sup>##REF##21715992##22##</sup></p>", "<p> Supervisors, and managers can promote positive cultural change by modeling support seeking behavior themselves, normalizing self-care<sup>##REF##32232665##19##</sup> and by signaling its importance with structural changes. For example, organizations can work to structurally incorporate or mandate ‘downtime’ in residents’ schedules to offer informal opportunities for debriefing, peer discussion, and recovery activities. Management can also work with clinical supervisors and team leaders to design opportunities for group reflections and discussion, eg, biweekly or monthly. Such group reflections should be attended by, and ideally led, by senior staff to promote an open culture and reduce residents’ fears of sharing their own struggles.<sup>##REF##32232665##19##,##REF##21715992##22##</sup> This can help build in necessary encouragement for health care providers to ‘talk about’ their own support needs so that these needs can be adequately addressed by the organization.</p>" ]	[]	[ "<p>Medical residents are significantly impacted by burnout and depression. Recent events have only further increased the pressure and demands on the healthcare sector, intensifying the burden facing residents and posing a threat to residents’ well-being. As a result, significant efforts are being made to provide formalized support and well-being programs. Yet, emergent evidence indicates that residents do not sufficiently utilize this form of support. Considering the organizational investment and focus on formalized support programs, we conducted a mixed-method study to investigate residents’ utilization of formalized well-being support, and potential reasons for non-use. Our study was conducted during a period of increased work burden and stress for medical residents, where formalized support was specifically offered and targeted to medical staff. Our findings confirm earlier results of low support utilization and point to the importance of informal support mechanisms, in particular peer support. We conclude by discussing the role of managers and educational programs in facilitating a positive cultural shift to promote and support residents in seeking support.</p>", "<p>\n<bold>Citation:</bold> Gifford R, van Rossum TR, Fleuren B, Westra D. Let’s talk about it: the utility of formalized support for medical residents. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7463. doi:10.34172/ijhpm.2023.7463</p>" ]	[ "<title>Ethical issues</title>", "<p> Ethical approval was granted for this study by Maastricht University’s Research Ethics Committee (FHML-REC/2020/110).</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This work was supported by the Netherlands Organization for Health Research and Development (ZonMw) under grant number 1043002201001.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["4"], "person-group": ["\n"], "surname": ["Fern\u00e1ndez-S\u00e1nchez", "P\u00e9rez-M\u00e1rmol", "Santos-Ruiz", "P\u00e9rez-Garc\u00eda", "Peralta-Ram\u00edrez"], "given-names": ["JC", "JM", "AM", "M", "MI"], "article-title": ["[Burnout and executive functions in palliative care health professionals: influence of burnout on decision making]"], "source": ["An Sist SanitNavar"], "year": ["2018"], "volume": ["41"], "issue": ["2"], "fpage": ["171"], "lpage": ["180"], "pub-id": ["10.23938/assn.0308"]}, {"label": ["9"], "mixed-citation": [" Accreditation Council for Graduate Medical Education (ACGME). Common Program Requirements (Residency). "], "uri": ["https://www.acgme.org/Portals/0/PFAssets/ProgramRequirements/CPRResidency2020.pdf"]}]	{ "acronym": [], "definition": [] }	22	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 13; 12:7463	oa_package/c6/d2/PMC10590234.tar.gz
PMC10590235	0	[ "<title>Introduction</title>", "<p> I thoroughly enjoyed Powell and Manion’s<sup>##REF##37579456##1##</sup> detailed consideration of health policy analysis. Their editorial adds to the growing literature that demonstrates policy analysis as legitimate, and crucial, for health research. However, their analysis underemphasises institutions. In particular, the dynamic role of structure and agency is under considered.</p>", "<p> My response here is not to criticise, but to add to, their insightful analysis theories of the policy process. The main flaw in Powell and Manion’s analysis and argument is limited engagement with institutions. Their focus is theories of the policy process, using Weible and Sabatier’s<sup>##UREF##0##2##</sup> introductory text. Once these theories are introduced, they then review the ‘health policy process’ literature for consideration of these theories, finding that few of these theories are used in that literature. This line of analysis is all well and good, and usefully demonstrates how a deeper engagement with cross-disciplinary scholarship is needed to add depth to health policy analysis.</p>", "<p> However, the argument falters in their conclusion about institutional factors tending to be static in health policy analysis, relative to theories of the policy process. I recognise that they take aim at the use of these factors in health policy process models as ‘lists’ rather than full explanations. But their under consideration of the dynamics of institutions means their analysis comes up short.</p>" ]	[]	[]	[]	[]	[ "<p>Powell and Manion present an important review of reviews about health and policy research. They zero in on theories of the policy process as the most likely to unearth what is really going on in health policy. Here I contend that their analysis insufficiently attends to institutions. Powell and Manion situate ‘institutions’ (with ‘Ideas’ and ‘Interests’) as a ‘health policy process models’ that ‘tend to’ list factors rather than connect them. Rather, I show how there is a rich history of considering institutions in the political science literature that is under considered by Powell and Manion. By necessity for a Public Health audience I quickly pull back the covers on ‘rigour’ and ‘causation’ to demonstrate what is ‘fit for purpose’ in rigorous institution focussed policy analysis. I conclude by arguing how institutionally focussed public health policy analysis is vital for understanding and addressing heath inequities. That focus necessitates research that provides better, explicit, conceptualisations of power in health policy: especially drawing out the roles played by structure and agency. I offer some recent examples.</p>", "<p>\n<bold>Citation:</bold> Harris P. Health policy analysis requires attending to institutions: Comment on \"Modelling the health policy process: one size fits all or horses for courses?\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8085. doi:10.34172/ijhpm.2023.8085</p>" ]	[ "<title>Why Institutions Matter: Structure <italic toggle=\"yes\">and</italic> Agency</title>", "<p> There is another foundational text about policy that emphasises institutions as the basis for understanding the essentials of policy. I urge readers to start with, or go back to, Howlett and colleagues’<sup>##UREF##1##3##</sup> (updated in 2022 with a new title but same institutional emphasis) ‘Policy cycles and subsystems’ <italic toggle=\"yes\">before</italic> reading Weible and Sabatier. Why so? Institutional analysis, looks, Howlett et al explain, to the structure of political and economic arrangements. These structures are famously described ‘rules of the [policy] game.’<sup>##UREF##2##4##</sup> ‘Institutions,’ political scientists therefore claim, ‘matter.’<sup>##UREF##3##5##,##UREF##4##6##</sup></p>", "<p> Howlett et al importantly explain that their disciplinary orientation, is Statist. That is, their core concern is with the State — formed around but going beyond government — as the main arbiter of policy. The State is an institution that is made up of actors (the people and organisations involved), ideas (the content) and structures (the rules and mandates that condition institutions). Statism is deeply connected to a whole body of political theory, institutionalism,<sup>##UREF##5##7##</sup> which is based on shifting attention to the role of structure and agency in policy. Structures, in contrast to agency, focus on the conditions that ‘structure’ society by creating the rules and mandates that institutions tend to maintain. Change, if and when that comes about, occurs through the power of agency, for instance the role of individuals or groups in disrupting the status quo to create new rules and mandates. In this way, institutions embody both structure and agency, and a full and deep policy analysis recognises that distinction.<sup>##UREF##6##8##</sup></p>", "<p> Not everyone emphasises this structure and agency differentiation. Peters,<sup>##UREF##7##9##</sup> for instance navigates the history of institutional analysis to land on the same three ‘I’s’ (institutions, ideas, and interests) that Powell and Manion claim as static factors in health policy analysis. Similarly, Carol Weiss in her seminal work on evaluation evidence in policy, falls on the three I’s.<sup>##UREF##8##10##</sup> As long as the dynamics created both by structures and agency are kept in full focus, then institutions clearly do matter for policy analysis.</p>", "<p> A quick text search for the term ‘structure’ in Powell and Manion’s text shows the word is absent. That absence has similarly been picked up in theories of the policy process.</p>", "<p> For example, in the political science literature scholars have taken theories of the policy process to task for limited unpacking of institutions.<sup>##UREF##9##11##,##UREF##10##12##</sup> The ‘Big Three’<sup>##UREF##11##13##</sup> — Multiple Streams Analysis (MSA), Advocacy Coalition Framework (ACF), and Punctuated Equilibrium Theory (PET) — have been especially accused of insufficient explicit attention on the structuring dynamics of institutions on policy as the ‘[formal and informal] rules…and social norms’ that constrain and shape the behaviour of agents and networks in the policy process (p. 120).<sup>##UREF##9##11##</sup> That omission — aside from Ostrom’s Institutional Analysis and Development theory — leads to questions over whether theories of the policy process provide sufficient causal depth of synthesis and understanding about the structural rules and policy-making.<sup>##UREF##9##11##,##UREF##10##12##</sup></p>", "<p> A quick diversion into what is meant by causation is necessary here. Powell and Manion dance around causation, using ‘rigour’ rather than the term ‘causal.’ That omission opens up a world of confusion for disciplines like Public Health that have a tradition of focussing in on a particular type of causal inference. Policy analysis belongs to the social sciences. The emphasis is complexity and conditions. Public health research has tended to take on a reductionist approach to causality that factors out complexity and conditions in the search for certainty. Neither is wrong, but both are different. Public health intervention focussed research falls into what Howlett et al term ‘research <italic toggle=\"yes\">for</italic> policy.’ Policy analysis falls under what Howlett et al<sup>##UREF##1##3##</sup> term ‘research <italic toggle=\"yes\">of</italic> policy.’ By opening up the can of worms of ‘rigour,’ Powell and Manion risk conflating two very different, albeit complementary, analytic enterprises. Indeed, ‘rigour’ in most if not all of the studies reviewed by Powell and Manion concerns opaque or omitted reporting of data collection, analysis and use of theory. None of those papers uses terms like ‘causal certainty.’ Most support the widespread support in political science for using more than one theory of the policy process given the complexity of the object that is policy.<sup>##UREF##12##14##</sup> Deductive theory testing to explain the reality of policy is, by and large, insufficient.<sup>##UREF##6##8##</sup></p>", "<p> Thus far I have introduced the depth provided by institutional theory as a blind spot in Powell and Minion’s otherwise excellent editorial. Here I want to drill down into why, with a health lens, that omission matters. There is a raft of evidence that the health inequity is persistent and worsening. What is missing from the above analysis is a focus on the essential mechanism in policy systems that maintains those health inequities: power. Power and a structural focussed institutional analysis of policy go hand in hand, as I demonstrate shortly. Powell and Manion, however, only refer to power in their description of two health policy analysis sources.</p>", "<p> Powell and Manion suggest that a full policy analysis requires additional literature beyond theories of the policy process. My and my colleagues’ work — in the ‘determinants of health’ body of health policy identified by Powell and Manion — supports that position. Indeed, I have recently identified the point in my program where theories of policy process proved unable to capture the nuances of the policy system I was investigating.<sup>##UREF##6##8##</sup> Ultimately, however, we have found that while additional literature helps explain the nuances of a particular policy being investigated or analysed, an explicit focus on power is necessary to draw out those nuances. Turning full circle to my points above, we have demonstrated how power in policy is agentic, ideational, and structural.<sup>##REF##32198290##15##</sup> Our body of work has provided increasingly sophisticated frameworks to health focussed policy analysis and evaluation.<sup>##REF##34192622##16##,##UREF##13##17##</sup> We have, for instance, shown how policy systems are set up and maintained (termed Path Dependencies) to create the conditions for increasing health inequities. Specifically, for instance- using a mix of theories to explain data — explained how power and governance are mutually reinforcing.<sup>##UREF##6##8##</sup> That intertwining actively omits health equity from policy goals like ‘economic growth’ when equity is perceived to challenge the values underpinning those goals, such that pro-equity voices are not allowed a seat, voice or influence. Nevertheless we have also shown how the power of ideas, driven by actors to disrupt the status quo, can disrupt those entrenched power dynamics.<sup>##REF##34192622##16##</sup> Part of the challenge of this type of analysis is that change is often slow, incremental, multi-faceted and long term. Research funding, given its tight timeframes and particular interest in tight causal analysis of ‘what works,’ often structures out the research Powell and Minion’s editorial advocates. Institutionally centred analyses, however, provide for deeply nuanced explanations of policy that directly challenge Powell and Manion’s conclusion that the health policy analysis literature is ‘conceptually weaker’ than theories of the policy process.</p>", "<p> In conclusion, Powell and Manion provide an excellent introduction to the challenges of health policy analysis that is disconnected from the political science literature. However, they seem to be treading a fine line with their coverage of the theories of the policy process which risk under-playing the structural and agentic power of institutions.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that he has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "mixed-citation": [" Weible CM, Sabatier P. Theories of the Policy Process. Routledge; 2018. "]}, {"label": ["3"], "mixed-citation": [" Howlett M, Ramesh M, Perl A. Studying Public Policy: Policy Cycles and Policy Subsystems. 3rd ed. Canada: Oxford University Press; 2009. "]}, {"label": ["4"], "mixed-citation": [" North DC. Five propositions about institutional change. In: Knight J, Sened I, eds. Explaining Social Institutions. The University of Michigan Press. 1995:116-131. "]}, {"label": ["5"], "person-group": ["\n"], "surname": ["March", "Olsen"], "given-names": ["JG", "JP"], "article-title": ["The new institutionalism: organizational factors in political life"], "source": ["Am Polit Sci Rev"], "year": ["1983"], "volume": ["78"], "issue": ["3"], "fpage": ["734"], "lpage": ["749"], "pub-id": ["10.2307/1961840"]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Hall", "Taylor"], "given-names": ["PA", "RC"], "article-title": ["Political science and the three new institutionalisms"], "source": ["Polit Stud"], "year": ["1996"], "volume": ["44"], "issue": ["5"], "fpage": ["936"], "lpage": ["957"], "pub-id": ["10.1111/j.1467-9248.1996.tb00343.x"]}, {"label": ["7"], "mixed-citation": [" Hall PA. Governing the Economy: The Politics of State Intervention in Britain and France. New York: Oxford University Press; 1986. "]}, {"label": ["8"], "mixed-citation": [" Harris P. Illuminating Policy for Health: insights from a decade of researching urban and regional planning. Palgrave McMillan; 2022. "], "pub-id": ["10.1007/978-3-031-13199-8"]}, {"label": ["9"], "mixed-citation": [" Peters BG. Institutional Theory in Political Science: The New Institutionalism. 4th ed. Edward Elgar Publishing; 2019. "]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Weiss"], "given-names": ["CH"], "article-title": ["The interface between evaluation and public policy"], "source": ["Evaluation"], "year": ["1999"], "volume": ["5"], "issue": ["4"], "fpage": ["468"], "lpage": ["486"], "pub-id": ["10.1177/135638909900500408"]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Real-Dato"], "given-names": ["J"], "article-title": ["Mechanisms of policy change: a proposal for a synthetic explanatory framework"], "source": ["J Comp Policy Anal Res Pract"], "year": ["2009"], "volume": ["11"], "issue": ["1"], "fpage": ["117"], "lpage": ["143"], "pub-id": ["10.1080/13876980802648268"]}, {"label": ["12"], "person-group": ["\n"], "surname": ["van der Heijden", "Kuhlmann", "Lindquist", "Wellstead"], "given-names": ["J", "J", "E", "A"], "article-title": ["Have policy process scholars embraced causal mechanisms? A review of five popular frameworks"], "source": ["Public Policy Adm"], "year": ["2021"], "volume": ["36"], "issue": ["2"], "fpage": ["163"], "lpage": ["186"], "pub-id": ["10.1177/0952076718814894"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["John"], "given-names": ["P"], "article-title": ["Is there life after policy streams, advocacy coalitions, and punctuations: using evolutionary theory to explain policy change?"], "source": ["Policy Stud J"], "year": ["2003"], "volume": ["31"], "issue": ["4"], "fpage": ["481"], "lpage": ["498"], "pub-id": ["10.1111/1541-0072.00039"]}, {"label": ["14"], "person-group": ["\n"], "surname": ["Cairney"], "given-names": ["P"], "article-title": ["Standing on the shoulders of giants: how do we combine the insights of multiple theories in public policy studies?"], "source": ["Policy Stud J"], "year": ["2013"], "volume": ["41"], "issue": ["1"], "fpage": ["1"], "lpage": ["21"], "pub-id": ["10.1111/psj.12000"]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Schram", "Townsend", "Mackean"], "given-names": ["A", "B", "T"], "article-title": ["Promoting action on structural drivers of health inequity: principles for policy evaluation"], "source": ["Evid Policy"], "year": ["2022"], "volume": ["18"], "issue": ["4"], "fpage": ["761"], "lpage": ["775"], "pub-id": ["10.1332/174426421x16420923635594"]}]	{ "acronym": [], "definition": [] }	17	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 7; 12:8085	oa_package/bd/f8/PMC10590235.tar.gz
PMC10590236	0	[]	[]	[]	[]	[ "<title>Conclusion</title>", "<p> Research investments in an organization with a research and translation mandate can make important gains for research impact across domains, but the pathways are highly context dependent and contingent on a multitude of individual, organizational, and macro-level factors. Research capacity building aspirations should be directed towards creating embedded, learning health systems, reflective of research literacy and continued investments in resources spanning personnel, training, workflow, technological systems, and portfolio commitments, as examples. Fundamental however, is the need for a value and operational alignment; namely, that the support for research within institutions needs to match what institutions do to support it (eg, fund research activities, reduce service requirements). While these formidable challenges present opportunities for all health systems, attention towards the unique circumstances of regional authorities and health systems is particularly warranted.</p>" ]	[ "<p>Brown et al show that research investments in an organization with a research and translation mandate can make important gains for research impact across domains, including quality of care and patient outcomes. Their multi-stage mixed methods evaluation provides insight into research capacity development in rural health systems in Australia and draws attention towards persistent geographic inequities. In extension of this important contribution, here, a focus on the \"what and the why\" of embedded research is offered. Specific attention is paid to the sustainability potentials of systematized data capture systems, funding-operational mandate alignments, researcher-scientist career pathways, and networked approaches to mentorship.</p>", "<p>\n<bold>Citation:</bold> Archibald MM. Embedded research: possibilities for learning health systems: Comment on \"‘We’re not providing the best care if we are not on the cutting edge of research’: a research impact evaluation at a regional Australian hospital and health service.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7694. doi:10.34172/ijhpm.2023.7694</p>" ]	[ "<p> In a timely article reflective of the need for renewed synergy between research practices and health services, Brown et al<sup>##REF##35643418##1##</sup> argue for embedded research to improve quality of care and patient outcomes. They present a 3 stage mixed methods evaluation study inclusive of realist logic to examine the impact of research investment from 2008-2018 at a regional hospital and health service in Queensland Australia, and identify contextual conditions influencing the attainment of impact markers. The evaluation seeks to gain insight into research capacity development by evaluating research investment, activity and impact at a regional hospital and health service in Australia.</p>", "<p> The authors highlight a need for research investment and capacity building in rural areas, citing that persistent geographic inequities exist. Consequently, these rural areas miss out on the benefits attributable to embedded research. While the authors identify a host of factors influencing its possible attainment with a focus on research capacity and investment, embedded research as a concept warrants additional attention. In complement to the work of Brown and colleagues, here, the question is presented: <italic toggle=\"yes\">What is embedded research?</italic> And further, <italic toggle=\"yes\">why does it matter? </italic></p>", "<title>Embedded Research</title>", "<p> Embedded research is inherently pragmatic and involves the testing and subsequently the smooth integration of interventions into existing work flows, using standard care and ideally, routinely collected measures.<sup>##REF##33619464##2##</sup> Platt et al<sup>##REF##34192427##3##</sup> suggest embedded research involves a learning health system, emphasizing the use of embedded pragmatic trials that involve existing clinical staff instead of allocated research staff, use routinely collected data instead of research-specific metrics that require additional documentation, and are integrated into standard care. Such systems presume that (<italic toggle=\"yes\">a</italic>) health systems routinely collect data on important impact markers pertinent to clinical care, practice, policy and patient outcomes; (<italic toggle=\"yes\">b</italic>) health systems collect these data in a manner amendable to timely export and data standards, such as electronic health records (EHRs); (<italic toggle=\"yes\">c</italic>) health professionals are in some way compensated for this work, because pragmatic trials still require research literacy and protocol compliance; (<italic toggle=\"yes\">d</italic>) health professionals have the willingness to become researchers in this capacity, and that (<italic toggle=\"yes\">e</italic>) they have the research literacy to work in this capacity. Notably, embedded research must — in the current climate of complexity and change mandating adaptation — account for a more pluralistic view of research and evidence.<sup>##UREF##0##4##</sup> The current article by Brown et al<sup>##REF##35643418##1##</sup> speaks to some of these critical attributes. Perhaps most notable in their argument is the need for research capacity and for a systematic approach to research.</p>", "<title>Establishing a Systematic Approach to Research</title>", "<p> In their evaluation of the regional hospital and health service under investigation, Brown et al<sup>##REF##35643418##1##</sup> presented the key finding that an organization-wide, systematic process to enable research translation had not yet been established.This is likely to be the norm, rather than the exception in health systems worldwide. There are a number of factors influencing this, including the broader socio-cultural understanding of what research is, how it should be conducted, and what counts as quality evidence; questions of dominion, ownership and expertise around “specialty” skills such as research; growing awareness, stemming from the evidence based practice, knowledge translation, and implementation science movements that the mere presence of research does not itself result in practice and policy changes; and health system pressures, such as those presented by the novel coronavirus, which catalyzed the need for rapid assessment and implementation of effective treatments using a previously unparalleled global and embedded approach.<sup>##REF##34192427##3##, ####UREF##0##4##, ##REF##29524952##5##, ##REF##30219065##6####30219065##6##</sup></p>", "<p> Critically, a systematic process for research translation requires the use of consistent and routinely collected measures within health systems. Indeed, while evaluation using frequently occurring and consistent measures is key to assessing the impact of research activities, routinely collected organizational metrics/measures of research capacity building are often absent from organizations. Processes to collect data on practice, policy and workforce and health impacts of research are also needed, and these need to be systematic. Brown et al<sup>##REF##35643418##1##</sup> rightly argue that this should be a priority moving forward.</p>", "<p> Using clinical data to improve patient care requires that the data points collected are meaningful, done so consistently, and are integrated as part of routine/standard care as much as is possible. Also critical is individuals’ capacity to operate well within organizations where such data is routinely collected. Ideally, process-oriented and values-based capacity building would accompany the integration of such data collection into EHRs wherever possible and include quality data standards to create systems ready for rapid-cycle feedback and improvement: ie, research ready, learning health systems.<sup>##REF##33619464##2##</sup> This is in part, the research infrastructure that Brown and colleagues identify as a critical component of their evaluation, yet goes beyond this to emphasize quality data metrics within each health system. Extending this view with the purview towards more multisite integration, enabling for instance, multi site trials, raises interest in the coordination of data capture within aligned technological systems (eg, EHRs), to avoid the need to reconfigure programming and data codes for each participating health system.<sup>##REF##33619464##2##</sup> As such, while Brown and colleagues<sup>##REF##35643418##1##</sup> emphasize the persistent geographic inequities that result from “missing out on the health and health system benefits attributable to embedded research” (p. 1), we are reminded that hospitals and health systems in major cities have in many cases not yet coordinated their data capture systems, impeding the learning potentials made possible through embedded research. Brown et al<sup>##REF##35643418##1##</sup> do well to draw attention to the under researched area of research capacity development in non-metropolitan settings in Australia.</p>", "<title>Research Capacity and Literacy as Critical to Research Capacity and Embedded Research Systems</title>", "<p> Research capacity is a broad term inclusive of such concepts as research infrastructure, research literacy, resources and other components that improve an organization’s ability to conduct research. The research capacity building process emphasizes developing sustainable abilities — in individuals and/or organizations — to conduct quality research.<sup>##REF##30219065##6##</sup> Indeed, research capacity is a multi-level concept, with relevant individual, organizational, and health system level applications. From an individual perspective, the adequate presence of on-the-ground personnel (eg, clinicians) with the time, support, interest/desire and know-how to conduct research is paramount, as is the “research literacy” of staff as discussed by Brown et al.<sup>##REF##35643418##1##</sup> Such components are integral to creating, and ultimately sustaining, embedded research systems.</p>", "<p> Through their evaluation, Brown et al<sup>##REF##35643418##1##</sup> identified a number of barriers to research literacy and capacity, such as managerial awareness of the time required to conduct research, the need for time compensation to off set clinical time with research time as well as protected time to gain research know-how, for example. Finding ways to increase – as Brown and colleagues<sup>##REF##35643418##1##</sup> refer to it – the “research literacy” of staff is indeed paramount to creating embedded and learning health systems. How to accomplish this objective, when clinical staff are already stretched within resource-constrained health systems? This creates opportunities for boundary spanning and capacity building roles, such as those of the knowledge broker and local champions, and also for dual expertise roles, such as those of the clinician-researcher.</p>", "<p> The clinician-researcher or clinician-scientist career pathway hold marked potential for improving institutional research capacity and the embeddedness of research.<sup>##REF##27254011##7##,##UREF##1##8##</sup> It is one avenue with targeted awareness and support at the trainee and early career levels in Canada, the United States and the Netherlands, for instance, as exemplified through funding and training opportunities provided by the Canadian Child Health Clinician Scientist and Training Upcoming Leaders in Pediatric Science programs, for example. The clinician-scientist career pathway is considered by some to be indispensable to the future of evidence-informed healthcare, particularly in light of collaborative and interdisciplinary necessities.<sup>##REF##27254011##7##</sup> While Brown et al<sup>##REF##35643418##1##</sup> identified that clear clinician-researcher career pathways are critical to attaining the goal of becoming a leading hospital research institute, threats to the physician-researcher pipeline have been reported, and the pathways for allied-health clinician scientists remain notably underdeveloped.<sup>##REF##27254011##7##,##UREF##2##9##</sup> Investments for clinician-scientists must acknowledge the prolongation and intensity of training required to gain both clinical and research proficiency, the personal work/life demands accompanying the training and career pathways, and the importance of mentorship for allied-health and physician-scientists, which are often at a shortfall due to a shortage of comparable faculty to prepare the next generation.<sup>##UREF##2##9##</sup></p>", "<p> Leadership in health systems needs to think creatively and with a sense of urgency about these career pathways, as well as the impact of mentorship on research capacity. Mentorship, particularly in consideration of rural hospitals and health systems, should leverage the importance of networks that are gaining recognition within the complexity science literature.<sup>##REF##29524952##5##,##REF##23425990##10##,##REF##26663417##11##</sup> A mechanism to create links and enable mentorship networks across disciplinary and geographic boundaries would be advantageous, if not necessary, to advancing a sustainable approach to clinical-research mentorship. Empirical literature on networked approaches to mentorship, including the Developmental Network model of mentorship for instance, should inform organizational initiatives.<sup>##REF##26663417##11##</sup> Recognizing health professional educational training and employment as a continuum, a culture of research mentorship and opportunities for horizontal mentorship between peers should be established throughout training in the health sciences, to foster a collaborative research approach, provide social supports, candid advice, as well as early exposure to and aptitude for research.<sup>##REF##23425990##10##, ####REF##26663417##11##, ##UREF##3##12##, ##UREF##4##13####4##13##</sup></p>", "<title>Finances, Investment, and Mandate Alignment</title>", "<p> Financial investment in research made important impact gains in Brown and colleagues’ evaluation study.<sup>##REF##35643418##1##</sup> Yet, a major contextual barrier to research engagement that the authors identified was that research was not directly incentivised through the existing health system-funding model or service agreements. This points to a systemic issue that without creative resolution, will continue to thwart the true integration and embeddedness of research into health systems. As such, while Brown et al<sup>##REF##35643418##1##</sup> go on to speak about the alignment of funding and research priorities, it is also apparent how embedded research may compete with operational imperatives.<sup>##REF##34192427##3##</sup></p>", "<p> Platt et al<sup>##REF##34192427##3##</sup> offer 4 possible solutions to overcome barriers associated with costs, competing research and operational imperatives, and low research participation. These include that funders (1) reimburse health systems for costs of hosting trials; (2) establish research infrastructure in highly engaged systems; (3) shift the burden of research administration, often to coordinating centres; and (4) increase public awareness and reputational benefits associated with systematic research. Notably, the establishment of research infrastructure could also be targeted towards regional health authorities and health systems to help overcome the identified inequities. Increasing public awareness about the benefits of systematic research is aligned with what Brown et al<sup>##REF##35643418##1##</sup> identified as the external expectation to become involved in research, a pertinent example of a professional driver for research capacity and engagement.</p>", "<p> While Brown et al<sup>##REF##35643418##1##</sup> identified relevant broad contextual factors influencing research capacity, further attention to the dramatic shifts in the economics of healthcare worldwide is also warranted.<sup>##UREF##2##9##</sup> In Canada, much of the economic debate — catalyzed by the COVID-19 pandemic — has focused upon policy reform in previously neglected areas, such as long term care and pharmacare.<sup>##REF##33551010##14##</sup> Rapid growth of health care expenditures is considered one of the most important economic trends in America, and it is within this context that research investment must be considered. Higgins<sup>##UREF##5##15##</sup> and others have argued that investment in health research saves lives, and that current investments of the New Zealand government of 0.6%-0.8% of health spending into research is well below the estimated 2.4% required to improve health outcomes, including outcomes at the population health level. Positioning health research investment as a public health issue is necessary to garner public support; locating this attention towards research capacity investments as embedded in health systems is critical to maximizing the impact return of health research expenditures.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that she has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["4"], "person-group": ["\n"], "surname": ["Greenhalgh", "Fisman", "Cane", "Oliver", "Macintyre"], "given-names": ["T", "D", "DJ", "M", "CR"], "article-title": ["Adapt or die: how the pandemic made the shift from EBM to EBM+ more urgent"], "source": ["BMJ Evid Based Med"], "year": ["2022"], "volume": ["27"], "issue": ["5"], "fpage": ["253"], "lpage": ["260"], "pub-id": ["10.1136/bmjebm-2022-111952"]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Boaz", "Hanney", "Jones", "Soper"], "given-names": ["A", "S", "T", "B"], "article-title": ["Does the engagement of clinicians and organisations in research improve healthcare performance: a three-stage review"], "source": ["BMJ Open"], "year": ["2015"], "volume": ["5"], "issue": ["12"], "fpage": ["e009415"], "pub-id": ["10.1136/bmjopen-2015-009415"]}, {"label": ["9"], "mixed-citation": [" National Institutes of Health. Physician-Scientist Workforce Working Group Report. June 2014. "], "uri": ["https://acd.od.nih.gov/documents/reports/PSW_Report_ACD_06042014.pdf"]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Munce", "Archibald"], "given-names": ["SE", "MM"], "article-title": ["\u201cThe future of mixed methods: a five year projection to 2020\u201d an early career perspective"], "source": ["J Mix Methods Res"], "year": ["2017"], "volume": ["11"], "issue": ["1"], "fpage": ["11"], "lpage": ["4"], "pub-id": ["10.1177/1558689816676659"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Zheng"], "given-names": ["DX"], "article-title": ["The need for horizontal mentorship networks to facilitate medical students\u2019 engagement in research"], "source": ["Acad Med"], "year": ["2022"], "volume": ["97"], "issue": ["2"], "fpage": ["167"], "lpage": ["169"], "pub-id": ["10.1097/acm.0000000000004493"]}, {"label": ["15"], "mixed-citation": [" Higgins C. Health research saves lives. Eur J Public Health 2020;30(Suppl 5):ckaa166.1262. "], "pub-id": ["10.1093/eurpub/ckaa166.1262"]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 7; 12:7694	oa_package/e9/6f/PMC10590236.tar.gz
PMC10590237	0	[]	[]	[]	[]	[]	[ "<p>\n<bold>Citation:</bold> Lu J, Ying X, Li Z. Value-based generic drug evaluation focus on Chinese real-world evidence. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7970. doi:10.34172/ijhpm.2023.7970</p>" ]	[ "<title>Dear Editor,</title>", "<p> Increased use of cheap generics could lead to significant savings in drug spending. In the United States, generics make up 90% of all drugs. More than 95% of China’s 170 000 drugs are generic. Meanwhile, there is a broad class of generic drugs called me-too drugs. More than 60% of the Essential Medicines on the World Health Organization (WHO) list are me-too drugs.<sup>##REF##32358800##1##</sup> After generics replace branded drugs, we face an impossible trinity. Impossible Trinity refers to drug policy’s difficulty in achieving three objectives (high quality, low price, and adequate supply) simultaneously.<sup>##UREF##0##2##</sup> East Asia, Europe, the United States, and the Australian governments have implemented their unique methods for drug quality control and re-evaluation (##FIG##0##Figure##).</p>", "<p> The Chinese government has faced daunting challenges from population aging and rising drug costs. Their policy-makers aim to ensure equitable access to affordable, safe, effective, and sustainable drug supplies. Previously, China’s healthcare authorities used the lowest-priced generic drugs to improve the health of residents. Inevitably, some generic drugs are in short supply or of poor quality. In response, the Chinese Health Commission has strengthened its drug evaluation orientation, shifting from price-based to value-based. Subsequently, the guidelines for the management of Clinical Evaluation of drugs were published in 2021, which is the research focus of drug screening in the Healthy China Initiative from 2021 to 2030.<sup>##UREF##1##3##</sup> The results of the evaluation should be applied to the selection and dynamic adjustment of the national essential drug list to control unreasonable drug expenditure.</p>", "<p> China’s drug value evaluation focuses on policy and technology assessment, integrating subjective and objective evaluation. The evaluation considers six dimensions: safety, effectiveness, economy, innovation, suitability, and accessibility. Safety indicators include adverse event rates, while efficacy measures prioritize clinical outcomes. Economic indicators consider drug prices, which can vary for generics. However, consensus has not been reached on evaluation methods and indicators for drug innovation, suitability, and accessibility.</p>", "<p> In the past, there have been flaws in the policy on generic drugs. The effectiveness of some generics has yet to be thoroughly validated, leading to uncertain treatment outcomes. Long-term safety issues have been overlooked, posing risks to patients. Drug pricing and reimbursement policies are imbalanced, causing high prices and limited accessibility. Lack of guidance on drug use can result in misuse. Assessing the value of non-patented drugs faces obstacles such as limited research data, resources, and complexities in the market. Some regulatory agencies prioritize innovative drugs, leading to incomplete evaluation criteria. Limited market competition reduces motivation for evaluation.</p>", "<p> It is possible to use real-world data to evaluate generic drugs. In middle-income countries, little data on solutions from randomized trials.<sup>##REF##36593777##4##</sup> According to the 2022 China Health Statistics Yearbook, with 3275 tertiary hospitals in China, patient drug use data is enormous. Combining hospital data to generate real-world evidence would be more effective and powerful. There are two apparent barriers to medicine evaluation in China. First, the hospital’s data resources must be retrievable, and data collection and centralization are brutal. As a result, the government has established the National Cancer Center, the National Cardiovascular Center, and the National Children’s Medical Center to set up evaluation bases and collect data automatically. Secondly, the multi-criteria decision-making analysis becomes a model solution to unify subjective opinions and objective clinical data in the evaluation process.<sup>##REF##26519081##5##</sup> The model-oriented drug evaluation can quickly adapt to real-world data. For example, when the price of a drug is adjusted, the model can update the results sustainably and quickly. Model-oriented pricing and compensation of essential national drugs are becoming vital to a national drug management system. As a decision-making tool, drug evaluation aims to form a comprehensive and universal drug evaluation system.</p>", "<p> The evaluation center collects data from public tertiary hospitals, focusing on real-world applications and patient treatment records rather than pharmaceutical companies. The goal is to have comprehensive coverage across all 23 provinces in China, with at least 100 designated hospitals for data collection. Continuous monitoring allows for the assessment of long-term trends and effects of drug usage. The evaluation results are used to update national drug catalogues, ensuring that only evaluated and approved drugs are included, providing reliable treatment options for patients. Additionally, the evaluation data is a basis for healthcare and insurance institutions to update their internal drug catalogues and guidelines, ensuring access to the latest and most effective medications.</p>", "<p> As data integration improves, breaking barriers between hospitals has become the mainstream direction in medicine. Establishing a medicine evaluation system aims to expand the scope and improve data quality. Future drug evaluations will involve stakeholders from governments, medical institutions, and academia to prioritize population needs and ensure standardized, scientific, and consistent evaluations. Assessing generic drugs using real-world hospital data confirms their safety, efficacy, and equivalence to branded pharmaceuticals.</p>", "<p> We have the following suggestions for government policy-makers. First, using real-world data to compare the clinical effects of generic drugs and original medications can provide accurate evidence and inform policy decisions. Second, conducting budget impact analyses can assess the potential cost savings of generic drug substitution, considering factors like drug prices, patient numbers, and treatment outcomes. Lastly, collecting patient satisfaction data can help understand the acceptance, effectiveness, and side effects of generic drugs, allowing for policy adjustments and guidance. These recommendations will help the government evaluate the effectiveness and cost-saving potential of generic drugs and make informed decisions to promote their appropriate use.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nOverview of the Global Post-marketing Medicine Evaluation Program.</p></statement></fig>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"ijhpm-12-7970-g001\" position=\"float\"/>" ]	[]	[{"label": ["2"], "mixed-citation": [" Hemel DJ, Ouellette LL. The generic drug trilemma. In: Entrepreneurship and Innovation Policy and the Economy. National Bureau of Economic Research; 2022. "]}, {"label": ["3"], "mixed-citation": [" NHC. Notice of Comprehensive Clinical Evaluation of Drugs. 2021. "], "uri": ["http://www.nhc.gov.cn/yaozs/s2908/202107/532e20800a47415d84adf3797b0f4869.shtml"]}]	{ "acronym": [], "definition": [] }	5	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 10; 12:7970	oa_package/33/c5/PMC10590237.tar.gz
PMC10590238	0	[ "<title>Introduction</title>", "<p> In his insightful editorial, Ronald Labonté writes that the COVID-19 pandemic demonstrated that socioeconomic inequality is lethal.<sup>##REF##35942959##1##</sup> I agree. Recognizing that the pandemic is internal to capitalism sharpens the contradictions between a world shaped by the profit motive and health justice.<sup>##UREF##0##2##</sup> Labonté identifies capitalism’s economic growth imperative as the underlying problem. As such, reforms like stakeholder capitalism, the pursuit of capitalist ‘green recoveries,’ and policy options that could improve well-being within the growth paradigm cannot address the problem. He concludes that a transformative shift away from an economic system centered on economic growth to one that enhances health, prosperity, and well-being is necessary. Labonté proposes that health equity and environmental sustainability may be best obtained through what he calls a <italic toggle=\"yes\">post-growth, sustainable caring economy</italic>.</p>", "<p> Hence, given the importance of care in formulating alternatives, I wish to complement Labonté’s editorial by elaborating on ‘care economies’ and the work of social reproduction. I begin by noting that the existing care economy is a structural part of capitalism that largely generates and sustains inequities. The ways in which capital organizes production and reproduction combine with systems of oppression by gender and race to generate vulnerability among the diverse populations.<sup>##REF##33905301##3##</sup> This reinforces Labonté’s argument that transformation is needed; that minor changes compatible with the growth imperative are unable to address the problems it creates. I then clarify the meaning of transformation in relation to care economies and the labor they entail. Transformation could, and should, change the perceived value, status, and material rewards of work in the care economy. It should shift the gender division of labor and reduce related socioeconomic inequality and gender inequality/inequities. Finally, I touch on the policy tools Labonté describes, highlighting how they connect to my broader point: that the care economy is currently an integral, but devalued part of capitalism; for a transformation to take place, raising perceived value, status, and relative material rewards of caring work and the people who do it must be an explicit policy goal.</p>" ]	[]	[]	[]	[]	[ "<p>Labonté proposes that health equity and environmental sustainability may be best obtained through a care economy. Because a care economy plays a key role in Labonté’s formulation, its position in the capitalist political economy, the work it entails, and the workers who do it all merit further reflection. I aim to complement Labonté’s editorial by elaborating on care economies and the work of social reproduction. The existing care economy is a structural part of capitalism that largely generates and sustains inequities, reinforcing Labonté’s argument that transformation is needed. Transformation could, and should, change the perceived value, status, and material rewards of work in the care economy. I then touch on the policy tools Labonté describes, highlighting how they connect to my broader point: that the care economy is currently an integral, but devalued part of capitalism. For a transformation to take place, raising perceived value, status, and material rewards of caring work and the people who do it must be an explicit policy goal.</p>", "<p>\n<bold>Citation:</bold> Cohen J. The values of the care economy: Comment on \"Ensuring global health equity in a post-pandemic economy.\" <italic toggle=\"yes\">Int J Health Policy Mana</italic>g. 2023;12:7762. doi:10.34172/ijhpm.2023.7762</p>" ]	[ "<title>Care and transformation</title>", "<p> Care economies appear in Labonté’s comments in two forms: (<italic toggle=\"yes\">a</italic>) as an economy that already exists and (<italic toggle=\"yes\">b</italic>) as something to transition to — a future to be achieved. I’ll call the former the <italic toggle=\"yes\">care economy</italic> and the latter a <italic toggle=\"yes\">Health and Social Care Economy</italic> (HSCE). Linking the two is the transformation away from the existing political economy in which the capitalist pursuit of profits dominates the pursuit of human well-being.</p>", "<p> At present, profit-seeking drives production and consumption; it is the engine of capitalist growth. Growth has multiple sources but cost minimization, particularly minimizing the cost of the unique input — labor — is key. Profit-seeking incentivizes and exploits discrimination at multiple scales and reinforces inequities to reduce costs, for example by clustering marginalized populations into a smaller set of gendered and racialized jobs. Occupational segregation depresses wages and workers’ bargaining power in those jobs while reducing competition for higher status, better paid work. A care economy is present but is seen as marginal to ‘The Economy’; popularly imagined as production and paid work outside of the household. Care economy work is essential; however it is often low status, poorly paid or unpaid, and is disproportionately done by women. The care economy is therefore integral to socioeconomic inequality and inequities in the capitalist political economy.</p>", "<p> In a transformed world a different engine would displace the profit motive. The sustainable reproduction of life is a powerful alternative. It is already present in many of the activities undertaken by individuals in the care economy, such as childbirth (labor), childcare, eldercare and the day-to-day tasks typically done in the household. It is life-making. The transformation to a HSCE therefore hinges on changes to the perceived value, status, and material rewards of caring work — the work of <italic toggle=\"yes\">social reproduction</italic>. A broadscale economy guided by the sustainable reproduction of life could offer a far more egalitarian economic system. Work would no longer need to be organized around profit maximization; its pay and status could reflect its <italic toggle=\"yes\">social value</italic>. Where the profit motive incentivizes using inequities to enhance economic growth, its replacement could incentivize equity-enhancing production and reproduction of public goods. The incentive to deploy social oppressions to minimize costs by systematically paying, ie, women less than men would evaporate, at least in theory. Health, education, and social services, all sectors in which women are concentrated, could become the most highly valued and well-paid sectors of the economy, over the financial sector, for example. This possible HSCE should shift the gender division of labor and reduce related socioeconomic inequality and gender inequality/inequities.</p>", "<p> Such a transformation may seem implausible. The entrenched interests of capital have used inequities to serve capital accumulation, hence a transformation is likely to be resisted by entities that profit, or otherwise benefit, from inequities. Labonté notes that the immediate challenge to transformation is the rise of authoritarianism and the decline of democratic accountability. Authoritarianism, and conservatism more generally, are heavily invested in maintaining inequitable social relations. The maintenance of inequity is their raison d’être.<sup>##UREF##1##4##</sup> The profit motive is compatible with authoritarianism; both rely on and reinforce inequities.</p>", "<p> However, a transformation <italic toggle=\"yes\">of some kind</italic> seems inevitable. In the context of mass consumption primarily in the Global North and ecological devastation, the reproduction of life itself is increasingly unsustainable. Labonté notes several policy tools that could facilitate a socially desirable transformation. Women, the care economy, and the gender division of labor are missing from the policy discussion but are salient to conversations about tax justice, fiscal and monetary policy, and the lending practices of international financial institutions. I will return to this point after I elaborate on the substance of the existing care economy.</p>", "<title>Capitalism and the Existing Care Economy</title>", "<p> The care economy consists of the day-to-day work required to “maintain existing life and to reproduce the next generation.”<sup>##REF##12316382##5##</sup> Women are disproportionately tasked with this work through the gender division of labor. People are produced, both physiologically through women’s [going into] labor and through ongoing effortful activity done primarily by women. In this way, societies rely on women and their labor for their ongoing existence. Despite its obvious importance most care work is unpaid or poorly paid and relatively low status.</p>", "<p> Gender is central to the capitalist organization of work. It influences the paid and unpaid work activities that women and men are expected to take on. In unpaid work, the burden of reproductive labor on women increased during COVID-19, as is reflected in data about who left the labor force.<sup>##REF##33905301##3##</sup> During the pandemic, people, especially women, were forced to act as “shock absorbers” by providing home-based care for the sick and taking on additional household labor. However, pandemic damage mitigation expands the already-fraught work of reproducing life in non-pandemic conditions, potentially to the detriment of health generally and to women’s health in particular.<sup>##REF##32357173##6##,##UREF##2##7##</sup> It also increases women’s risk of exposure and reinfection at home.</p>", "<p> The care economy includes paid work in health, education, and social services. Women are concentrated in these sectors (ie, 85% of nurses and midwives are women globally) which also entail high risk of exposure.<sup>##UREF##3##9##</sup> Higher infection rates for working-age (20-59 years) women are documented during COVID-19 peaks.<sup>##REF##36016899##8##</sup> In one case women were 80% of care workers but up to 90 percent of care workers with COVID-19. Just as societies rely fundamentally on women and their labor, healthcare systems depend fundamentally on women’s continued participation as suppliers of care.</p>", "<p> There is a substantial gender pay differential — globally, women earn 24% less than men — in the care sector, even after accounting for age, education, occupational category, working time, and public/private sector employment.<sup>##UREF##3##9##</sup> Occupational demands, such as inflexible work schedules or long shifts, may conflict with women’s responsibility for care and other household work. Likewise, gendered responsibility for household work can limit women workers’ ability to meet occupational demands because paid occupations are not designed to accommodate realities of women’s lives.<sup>##REF##32357173##6##,##UREF##2##7##</sup> Many women in the paid care economy experience related distress and burnout. The household can be a dangerous worksite as well.<sup>##UREF##4##10##</sup> Responsibility for care can be detrimental to one’s own well-being.<sup>##REF##32357173##6##,##UREF##2##7##</sup></p>", "<p> The paid and unpaid work in the care economy is therefore an integral part of socioeconomic inequality: the capitalist organization of work generates and reinforces inequities with material consequences. Therefore, in its present form, the massification of the care economy is not particularly appealing. However, the lamentable problems of reproductive labor and paid care work are emphatically <italic toggle=\"yes\">not</italic> their existence. <italic toggle=\"yes\">The problems are the inequitable gender roles that task women with the work and the gendered value systems that leave it un- or poorly-compensated and devalued</italic>.</p>", "<title>Policy for a Health and Social Care Economy</title>", "<p> The points above clarify that gender inequality/inequities are not “women’s issues.” They are social problems, constraints on the supply of care, and sources of systemic instability in healthcare and society. The pursuit of gender equity is crucial to any transition away from the existing organization of work. Without it, a transition is unlikely because of the low status of care as “women’s work” — but even if there were a transition, there is little reason to expect that the gender division of labor would change automatically or appreciably. In other words, for a transformation to take place, raising the perceived value of women and the work they are tasked with must be a policy goal. Policy, economic and otherwise, is not likely to change perceived value or the gender division of labor unless that change is an explicit aim for policy-makers.</p>", "<p> Labonté describes the disproportionate and negative impacts of COVID-19 on women as a rationale for greater public investment in health and social protection. He recognizes the consequences of the pandemic and of government policy on women that manifest through the gender division of labor. Yet women are missing from the discussion of policy — specifically taxes, modern monetary theory, and International Monetary Fund reform. Seemingly ‘gender-neutral’ policy is common, but policy rarely has gender-neutral outcomes. Gender analysis is needed to understand these effects.</p>", "<p> Despite the silence, progressive policy reform is typically directed at improving the conditions of social reproduction. For example, to Labonté the aim of global tax justice is the reallocation of accumulated wealth toward health and social benefits that could support people and households. At the macroeconomic level, low interest loans without the structural adjustment policies that are well-documented as exacerbating gender inequality/inequities could enable social spending in underdeveloped countries. At a micro/sectoral level, higher pay or additional benefits for care workers would contribute to socioeconomic equality and gender equality. They could also raise the status and perceived value of the work, making it more attractive to workers. Changing the perceived value, status, and material rewards of caring work and the people who do it is what would make the transformation transformative in people’s day-to-day lives.</p>", "<p> Finally, I have not touched on the question of degrowth policy/language or on reduced consumption of material goods in the Global North.<sup>##REF##37579356##11##</sup> The myriad other forms of sustainable, humanizing growth in capabilities and interdependency could be framed as regrowth. Higher ‘consumption’ of tangible and intangible things that improve quality life — like better health, time for leisure, solidarity, friendship — are likely to appeal to many people. Denaturalizing capitalism as the sole option in the popular imagination (of Global Northerners) can be empowering. I hesitate to use economistic language, but it could provide a bridge for a social rethinking what and who an economy, any economy, is <italic toggle=\"yes\">for</italic>. Every society has an economy to provision life: the form and social possibilities beyond the profit motive are endless. There is much to be gained from valuing caring work and the people who do it.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that she has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "mixed-citation": [" Cohen J. The Feminist Political Economy of Health Justice. September 29, 2021. Bill of Health. Petrie-Flom Center, Harvard Law. "], "uri": ["https://blog.petrieflom.law.harvard.edu/2021/09/29/feminist-political-economy-health-justice/"]}, {"label": ["4"], "mixed-citation": [" Robin C. The Reactionary Mind: Conservatism from Edmund Burke to Sarah Palin. Oxford: Oxford University Press; 2013. "]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Cohen"], "given-names": ["J"], "article-title": ["Precarity of subsistence: social reproduction among South African nurses"], "source": ["Feminist Economics"], "year": ["2023"], "volume": ["29"], "issue": ["1"], "fpage": ["236"], "lpage": ["265"], "pub-id": ["10.1080/13545701.2022.2123950"]}, {"label": ["9"], "mixed-citation": [" World Health Organization (WHO), International Labour Organization (ILO). The Gender Pay Gap in the Health and Care Sector: A Global Analysis in the Time of COVID-19. Geneva: WHO, ILO; 2022. "], "uri": ["https://www.who.int/publications/i/item/9789240052895"]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Bergmann"], "given-names": ["BR"], "article-title": ["Occupational segregation, wages and profits when employers discriminate by race or sex"], "source": ["East Econ J"], "year": ["1974"], "volume": ["1"], "issue": ["2"], "fpage": ["103"], "lpage": ["110"]}]	{ "acronym": [], "definition": [] }	11	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 20; 12:7762	oa_package/28/a2/PMC10590238.tar.gz
PMC10590239	0	[ "<title>Background</title>", "<p> Globally there is well recognized transition towards diets that contain more sugar, fat, salt and refined carbohydrates and contain a greater proportion of caloric sweeteners, vegetable oils, animal-sourced foods, and ultra-processed foods (UPFs).<sup>##UREF##0##1##, ####UREF##1##2##, ##REF##32630022##3####32630022##3##,##REF##22221213##5##</sup> This dietary trend is recognized as a key driver of obesity and diet-related non-communicable diseases (DR-NCDs) worldwide<sup>##UREF##0##1##, ####UREF##1##2##, ##REF##32630022##3####32630022##3##</sup> and is occurring at a faster rate in low-, and particularly middle-income countries than occurred in high-income countries due to rapid economic development, urbanization, and industrialization.<sup>##REF##22221213##5##,##REF##21872749##6##</sup> UPFs, defined as ready-to-eat products, composed of substances derived from foods combined with cosmetic additives and derived from a series of industrial processes<sup>##UREF##3##7##</sup> are particularly unhealthy. They include for example, most sugary drinks, confectionary, savoury snacks, baked goods, and sweet biscuits. UPFs represent an increasing proportion of people’s daily energy intake globally<sup>##REF##32630022##3##</sup> now contributing more than 50% of energy intake in high-income countries and up to 30% in middle-income countries where consumption is particularly on the rise.<sup>##REF##32761763##8##,##UREF##4##9##</sup></p>", "<p> These patterns of increased consumption have, in part, been driven by global market integration. This has been achieved through trade and investment liberalization (as well as technological developments) that has contributed to the production of larger volumes of UPFs with long shelf lives enhancing their tradability; promoted foreign direct investment by transnational corporations into food processing and retailing; and facilitated intensive global food marketing and advertising.<sup>##REF##32761763##8##,##REF##15975180##10##, ####REF##22802732##11##, ##REF##16569239##12####16569239##12##</sup></p>", "<p> As populations increasingly undergo the nutrition transition, ensuring equitable access to healthy food and preventing DR-NCDs has been recognized as critical to achieving sustainable development.<sup>##REF##30700377##13##</sup> This is reflected in the Declaration of the United Nations (UN) Decade of Action on Nutrition 2016‐2025 and the 2018 UN Political Declaration on Prevention and Control of NCDs; and the inclusion of both nutrition and NCD targets within the Sustainable Development Goals. To achieve these targets, there have been repeated calls for government leadership and policy action that moves beyond abdicating responsibility for unhealthy eating to individuals and towards addressing the multiple food system drivers that create obesogenic food environments including in agriculture, trade, investment, public policy, and marketing.<sup>##REF##16569239##12##, ####REF##30700377##13##, ##UREF##5##14##, ##UREF##6##15##, ##UREF##7##16####7##16##</sup></p>", "<p> Various frameworks and guidelines exist to inform such action.<sup>##UREF##6##15##, ####UREF##7##16##, ##REF##24103073##17####24103073##17##</sup> These include actions targeting the food supply (eg, removing sugar subsidies and implementing agricultural policies that incorporate health outcomes) and more directly the food environment (eg, taxes and import tariffs, healthier product reformulation, food standards in public institutions, banning unhealthy food marketing to children, targeted subsidies, and food labelling).<sup>##REF##21872749##6##,##REF##24103073##17##</sup> However, the vast majority of governments have failed to translate these frameworks into policy action that adequately addresses the food system drivers of unhealthy diets, obesity and DR-NCDs.<sup>##REF##21872749##6##,##UREF##8##18##</sup> Further, minimal consideration has been given specifically to UPF in strategies aiming to reduce obesity or DR-NCDs.<sup>##REF##32630022##3##</sup></p>", "<p> As such, while a few countries have made progress on under-five obesity, the vast majority are off-track for meeting adult obesity and DR-NCD targets by 2025.<sup>##UREF##8##18##,##UREF##9##19##</sup> Corporate influence, particularly from large transnational food corporations, and lack of political will have been identified as two key reasons for policy inaction.<sup>##REF##30700377##13##,##UREF##8##18##,##REF##27034196##20##</sup> A small but growing body of public health policy literature seeking to explain these factors explores how political economy factors including political and economic actors, interests, institutions and ideas interact to limit political will and enhance corporate influence over DR-NCD prevention policy.<sup>##REF##32761763##8##,##UREF##8##18##,##REF##27034196##20##, ####REF##31245905##21##, ##REF##28161671##22##, ##REF##33895830##23##, ##REF##25433616##24##, ##UREF##10##25####10##25##</sup></p>", "<p> In line with a call for greater consideration of power in policy-making, more explicit analyses of how political economy factors shape power relations and inequities in DR-NCD policy-making are also emerging.<sup>##REF##33895830##23##,##UREF##11##26##,##UREF##12##27##</sup> For example, we recently explored how health harmful commodity corporations including tobacco, alcohol, and UPF corporations can exercise and benefit from different forms of power (instrumental, structural and discursive) via various mechanisms (eg, ideas, evidence, and institutions) to promote NCD policy inaction at the nexus of trade and health.<sup>##REF##33895830##23##</sup></p>", "<p> It has also only more recently been recognised that NCD prevention policy action/inaction occurs within a wider complex system of multiple inter-dependent political economy factors in feedback relationships.<sup>##UREF##8##18##,##REF##33895830##23##,##UREF##12##27##</sup> For example, one such feedback loop involves international trade and investment liberalization which has incentivized governments to promote and producers to deliver large volumes of commodities for export/use in global supply chains. The multinational agribusiness firms that have thrived under these conditions have, in turn, acted to maintain them, eg, by using the economic power gained for lobbying for trade policy that bring them financial benefit<sup>##REF##21284237##28##</sup> while entrenching limited nutrition policy space.</p>", "<p> Complex system problems involve multiple such feedback processes and, as such, are not caused by simple linear cause and effect relationships. Instead the behaviour of such ‘problem systems’ can vary over time (displaying dynamic complexity) making it difficult to predict the impact of interventions aimed at addressing the problem.<sup>##UREF##13##29##</sup> Further, when dynamic complexity is not taken into account, proposed solutions to a complex system problem can be too limited in scope, low impact and generate unintended consequences over time.<sup>##UREF##14##30##</sup></p>", "<p> Causal complexity in NCD prevention policy inaction is difficult to capture and analyze using traditional health policy process analysis methods.<sup>##REF##32563223##31##</sup> This has sparked an interest in applying systems thinking methods where policy action/inaction is understood as emerging from the dynamics of a wider political economy system.<sup>##REF##30700377##13##,##UREF##12##27##</sup> It involves mapping the interactions between multiple components within a complex system to understand how system behaviour changes over time.<sup>##UREF##15##32##</sup> This may offer a promising tool for more reliably identifying impactful system-level solutions to NCD prevention policy inertia. However, with system methods only more recently being considered by public health policy process researchers, application of these methods in this research area remain limited. We identified just two studies that used system dynamics methods to explore the politics of food/nutrition policy-making. These were Baker and colleagues’ study exploring political commitment to ending malnutrition and how factors shaping nutrition actor network effectiveness can be strengthened<sup>##REF##31245905##21##</sup> and Clarke and colleagues’ use of systems thinking methods to explore the underlying dynamics of obesity prevention policy-making in Australia.<sup>##REF##33481898##33##</sup></p>", "<p> Further utilizing systems thinking approaches in this area, the aim of this work was to deepen understanding of the causal complexity of DR-NCD policy inaction due to multiple inter-dependent political economy mechanisms and different forms of transnational corporate power. Using South Africa as a case study, we apply system dynamics methods to develop several dynamic hypotheses to describe the problem of DR-NCD policy inaction. We then use these to identify potential leverage points in the system which may shift the existing power dynamics to facilitate greater political commitment for healthy, equitable and sustainable food system transformation.</p>" ]	[ "<title>Methods</title>", "<title> Systems Thinking and System Dynamics </title>", "<p> A systems thinking approach facilitates the organization of complex information with a focus on the whole system.<sup>##REF##29190662##34##</sup> System dynamics, the systems thinking method used in this work, is based on a number of underlying characteristics of complex systems. These include that complex systems are made up of multiple interacting elements; these interactions drive system behaviour over time; relationships between elements are characterized by reinforcing and balancing loops; relationships between elements are also characterized by “stocks” and “flows” (eg, of resources, information or people); and cause and effect relationships change elements at different rates over time.<sup>##UREF##16##35##,##REF##26961081##36##</sup> The system dynamics process involves defining a problem preventing certain desired outcomes; qualitatively mapping the problem system structure; developing a dynamic numerical simulation model; testing different scenarios; and designing and comparing the effect of different policy options on key outcomes over time.<sup>##UREF##17##37##</sup> This work undertakes the qualitative mapping step alone aiming to deepen understanding of the causal complexity of NCD prevention policy inaction.</p>", "<title> Case Study Selection</title>", "<p> South Africa was selected as a case study for this work due to a combination of political, economic and health characteristics. Firstly, South Africa is a middle-income country that underwent a rapid period of trade and investment liberalization after Apartheid ended in 1994 and remains a relatively open economy to trade and investment. Secondly, South Africa’s geographic position and infrastructure makes it an attractive strategic hub from which UPF-producing corporations can develop new markets across Africa. This combined with South Africa’s recognition as a regional policy leader, may mean food corporations have particular interest in securing and maintaining a favourable regulatory environment in South Africa to prevent regional and continental policy transfer.</p>", "<p> At the same time, there has been significant growth in sales of UPFs and beverages in South Africa between 2006-2019.<sup>##REF##32761763##8##</sup> Along-side continuing high levels of underweight and nutritional deficiencies, the percentage of children and adults who are overweight or obese has significantly increased in South Africa in recent years, with a parallel increase in the per capita food supply of fat, protein and total calories.<sup>##REF##22802733##38##</sup> An estimated 68% and 31% of South African women and men respectively, are overweight or obese.<sup>##UREF##18##39##</sup> Thirteen percent of children are overweight in South Africa,<sup>##UREF##18##39##</sup> more than double the world average.<sup>##UREF##19##40##</sup> In 2000, an estimated 36 504 deaths (7% of all deaths) in South Africa were attributed to excess body weight<sup>##REF##17952230##41##</sup> and overall, NCDs now account for 51% of all deaths annually.<sup>##UREF##20##42##</sup></p>", "<p> However, while the South African government has adopted some internationally recommended policies to promote healthy eating, a number of DR-NCD prevention policies have yet to be adopted in the country and there remains significant incoherence between trade and investment policy and DR-nutrition objectives.<sup>##UREF##21##43##</sup> This combination of factors allowed us to explore the dynamic complexity of how political economy mechanisms and corporate power may inhibit DR-NCD policy action over time.</p>", "<p> This study applied a participatory system dynamics modelling method using key stakeholder interviews to iteratively develop several initial causal loop diagrams (CLDs) hypothesizing how, over the past two decades of trade and investment liberalization, transnational corporate power may operate to weaken DR-NCD prevention policy norms in South Africa.</p>", "<title> Data Collection </title>", "<p> Semi-structured interviews with the offer of anonymity were selected as the method of data collection for this work (instead of group model building) for several reasons. These include the highly political nature of the topic area and highly unequal power relations between different policy actors which may limit frank discussion in a group model building setting.</p>", "<p> A stakeholder mapping exercise was initially undertaken to identify key policy actors with the assistance of a research collaborator within South Africa’s National Department of Health. Policy actors were selected purposively from the stakeholder mapping and then snow-ball sampling. Fifty key policy actors were invited for an interview from the following stakeholder groups: Department of Health (DH), Department of Trade and Industry (DTI), Department of Agriculture, Forestry and Fisheries (DAFF), National Treasury, intergovernmental organizations (IGOs), non-governmental organizations (NGOs) involved in supporting nutrition policy development, civil society groups (CSOs) involved in nutrition policy advocacy, academics with expertise in nutrition policy and/or the food system and food corporations. Twenty-nine policy actors agreed to take part in an interview, 13 did not respond and 10 declined the invitation (see ##TAB##0##Table 1##). Four policy actors were however subsequently excluded since they did not provide in their interviews any explanatory data relevant for model building, resulting in 24 interviews with 25 participants ultimately being included. All government participants were Chief or Deputy Directors within their respective departments with one Deputy Director General. We attempted to conduct interviews with government stakeholders in both senior technical and more political roles (including Director Generals and Ministers), however it was extremely challenging to gain access to the latter group despite extensive attempts including via one of the investigators based within the DH. Industry representatives were governance and regulatory experts; and IGO, NGO, and CSO representatives had each been engaged in recent relevant nutrition policy processes in South Africa.</p>", "<p> Each policy actor participated in a semi-structured interview lasting on average between 45-75 minutes between May and September 2019. Interviews were conducted in-person in Cape Town or Pretoria or telephonically where in-person interviews were not possible. The interview guide was structured to elicit an in-depth understanding of key policy actors’ ideas, values, interests and positions in relation to nutrition and trade, investment and economic objectives; perceptions of the influences that trade and investment agreements and other trade and investment-related factors have on nutrition policy processes; and the strategic approaches adopted by stakeholders to achieve their desired nutrition or trade/economic objectives. Wherever possibly ‘why’ and ‘how’ questions were used during the interviews to get at the causality that participants perceived. All interviews were recorded and later transcribed in full and handwritten notes transferred into Microsoft Word documents.</p>", "<title> Data Analysis</title>", "<title> Individual Causal Loop Diagram Development </title>", "<p> Data analysis was undertaken using purposive text analysis (PTA) to systematically identify causal statements from which linkages between system variables/elements could be identified to inform model conceptualization.<sup>##UREF##21##43##,##UREF##22##44##</sup> In PTA coding is initially inductive, later also employing a deductive approach as a coding index develops during the text analysis process. Data interpretation and model conceptualization was also informed by a conceptual framework for analysing different forms (instrumental, structural, and discursive) and mechanisms of power in health policy-making that we previously developed, tested and refined in a related realist review.<sup>##REF##33895830##23##</sup> Details of the conceptual framework, including descriptions of the different forms and mechanisms of power, and how the framework was developed are included in ##SUPPL##0##Supplementary file 1##.</p>", "<p> For each interview transcript all data segments describing a causal process were extracted and documented on a PTA coding chart. The cause variable, effect variable and the polarity of the relationship was then represented in a simple words and arrow diagram (See ##SUPPL##1##Supplementary file 2## for an example of a PTA coding chart).<sup>##UREF##21##43##,##UREF##22##44##</sup> These were then merged into CLDs for each participant, representing each participant’s mental model defined as “a relatively enduring and accessible, but limited, internal conceptual representation of an external dynamic system.”<sup>##UREF##23##45##</sup></p>", "<p> As PTA and CLD development progressed, standardised system variables were developed in an iterative process to include varied descriptions of the same causal phenomena by different participants in a single more generalized variable/relationship.<sup>##UREF##22##44##</sup> Some causal relationships were also decomposed further by identifying implicit structures implied by the context (see ##SUPPL##2##Supplementary file 3## for examples of merging and generalizing variables and decomposing CLDs).<sup>##UREF##22##44##</sup></p>", "<title> Shared Causal Loop Diagram Development</title>", "<p> First, groups of two to four individual mental models (represented as CLDs) of participants with different perspectives on the same policy issue were composed. The individual CLDs in each group were then combined to generate seven shared CLDs based on different policy issues (eg, front of package food labelling, tax on sugar-sweetened beverages or marketing of breast milk substitutes). We then mildly ‘pruned’ the seven ‘policy issue’ CLDs – keeping delays and feedback structures but removing linear linkages.<sup>##UREF##21##43##</sup> Next we combined the seven shared ‘policy issue’ mental models into final shared mental model (SMM) for all participants.<sup>##UREF##21##43##</sup></p>", "<p> Details of the systematic approach to CLD combination can be found in ##SUPPL##2##Supplementary file 3## and in Milsom.<sup>##UREF##24##46##</sup> While the majority of stakeholders (participants) provided additive rather than conflicting views, there were rare occasions where one or more stakeholders identified a relationship that another stakeholder expressly denied. In these instances, the relationship identified by the stakeholder with the closest experience of that part of the system was considered most accurate and was reflected within the final SMM.</p>", "<p> In a third step, the SMM was simplified and generalized for improved usability. This involved additional pruning<sup>##UREF##21##43##</sup> of the SMMs to remove remaining linear linkages. Additionally, structures describing similar phenomena, but in more detail were aggregated into variables and relationships at a higher level of abstraction (##SUPPL##2##Supplementary file 3## provides an example).<sup>##UREF##21##43##,##UREF##22##44##</sup></p>", "<p> Now with a more detailed understanding of the interview data and broad sense of the overall system structure, it was possible to clarify certain parts of the model in an iterative process, moving from the two SMMs to the PTA coding charts and back. This included adding feedback processes that had not initially been obvious during the PTA and structures implied by the context but not explicitly mentioned in stakeholder interviews. For example, DH policy-makers did not specifically state that their increased focus on food/nutrition policies was due to increasing prevalence of DR-NCDs in South Africa, but this was considered a valid relationship to incorporate into the model structure (see sub-system I, DR-NCD prevalence <bold>→</bold> perceived salience of nutrition problem/impacts and solutions)given the government’s increased focus on food/nutrition policy following data illustrating a progressive increase in diet-related NCD prevalence.</p>", "<p> Finally, to further develop the SSM we drew on the findings of a related realist review,<sup>##REF##33895830##23##</sup> identifying two additional variables and nine linkages. These were initially included in the model to be reviewed for real-world relevance by stakeholders during model validation. At this stage due to the large number of variables and feedback loops, to improve usability of the SMM, it was divided into two distinct SMMs according to the forms of power described in the conceptual framework used in the analysis.<sup>##REF##33895830##23##</sup> The two SMMs were however highly inter-connected as indicated by a relatively high number of the same elements appearing in both sub-systems (eg, ‘strength of neoliberal beliefs, values and norms’ appears in both sub-systems).</p>", "<title> Model Validation </title>", "<p> We applied a series of validity tests to build confidence that the SMMs, as closely as possible, represented the aspects of the system that are relevant to the problem under study (the details of these can be found in Milsom<sup>##UREF##24##46##</sup>). The most important of these was to validate the resulting SMM via 90-minute structured dialogue sessions<sup>##UREF##25##47##,##UREF##26##48##</sup> with eight key stakeholders previously interviewed (including representation from each of the stakeholder groups involved in model conceptualization, see ##TAB##0##Table 1##). These stakeholders were local to South Africa and were known to have intimate knowledge of the system problem being examined. These sessions were conducted in November 2020. Each interview focused on presenting and discussing the model’s structure, behaviour and structure–behaviour connections.<sup>##UREF##26##48##</sup> Participants were encouraged to question the real-world validity of the variables and feedback structures presented to them (particularly those added from the literature) and highlight flaws or missing structures.<sup>##UREF##26##48##</sup> Detailed notes were taken by the interviewer (PM) during these sessions. Model structures not validated by stakeholders were removed and some parts that had not been fully understood from analysing the original interview data were clarified. ##SUPPL##3##Supplementary file 4## includes both prevalidated SMMs for comparison. Once the SMM was adequately revised to address the flaws and missing structures identified by stakeholders, it was considered to be the final conceptual model (a complex system model divided into two sub-systems of DR-NCD policy-making).<sup>##UREF##21##43##</sup></p>" ]	[ "<title>Results</title>", "<p> The conceptual model represents interactions between elements (eg, actions, conditions, and resources) that may explain observed limitations on DR-NCD policy progress over time despite increasing obesity and NCD prevalence in South Africa. The variables are connected via arrows representing causal links and form feedback loops – cycles of cause and effect that determine how the system’s behaviour changes over time.<sup>##REF##26961081##36##</sup> Reinforcing loops reinforce system behaviour over time and balancing loops regulate the effects of changes imposed on the system.<sup>##UREF##14##30##</sup></p>", "<title> Instrumental Power</title>", "<p> Sub-system I (##FIG##0##Figure 1##) illustrates stakeholders’ understanding of the dynamic relationships between different mechanisms of industry’s intrumental power (see ##SUPPL##0##Supplementary file 1##) over formal political decisions relating to DR-NCD policy. These mechanisms include relationships; knowledge and evidence; and rules.<sup>##REF##33895830##23##</sup> In this sub-system we identified six reinforcing loops and five balancing loops. ##TAB##1##Table 2## provides a key for both sub-systems.</p>", "<p>\n<italic toggle=\"yes\">R1 Food industry’s productive power:</italic> Illustrates how as the food industry’s economic and material power increases, so too does the tendency for the government to adopt trade and investment policy favourable to them which, in turn, facilitates industry growth, further increasing their economic and material power.</p>", "<p>\n<italic toggle=\"yes\">R2 Manufacturing doubt:</italic> Economic and material power of industry increases the food industry’s ability to ‘manufacture doubt’ (for example, stakeholders reported infant formula companies fund biased child nutrition research and education) which increases the additional evidence required to support policy adoption. This often leads to significant delays in the policy process while the required research is gathered or conducted. When it is not possible to undertake research due to lack of resources or methodological challenges, the likelihood of policy adoption is very low with policy-makers frequently citing lack of evidence as the reason for policy inaction. Policy inaction and a weak regulatory environment then tends to perpetuate weak pro-nutrition policy norms, providing no counter force to policy norms which further expands industry economic power.</p>", "<p>\n<italic toggle=\"yes\">R3 DH Funding challenge:</italic> With increasing dominance of neoliberal beliefs, values and norms greater importance is placed on economy-focused departments (eg, the DTI) than health and departmental budgets reflect this. With relatively less funding, the DH’s capacity to conduct/commission DR-NCD policy research and to enforce regulations which both decrease the likelihood of DR-NCD policy action, again maintaining weak pro-nutrition policy norms which cannot challenge the predominant neoliberal ideology resulting in persistently low funding allocations to the DH.</p>", "<p>\n<italic toggle=\"yes\">R4 Industry lobbying</italic>: The food industry’s economic and material power increases their lobbying capacity, which expands their participation in nutrition policy processes, and potentially also the weight of industry interests in policy decisions. This in turn increases the level of evidence and advocacy effort required by the DH to advance a proposed regulation reducing the likelihood of DR-NCD policy action which, yet again, perpetuates weak pro-nutrition policy norms and the predominant neoliberal ideology. This drives a regulatory environment that is increasingly favorable to the food industry, supporting industry growth and in turn expanding their economic and material power and lobbying capacity.</p>", "<p>\n<italic toggle=\"yes\">R5 Industry legitimacy</italic>: Increasing dominance of the neoliberal ideology also drives policy-makers to weigh economic considerations more heavily in nutrition policy decisions leading to a heightened perception of food industry legitimacy as a stakeholder in the policy process which increases industry’s participation in the policy process (in turn further emphasizing the weight of economic considerations, and specifically industry interests, in policy decisions). Through their participation, industry is able to deepen the perceived economic impact of a given policy, generating greater resistance to policy adoption, yet again maintaining weak pro-nutrition policy norms which fail to counter the predominant neoliberal ideology.</p>", "<p>\n<italic toggle=\"yes\">B1 Evidence-based policy-making:</italic> The level of evidence required to support a proposed policy increases with increased food industry participation in the policy process, their ability to ‘manufacture doubt’ about a policy’s effectiveness, the weight of economic considerations and industry interests in nutrition policy-making and perceived risk of a trade/investment dispute. These factors drive evidence-based policy-making which, over time, drives research, increasing the availability of evidence (and likelihood of policy adoption) and in turn ultimately reduces the level of additional evidence required. Lack of local funding can significantly slow this process and delay policy adoption.</p>", "<p>\n<italic toggle=\"yes\">B2 International instruments</italic>: Industry participation in policy processes can also prompt public health advocates to expose the nefarious tactics used by industry to prevent policy adoption/promote their products, as for example occurred in the case of tobacco corporations. Over time, this kind of exposure reduces public and therefore political acceptability of industry and can lead to the development of international rules and norms institutionalized in legally binding international treaties, over-riding any domestic institutional obligation, and committing governments to restrict industry participation in policy processes. B2 can then provide a counter force to R5 and reduce industry participation and influence in policy processes.</p>", "<p>\n<italic toggle=\"yes\">B3 Awareness of industry tactics:</italic> When the food industry’s nefarious tactics are exposed (eg, non-adherence to pledges of self-regulation), nutrition policy-makers report lowering their consideration of industry interests during subsequent related policy-making.</p>", "<p>\n<italic toggle=\"yes\">B4 Civil society pressure:</italic>The exposure of nefarious industry tactics can also drive the mobilization of a nutrition actor network (external to government), ultimately increasing the perceived salience of a DR-NCD policy problem which can, once a certain threshold is reached, reduce the influence of economic and industry concerns in nutrition policy decisions. Both balancing loops B3 and B4 may provide important counter forces to R5’s ‘vicious’ cycle of increasing industry influence in policy processes.</p>", "<p>\n<italic toggle=\"yes\">R6 Nutrition network mobilization:</italic> Nutrition networks (including NGOs, academia, communication and advocacy experts, grassroots groups, and other governments and spanning from the local to the international) can lead to expansion of the network’s strategic communication capacity (eg, public education, targeted lobbying strategies for different policy actors and use of various advocacy/communication tools) which may increase the resonance of pro-nutrition issue framing and in turn increase the perceived salience of the issue and proposed solution among stakeholders, ultimately reducing the weight of economic considerations during decision-making.</p>", "<p> However, when their participation in policy processes is limited by such processes as described above, multinational corporations are more likely to use or convince other governments to use legal threats, including threats of international trade and/or investment disputes. Such threats increase perceived risk of a trade dispute.</p>", "<p>\n<italic toggle=\"yes\">B5 International policy norms:</italic> Health policy-makers ensure adherence to international standards to lower the perceived risk of a trade/investment dispute. This can become problematic if international standards limit the comprehensiveness of a proposed policy since they also have been influenced by industry interests. Perceived risk of a trade/investment dispute also drives <italic toggle=\"yes\">B1 evidence-based policy-making,</italic> further sustaining the evidence-based policy-making approach.</p>", "<title> Sub-system II: Structural and Discursive Power</title>", "<p> Sub-system II (##FIG##2##Figure 2##) illustrates stakeholders’ understanding of the interactions between various mechanisms of structural and discursive power (see ##SUPPL##0##Supplementary file 1##). These mechanisms include ideologies, values, perception and preference shaping, organizational structures, and norms.<sup>##REF##33895830##23##</sup></p>", "<p>\n<italic toggle=\"yes\">R7 Agenda-setting:</italic> The economic power of the food industry prevents less powerful policy actors (eg, public health academics) from being able to promote on to the agenda of viable solutions, policy options that would have significant economic impacts on industry, including for example trade and investment policy levers. This is an aspect of industry’s structural power. This, in turn, allows the economic power of industry to continue to grow.</p>", "<p>\n<italic toggle=\"yes\">B8 Speaking the same language:</italic> Health policy-makers’ use of economic analytical tools (eg, costing analyses) and framing nutrition problems and policy solutions in economic terms can increase the likelihood of DR-NCD policy adoption by building broad support from more powerful economic policy actors. This can increase the comprehensiveness of the policy environment and strengthen pro-nutrition policy norms. Being a balancing loop indicates that using economic framing will only maintain norms at a steady state, not entirely transcend them.</p>", "<p>\n<italic toggle=\"yes\">R8 Resonating frames:</italic> Increased economic and material power of the food industry expands the capacity of industry to use various tactics (eg, issue framing and narratives communicated through corporate networks and the media as well as through privileged access to policy-makers) to shape the political discourse, looping back to reinforce the policy norms they tend to benefit from.</p>", "<p>\n<italic toggle=\"yes\">R9 Limited interpretation:</italic> The individualization of NCDs, where risk exposure is considered personal responsibility, not determined by complex structural drivers, is a natural extension of a socio-political context dominated by the imperative for economic growth. This interpretation tends to limit stakeholders’ ideational boundaries of conceivable policy solutions, ultimately weakening pro-nutrition policy norms and further strengthening the focus on economic growth. R9 therefore suggests that while policy actors can have agency over discursive power, it can also be deterministically generated from socio-political-economic system dynamics. Both R8 and R9 describe the dynamics of industry’s potential discursive (invisible) power.</p>", "<p>\n<italic toggle=\"yes\">R10 Shared understanding:</italic> Stakeholders reflected that, from their experience with access to medicines, institutional mechanisms can potentially contribute to disrupting industry discursive power. R10 illustrates that institutional structures and arrangements that increase inter-departmental co-ordination and cooperation may subsequently increase the capacity across departments to interpret and understand DR-NCDs as products of complex structural drivers across a range of sectors which, in turn, may expand stakeholders’ ideational boundaries of possible nutrition policy solutions, motivating further inter-departmental co-ordination and co-operation.</p>", "<p>\n<italic toggle=\"yes\">R11 Nutrition in all policies:</italic> Reducing policy-making silos and improving co-ordination between departments in economic policy development, can increase the DH’s influence within other policy domains including trade and investment and agriculture and lead to the inclusion of nutrition objectives in economic and agricultural policy and strategies, again increasing the desire for deeper inter-departmental coordination.</p>", "<p>\n<italic toggle=\"yes\">R12 Industry influence: </italic>Increased inter-departmental co-operation and collaboration can drive a shared understanding across government departments of nutrition as a system problem requiring a trans-sectoral approach. In turn this can weaken industry influence over nutrition-relevant policy decisions and promote the inclusion of nutrition objectives in economic and agriculture strategy/policy.</p>", "<p>\n<italic toggle=\"yes\">R13 Focus on food as a commodity not nutrition:</italic> Discursive power can be deterministically-driven creating policy environments that support the production of crops and food products (particularly ‘value-added’ products like UPFs) that maximize profit and their exportability. This normative approach to trade, investment and agricultural policy tends to drive ‘food bias’ where there is a perception, as one stakeholder reflected, that if there is sufficient food in the system, then the system ‘works,’ holding policies that would increase the nutritional quality of food, outside the boundaries of conceivable policy solutions. In turn, this contributes to poor policy coherence for nutrition across sectors and weakening of pro-nutrition policy norms over time which, without an alternative approach, strengthens the existing normative approach.</p>", "<p>\n<italic toggle=\"yes\">R14 Institutionalizing nutrition norms:</italic> Not including nutrition objectives in the overarching strategies of other nutrition-relevant policy areas including trade, investment and agriculture, leads to poor policy coherence for nutrition, weakening pro-nutrition policy norms and in turn further limiting the consideration of nutrition objectives across sectors. Non-health policy actors, for example, frequently cited that their mandate was to fulfil the economic and social development objectives laid out in the National Development Plan (NDP) however there is a significant lack of coherence between the NDP and nutrition policy. NDP objectives include increasing economic productivity and employment through agriculture, food processing and food retail and while food security is a key priority there is no mention of improving the nutritional quality of food.<sup>##UREF##27##49##</sup> Economic strategy/policy documents like the NDP set the economic strategy for a determined period (eg, 5 years) and generate a cascading effect shaping the objectives across government departments and the performance reviews of their appointed officials and employees generating a ‘bureaucratic inertia’ as described by one stakeholder.</p>" ]	[ "<title>Discussion of Policy Implications</title>", "<p> This work has used system dynamics methods to develop an initial complex system model of DR-NCD policy-making in South Africa mapping the inter-dependent political economy mechanisms that drive different forms of corporate power in the policy-making process. A growing body of research uses system dynamics or system mapping to better understand complex public health problems (and assess the effectiveness of alternative policy options), eg, obesity and other forms of malnutrition,<sup>##REF##30700377##13##,##UREF##28##50##,##REF##26153893##51##</sup> inequities in healthy eating,<sup>##REF##29190662##34##</sup> tobacco control,<sup>##REF##21566034##52##, ####REF##16449585##53##, ##REF##20466963##54####20466963##54##</sup> NCDs,<sup>##UREF##29##55##,##REF##6788801##56##</sup> neonatal mortality,<sup>##REF##27146327##57##</sup> and the social determinants of health.<sup>##REF##23123169##58##</sup> However, just a few studies have used system dynamics methods to explore the politics of health (or specifically) food policy-making.<sup>##REF##31245905##21##,##REF##33481898##33##</sup> Building on these, we suggest this work further illustrates the utility of using qualitative system mapping that visualises how causal factors are linked to each other in inter-dependent feedback processes. By revealing how an intervention affects both close and distant parts of the system, system mapping can provide deeper insight which strategies/interventions may be most useful for promoting more progressive and cohesive DR-NCD prevention policy.</p>", "<p> While it is not possible to reliably infer the short or long term impacts of interventions based on the system map alone, in this section we discuss some of the early strategic insights gained from this research. Adopting a systems thinking approach we discuss key feedback processes and potential leverage points in the system map developed in this work. We also consider how key interventions that have surfaced through analysing the system map as well as recommendations for driving NCD policy action identified by the Lancet Commission on Obesity, Undernutrition and Climate Change would impact on the DR-NCD policy-making system.<sup>##REF##30700377##13##</sup></p>", "<p> System actors tend to think and act in response to short causal chains and are generally insensitive to the presence of feedback between their decisions and the environment.<sup>##UREF##14##30##</sup> However, by understanding feedback relationships within the system, and particularly reinforcing loops, potentially powerful leverage points can be identified<sup>##UREF##14##30##</sup> that may shift power dynamics and promote DR-NCD policy action. The first key barrier-generating feedback processes identified in our system model, R1 in Sub-system I and R7 in sub-system II, reflect archetypal ‘success to the successful’ (or in this case, power to the powerful) systems traps.<sup>##UREF##14##30##</sup> Weakening these feedback processes that expand the economic and material power of UPF-producing and selling corporations over time, may be important strategies to promote DR-NCD policy action. Strategies here might include, for example, embedding a framework and objectives for nutrition based on the World Health Organization (WHO) NCD Global Action Plan, within the remit of national and regional trade bodies eg, the South African Development Community<sup>##UREF##27##49##</sup> and adopting regulations that internalize the true cost of food corporations’ products in terms of health and environmental impacts. In wealthy producing and exporting countries and regions the removal of perverse agricultural subsidies will likely be important eg, European Union subsidies on sugar.</p>", "<p> Other key barrier-generating feedback processes in sub-system I relate to nutrition policy actors’ adherence to strict evidence-based policy-making in response to industry pressure and in an effort to avoid legal disputes. However, considering more distal linkages within sub-system I indicates that an evidence-based approach can ultimately maintain weak pro-nutrition policy norms. This work therefore supports calls for an ‘evidence-informed and practice-based’ approach<sup>##REF##28161671##59##,##REF##15655036##60##</sup> to DR-NCD policy decisions that promotes active policy experimentation and evaluation, since it could break the undesirable feedback loop described, ultimately potentially strengthening pro-nutrition policy norms with various positive repercussions across the system including weakening the individualization of NCDs to expand ideational boundaries of policy solutions and greater policy coherence for nutrition across sectors.</p>", "<p> Strengthening a number of existing facilitative feedback loops within sub-system I system may also be important to drive DR-NCD policy action and coherence. These include R6 <italic toggle=\"yes\">nutrition network mobilization</italic>. In recent work Baker et al used system mapping methods providing a more detailed analysis of how nutrition networks may be strengthened to promote political commitment for malnutrition.<sup>##REF##31245905##21##</sup></p>", "<p> Driving a number of reinforcing loops in sub-system II including R10 <italic toggle=\"yes\">shared understanding</italic>, R11 <italic toggle=\"yes\">nutrition in all policies</italic>, R12 <italic toggle=\"yes\">reducing industry influence</italic> and R14 <italic toggle=\"yes\">institutionalizing nutrition norms</italic> will be important for overcoming the critical problem of nutrition not having a single departmental ‘home’ and, as a result, not being prioritized. Driving these loops could be important for promoting policy coherence across sectors towards generating a healthy and sustainable food system and reducing DR-NCDs. Key potential leverage points here include capacity building within the DH, DTI and DAFF and governance structures that ensure nutrition policy-makers are included in the development of trade and investment strategy and on negotiating teams. These interventions could make embedding a framework and objectives for nutrition within the remit of trade decision-making bodies, as suggested earlier, and including nutrition objectives within other key economic policy documents (eg, the NDP) more possible, in turn strengthening policy coherence and pro-nutrition policy norms.</p>", "<p> Another key leverage point is adding system structures that provides informational feedback where it was previously lacking, in other words making actors directly accountable for their own actions.<sup>##UREF##14##30##</sup> These can be hard to implement where they require those in power to agree to being more accountable. Nonetheless, they might include for example, making the DTI pay directly out of their own budget for the healthcare costs of people requiring chronic management of DR-NCDs due to their economic policies and strategic decisions that increase availability and consumption of UPFs. This could contribute to driving R11 <italic toggle=\"yes\">nutrition in all policies </italic>(sub-system II). Internalizing the cost of the health impacts of industry products would be another example which may have significant effects throughout the system.</p>", "<p> The rules of any system determine its scope and degrees of freedom (the number of ways the system can vary) and their adjustment can present high-leverage interventions.<sup>##UREF##14##30##</sup> Rules include laws (strongest), punishments, incentives and informal social agreements (weakest). Given the power of the rules governing a system, it is highly concerning as is illustrated in our complex system map and in related work,<sup>##REF##33895830##23##</sup> that the food industry (and other corporations) has significant influence over the rules of international trade and nutrition policy at both the domestic and international level. It is industry’s shaping of trade rules that has helped unleash the ‘success to the successful’ loops leading to accumulation of industry productive power earlier described.</p>", "<p> A key rule in the nutrition policy-making system is the South African Constitutional requirement that policy-makers engage with all interested stakeholders during policy development, including industry. This rule alone limits the scope for pushing the system towards reducing food industry involvement in DR-NCD-relevant policy processes. However, the Constitution also commits the government to comply with its international obligations. This includes international health instruments like the Framework Convention on Tobacco Control which, under Article 5.3, obligates parties to adopt measures that protect “their public health policies related to tobacco control from commercial and other vested interests of the tobacco industry.”<sup>##UREF##30##61##</sup> As such, systems thinking perspective may support proposals for a Framework Convention on Food Systems.<sup>##REF##30700377##13##</sup> This would drive sub-system I loop B2 <italic toggle=\"yes\">international instruments limiting industry engagement</italic>, controlling R5 <italic toggle=\"yes\">industry legitimacy</italic> to limit food industry participation and influence in policy development. The knock-on effects of such an instrument could powerfully facilitate policy action and promote pro-nutrition policy norms. That said, it may lead industry to adapt by strengthening more covert strategies to influence policy – including mechanisms of discursive power (eg, perception shaping through issue framing/narratives communicated through corporate foundations, opinion leaders and media capture).</p>", "<p> The overall goal or purpose of the system is one of the most powerful points of leverage in any system. Seeking the wrong goal will drive the system in an undesirable direction. For example, the goal of gross domestic product growth or economic growth more broadly, has been found to generate problems of unemployment, poverty, hunger, resource depletion, and environmental degradation.<sup>##UREF##31##62##</sup> Arguably, the nutrition policy-making system presented in this work is not driven by an overarching goal of ensuring a nutritious, sustainable and equitable food system, but more by food security objectives and by the goal of expanding food corporations’ global market share for the sake of economic growth. System goals, along with its rules and relationships arise from core underlying paradigms – deeply held beliefs and associated assumptions about how the world works.<sup>##UREF##14##30##</sup> During this research we identified a number of paradigmatic assumptions including ‘consumption-based growth is critical for development,’ ‘the food system is a resource to be converted to economic gain’ and ‘trade is ultimately good for health.’ As the system’s source, intervening at the level of the paradigm (in this case neoliberalism) can be transformative. A systems perspective therefore strongly supports increasing calls from the public health and new economics communities for a new paradigm that seeks to meet the health and social needs of the population within the means of the planet.<sup>##UREF##32##63##</sup> Paradigm shifts is a field of research in itself but broadly requires persistently highlighting failures of the existing paradigm, framing problems, challenges and solutions according to the new one, positioning advocates of the new paradigm in positions of power and visibility, and focusing on building broad support.<sup>##UREF##14##30##</sup></p>", "<p> Finally, it is important to note that while we’ve suggested a number of potential policy/strategic recommendations and their possible impacts, systems are highly resilient and actors within them will often respond with efforts to undermine system change (and maintain existing power relations). For example, industry may respond to a tax on sugar-sweetened beverages by introducing a low-sugar version alongside their regular product, increasing brand visibility, recognition and sales,<sup>##REF##30277610##64##</sup> indicating taxes may in fact do little to reduce the economic power of the food industry (or NCDs). Careful consideration of how system actors’ responses may undermine the intended effects of the interventions proposed in this section is therefore essential. Additionally, the feasibility of a number of the interventions outlined would require further consideration of other political economy factors described in the model.</p>", "<title> Limitations</title>", "<p> Important variables, links and feedback structures may not have been captured in the model for a number of reasons. Firstly, given system dynamic models are constructed based primarily on stakeholders’ understanding of the problem under investigation (and in this research, the addition of a small number of causal linkages from two literature reviews) it is quite possible the model contains inaccuracies and deficiencies due to stakeholder subjectivity and limited understanding.<sup>##UREF##33##65##</sup> While significant effort was made to include as many stakeholders as possible with intimate understanding of different aspects of the problem, it was challenging to access high level politicians/government officials who may have provided additional system insights. Second, due to the political nature of the research topic and the inherent vested interest of different stakeholders, it is possible some participants were sharing politically motivated reasoning or omitting certain casual relationships from discussion in the interviews. Failing to capture important variables is likely to have affected the reliability and depth of the insights gained.</p>", "<p> While having only the primary researcher (PM) conduct the PTA and model development ensured consistent coding it also introduces the risk of potential bias. However, this risk was reduced by having the same researcher also collect the data. This provided the opportunity for asking probing questions to gain a deeper understanding of the context of the data at the time of data collection<sup>##UREF##34##66##</sup> which facilitated response to “subtle nuances of, and cues to, meaning in the data” during data analysis<sup>##UREF##35##67##</sup> to reduce potential bias. A key to step to mitigate modeler bias was conducting follow-up model validation discussion sessions with a sub-set of stakeholders.<sup>##UREF##34##66##</sup></p>", "<p> Generalizability to other country contexts is limited given the context-specific nature of the problem under investigation. A next step would be to engage stakeholders in another country context to explore similarities and differences in the causal structure of the South African conceptual model.</p>", "<p> Finally, the conceptual model alone provides only preliminary insight into what actions might promote more progressive and coherent NCD prevention policy over time. We consider developing and experimenting with a numerical simulation model as important for confirming understanding of the system structure and testing the effectiveness of different interventions over time. As such, future work could involve proceeding to simulation modelling to further validate the system structure, understand the comparative strengths of the different feedback loops, how the systems behaviour changes over time and which interventions would be most effective in promoting more progressive DR-NCD policy in the long run. That said, this work does represent the first attempt to conceptualize DR-NCD policy inaction as a complex systems problem and to qualitatively map the causal structure of the problem by defining the feedback relationships between elements in CLDs.<sup>##UREF##36##68##</sup> We argue this does have stand alone utility for informing future thinking about how to promote healthy policy action. ##SUPPL##4##Supplementary file 5## provides reflexivity considerations.</p>" ]	[ "<title>Conclusion</title>", "<p> Using qualitative system dynamic modelling we developed a complex system model for understanding DR-NCD policy inaction due to political economy mechanisms and corporate power. This work demonstrates the utility in adopting a systems thinking approach that visualises the inter-dependence and feedback processes between different factors that drive patterns in health policy-making over time. Better understanding the complexity in health policy-making through use of complex system methods can facilitate the identification and more insightful evaluation of potential strategies for promoting more progressive health policy-making. Future work should explore the possibility of proceeding to quantitative simulation modelling to evaluate the dynamic short and long-term impacts of different strategies on the political economy and power dynamics in DR-NCD policy-making. A key benefit of using a systems thinking approach in future work (and to encourage ‘system doing’) may be to bring government stakeholders together in a group model building exercise to build a shared ‘systems’ understanding of the interconnectedness of drivers of not only NCDs themselves but also the observed pattern of policy inaction to effectively prevent NCDs. Doing so may facilitate non-health actors to see their own role in the system promoting greater inter-departmental co-operation to prevent DR-NCDs.</p>" ]	[ "<p>\n<bold>Background:</bold> Complex interactions between political economy factors and corporate power are increasingly recognized to prevent transformative policy action on non-communicable disease (NCD) prevention. System science offers promising methods for analysing such causal complexity. This study uses qualitative system dynamics methods to map the political economy of diet-related NCD (DR-NCD) prevention policy-making aiming to better understand the policy inertia observed in this area globally.\n</p>", "<p><bold>Methods:</bold> We interviewed 25 key policy actors. We analysed the interviews using purposive text analysis (PTA). We developed individual then combined casual loop diagrams to generate a shared model representing the DR-NCD prevention policy-making system. Key variables/linkages identified from the literature were also included in the model. We validated the model in several steps including through stakeholder validation interviews.\n</p>", "<p><bold>Results:</bold> We identified several inter-linked feedback processes related to political economy factors that may entrench different forms of corporate power (instrumental, structural, and discursive) in DR-NCD prevention policy-making in South Africa over time. We also identified a number of feedback processes that have the potential to limit corporate power in this setting.\n</p>", "<p><bold>Conclusion:</bold> Using complex system methods can be useful for more deeply understanding DR-NCD policy inertia. It is also useful for identifying potential leverage points within the system which may shift the existing power dynamics to facilitate greater political commitment for healthy, equitable, and sustainable food system transformation.</p>", "<p>\n<bold>Citation:</bold> Milsom P, Tomoaia-Cotisel A, Smith R, Modisenyane SM, Walls H. Using system dynamics to understand transnational corporate power in diet-related non-communicable disease prevention policy-making: a case study of South Africa. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7641. doi:10.34172/ijhpm.2023.7641</p>" ]	[ "<title>Ethical issues</title>", "<p> Participants provided written informed consent to participate in this study. Ethical approval for this research was granted by both the University of Cape Town’s Human Research Ethics Committee and the London School of Hygiene and Tropical Medicine’s Research Ethics Committee.</p>", "<title>Competing interests</title>", "<p> Simon Moeketsi Modisenyane was working for the South African Department of Health at the time of this research.</p>", "<title>Funding</title>", "<p> This work was supported by funding from the Wellcome Trust [203286/Z/16/Z] to support this research.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nSub-system I: Instrumental Power.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nSub-system II: Structural and Discursive Power.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Summary of Stakeholders Involved in Conceptual Model-Building\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Stakeholder Group</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Key Stakeholders Invited to Participate</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Key Stakeholders Interviewed</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Stakeholders Included in Model Conceptualization</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">DH</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">13</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">10</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">10</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Health Attachés for South African Embassy in Geneva or Washington DC (current or past)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">DTI</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National Treasury</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">DAFF</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">NGOs/CSOs/IGOs</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Academics</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Industry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Total</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>49</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>29</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>25</bold>\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>\nKey for Sub-systems I and II\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<p>\n\n</p>\n</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Non-communicable disease (NCD) prevention policy-making involving stakeholders with competing interests and values is usefully understood as being embedded within a complex system of multiple inter-connected and interdependent elements. </p></list-item><list-item><p>Within the diet-related NCD (DR-NCD) policy-making system, several inter-linked feedback processes involving different political economy factors and forms of power (instrumental, structural, and discursive) may be acting to further entrench corporate influence in policy-making over time, whilst other feedback processes may act to control it. </p></list-item><list-item><p>Becoming ‘systems thinkers’ and ‘system doers’ can deepen health policy-maker understanding of the dynamics of DR-NCD (and other health) policy inertia and assist them in identifying strategic leverage points across the policy-making system for promoting more progressive policy change. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> Modern diets high in sugar, fat, salt and refined carbohydrates and containing a greater proportion of caloric sweeteners, vegetable oils, animal-sourced foods, and ultra-processed foods (UPFs)<sup>##UREF##0##1##, ####UREF##1##2##, ##REF##32630022##3####32630022##3##</sup> are considered key drivers of obesity and non-communicable diseases (NCDs) globally. So far most governments have failed to take policy action to adequately address the underlying drivers of unhealthy diets. This research suggests this inaction relates to various complex, inter-linked and interdependent feedback processes involving political and economic factors that may be further entrenching the power and influence of transnational food corporations over time. This research also identified other feedback processes that may act to control corporate power. Without adopting strategies to address corporate power in NCD prevention policy-making with significant system-level impact, it is likely that NCD prevalence will continue to rise globally contributing to reduced household incomes, restricted quality of life, premature death and deepening health and economic inequality.<sup>##UREF##2##4##</sup></p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 1. The Conceptual Framework for Analysing Power in Public Health Policy-Making.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 2. Example of Purposive Text Analysis Coding Chart.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 3. Causal Loop Diagram Combination.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl4\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 4. Pre-validation Shared Mental Model.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl5\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 5. Reflexivity.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: DH, Department of Health; DTI, Department of Trade and Industry; DAFF, Department of Agriculture, Forestry and Fisheries; IGOs, intergovernmental organizations; NGOs, non-governmental organizations; CSOs, civil society groups.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7641-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7641-g003\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7641-g002\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7641-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7641-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7641-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7641-s004.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7641-s005.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" Schwab U, Lauritzen L, Tholstrup T, et al. Effect of the amount and type of dietary fat on cardiometabolic risk factors and risk of developing type 2 diabetes, cardiovascular diseases, and cancer: a systematic review. Food Nutr Res 2014;58. "], "pub-id": ["10.3402/fnr.v58.25145"]}, {"label": ["2"], "mixed-citation": [" World Health Organization (WHO). Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. Geneva: WHO; 2009. "]}, {"label": ["4"], "mixed-citation": [" WHO. Noncommunicable Diseases. 2018. "], "uri": ["https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases"]}, {"label": ["7"], "mixed-citation": [" Monteiro CA, Cannon G, Lawrence M, Costa Louzada MD, Pereira Machado P. Ultra-Processed Foods, Diet Quality, and Health Using the NOVA Classification System. Rome: FAO; 2019. "]}, {"label": ["9"], "mixed-citation": [" World Health Organization (WHO). Global Status Report on Alcohol and Health. WHO; 2018. "]}, {"label": ["14"], "mixed-citation": [" Food and Agriculture Organization (FAO), World Health Organization (WHO). Second International Conference on Nutrition, Conference Outcome Document: Framework for Action. Rome: FAO, WHO; 2014. "]}, {"label": ["15"], "mixed-citation": [" Pingault N, Caron P, Kalafatic C, et al. Nutrition and Food Systems. A Report by the High Level Panel of Experts on Food Security and Nutrition of the Committee on World Food Security. Rome: FAO; 2017. "]}, {"label": ["16"], "mixed-citation": [" World Health Organization (WHO). Global Action Plan for the Prevention and Control of NCDs 2013-2020. Geneva: WHO; 2013. "]}, {"label": ["18"], "person-group": ["\n"], "surname": ["Baker", "Hawkes", "Wingrove"], "given-names": ["P", "C", "K"], "article-title": ["What drives political commitment for nutrition? A review and framework synthesis to inform the United Nations Decade of Action on Nutrition"], "source": ["BMJ Glob Health"], "year": ["2018"], "volume": ["3"], "issue": ["1"], "fpage": ["e000485"], "pub-id": ["10.1136/bmjgh-2017-000485"]}, {"label": ["19"], "mixed-citation": [" International Food Policy Research Institute (IFPRI). Global Nutrition Report 2017: Nourishing the SDGs. Washington, DC: IFPRI; 2017. "]}, {"label": ["25"], "mixed-citation": [" Reich MR, Balarajan Y. Political Economy Analysis for Food and Nutrition Security. Health, Nutrition and Population (HNP) Discussion Paper. Washington, DC: World Bank; 2012. "]}, {"label": ["26"], "person-group": ["\n"], "surname": ["Harris"], "given-names": ["J"], "article-title": ["Power in the Zambian nutrition policy process"], "source": ["IDS Bull"], "year": ["2019"], "volume": ["50"], "issue": ["2"], "fpage": ["121"], "lpage": ["130"], "pub-id": ["10.19088/1968-2019.112"]}, {"label": ["27"], "mixed-citation": [" International Panel of Experts on Sustainable Food Systems. The New Science of Sustainable Food Systems: Overcoming Barriers to Food Systems Reform. IPES-Food; 2015. "]}, {"label": ["29"], "mixed-citation": [" Gr\u00f6sser SN. Complexity Management and System Dynamics Thinking. In: Gr\u00f6sser SN, Reyes-Lecuona A, Granholm G, eds. Dynamics of Long-Life Assets: From Technology Adaptation to Upgrading the Business Model. Cham: Springer International Publishing; 2017:69-92. "]}, {"label": ["30"], "mixed-citation": [" Meadows DH. Thinking in Systems: A Primer. White River Junction, Vermont: Chelsea Green Publishing; 2008. "]}, {"label": ["32"], "person-group": ["\n"], "surname": ["Carey", "Malbon", "Carey", "Joyce", "Crammond", "Carey"], "given-names": ["G", "E", "N", "A", "B", "A"], "article-title": ["Systems science and systems thinking for public health: a systematic review of the field"], "source": ["BMJ Open"], "year": ["2015"], "volume": ["5"], "issue": ["12"], "fpage": ["e009002"], "pub-id": ["10.1136/bmjopen-2015-009002"]}, {"label": ["35"], "person-group": ["\n"], "surname": ["Richardson"], "given-names": ["GP"], "article-title": ["Reflections on the foundations of system dynamics"], "source": ["Syst Dyn Rev"], "year": ["2011"], "volume": ["27"], "issue": ["3"], "fpage": ["219"], "lpage": ["243"], "pub-id": ["10.1002/sdr.462"]}, {"label": ["37"], "person-group": ["\n"], "surname": ["Saeed"], "given-names": ["K"], "article-title": ["Slicing a complex problem for system dynamics modeling"], "source": ["Syst Dyn Rev"], "year": ["1992"], "volume": ["8"], "issue": ["3"], "fpage": ["251"], "lpage": ["261"], "pub-id": ["10.1002/sdr.4260080305"]}, {"label": ["39"], "mixed-citation": [" National Department of Health, Statistics South Africa, South African Medical Research Council and ICF. South Africa Demographic and Health Survey 2016. Pretoria, South Africa, and Rockville, Maryland, USA; 2019,. "]}, {"label": ["40"], "mixed-citation": [" Development Initiatives. Global Nutrition Report: Shining a light to spur action on nutrition. Bristol, UK: Development Initiatives; 2018. "]}, {"label": ["42"], "mixed-citation": [" Global Health Observatory. Non Communicable Diseases Country Profile, South Africa. World Health Organization; 2018. "]}, {"label": ["43"], "mixed-citation": [" Tomoaia-Cotisel A. The Journey Toward the Patient-Centered Medical Home: A Grounded, Dynamic Theory of Primary Care Transformation [dissertation]. London School of Hygiene & Tropical Medicine; 2018. "]}, {"label": ["44"], "person-group": ["\n"], "surname": ["Kim", "Andersen"], "given-names": ["H", "DF"], "article-title": ["Building confidence in causal maps generated from purposive text data: mapping transcripts of the Federal Reserve"], "source": ["Syst Dyn Rev"], "year": ["2012"], "volume": ["28"], "issue": ["4"], "fpage": ["311"], "lpage": ["28"], "pub-id": ["10.1002/sdr.1480"]}, {"label": ["45"], "person-group": ["\n"], "surname": ["Schaffernicht", "Groesser"], "given-names": ["M", "SN"], "article-title": ["A comprehensive method for comparing mental models of dynamic systems"], "source": ["Eur J Oper Res"], "year": ["2011"], "volume": ["210"], "issue": ["1"], "fpage": ["57"], "lpage": ["67"], "pub-id": ["10.1016/j.ejor.2010.09.003"]}, {"label": ["46"], "mixed-citation": [" Milsom P. International Trade and Investment Liberalization, Corporate Power and Noncommunicable Disease Prevention Policy: A Case Study of Nutrition and Alcohol Policy Non-Decisions in South Africa [dissertation]. London: Department of Global Health and Development, London School of Hygiene & Tropical Medicine; 2021. "]}, {"label": ["47"], "mixed-citation": [" Forrester JW. Industrial Dynamics. Cambridge, MA: MIT Press; 1961. "]}, {"label": ["48"], "person-group": ["\n"], "surname": ["Andersen", "Luna-Reyes", "Diker", "Black", "Rich", "Andersen"], "given-names": ["DL", "LF", "VG", "L", "E", "DF"], "article-title": ["The disconfirmatory interview as a strategy for the assessment of system dynamics models"], "source": ["Syst Dyn Rev"], "year": ["2012"], "volume": ["28"], "issue": ["3"], "fpage": ["255"], "lpage": ["275"], "pub-id": ["10.1002/sdr.1479"]}, {"label": ["49"], "person-group": ["\n"], "surname": ["Thow", "Greenberg", "Hara", "Friel", "duToit", "Sanders"], "given-names": ["AM", "S", "M", "S", "A", "D"], "article-title": ["Improving policy coherence for food security and nutrition in South Africa: a qualitative policy analysis"], "source": ["Food Secur"], "year": ["2018"], "volume": ["10"], "issue": ["4"], "fpage": ["1105"], "lpage": ["1130"], "pub-id": ["10.1007/s12571-018-0813-4"]}, {"label": ["50"], "mixed-citation": [" Vandenbroeck P, Goossens J, Clemens M. Foresight Tackling Obesities: Future Choices \u2013 Obesity System Atlas. United Kingdom: Government Office for Science; 2007. "]}, {"label": ["55"], "person-group": ["\n"], "surname": ["Homer", "Hirsch", "Minniti", "Pierson"], "given-names": ["J", "G", "M", "M"], "article-title": ["Models for collaboration: how system dynamics helped a community organize cost-effective care for chronic illness"], "source": ["Syst Dyn Rev"], "year": ["2004"], "volume": ["20"], "issue": ["3"], "fpage": ["199"], "lpage": ["222"], "pub-id": ["10.1002/sdr.295"]}, {"label": ["61"], "mixed-citation": [" World Health Organization (WHO). Guidelines for Implementation of Article 5.3 of the WHO Framework Convention on Tobacco Control (Decision FCTC/COP3(7)). Geneva: WHO; 2008. "]}, {"label": ["62"], "mixed-citation": [" Forrester JW. World Dynamics. Cambridge, MA: Wright-Allen Press; 1971. "]}, {"label": ["63"], "mixed-citation": [" Raworth K. Doughnut Economics: Seven Ways to Think Like a 21st-Century Economist. London: Penguin Random House; 2017. "]}, {"label": ["65"], "person-group": ["\n"], "surname": ["Chaker", "El Manouar", "Janati Idrissi"], "given-names": ["F", "A", "MA"], "article-title": ["Towards a system dynamics modeling method based on DEMATEL"], "source": ["Int J Comput Sci Inf Technol"], "year": ["2015"], "volume": ["7"], "issue": ["2"], "fpage": ["27"], "lpage": ["40"], "pub-id": ["10.5121/ijcsit.2015.7203"]}, {"label": ["66"], "person-group": ["\n"], "surname": ["Turner", "Kim", "Andersen"], "given-names": ["BL", "H", "DF"], "article-title": ["Improving coding procedures for purposive text data: researchable questions for qualitative system dynamics modeling"], "source": ["Syst Dyn Rev"], "year": ["2013"], "volume": ["29"], "issue": ["4"], "fpage": ["253"], "lpage": ["263"], "pub-id": ["10.1002/sdr.1506"]}, {"label": ["67"], "mixed-citation": [" Strauss AL, Corbin JM. Basics of Qualitative Research: Techniques and Procedures for Developing Grounded Theory. 2nd ed. Thousand Oaks, CA: SAGE Publications; 1998. "]}, {"label": ["68"], "person-group": ["\n"], "surname": ["Forrester"], "given-names": ["JW"], "article-title": ["System dynamics, systems thinking, and soft OR"], "source": ["Syst Dyn Rev"], "year": ["1994"], "volume": ["10"], "issue": ["2-3"], "fpage": ["245"], "lpage": ["256"], "pub-id": ["10.1002/sdr.4260100211"]}]	{ "acronym": [], "definition": [] }	68	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 17; 12:7641	oa_package/28/e1/PMC10590239.tar.gz
PMC10590240	0	[ "<title>Background</title>", "<p> Healthcare costs have increased drastically worldwide over the past several decades and are expected to continue rising in the coming years.<sup>##REF##32207998##1##</sup> This rise in healthcare costs forces policy-makers to explore solutions to ensure good quality of care while working with limited financial resources.<sup>##REF##18474969##2##,##REF##24398253##3##</sup> One potential solution to solve this challenge is to reduce low-value care, ie, services for which there is little evidence of benefit for patients or that cause more harm than benefit (eg, risk of complications, psychological distress, treatment burden and financial loss).<sup>##REF##29741672##4##</sup> Currently, it is estimated that approximately one-third of all medical spending is related to low-value care.<sup>##UREF##0##5##</sup></p>", "<p> Choosing Wisely (CW) is an international campaign launched to open the discussion on low-value care and develop interventions to reduce overuse.<sup>##UREF##1##6##, ####REF##21795239##7##, ##UREF##2##8####2##8##</sup> However, the literature merely shows a slight decline or unchanged trends in low-value care following such CW campaigns.<sup>##REF##26457643##9##,##REF##28373333##10##</sup> Smaller reductions in the use of low-value care are associated with the release of CW recommendations than for a policy change eliminating reimbursement as shown recently for low-value use of vitamin D screening.<sup>##REF##32040158##11##</sup> Therefore, withdrawal of reimbursement through a policy change — or active disinvestment — has been suggested as a promising alternative.<sup>##REF##33794869##12##</sup> Active disinvestment has been associated with substantial reductions in low-value care and is considered an effective but underused de-implementation strategy.<sup>##REF##32040158##11##,##REF##32040167##13##</sup> However, it is also considered a very complex strategy, influenced by various potentially complicating factors (eg, level of support for disinvestment among clinicians and policy-makers), which make successful disinvestment a complex undertaking.<sup>##REF##33794869##12##,##REF##24290335##14##,##REF##31441277##15##</sup></p>", "<p> Given that less than half of the disinvestment initiatives have been successful until now,<sup>##REF##28712620##16##</sup> more research is needed to further explore and understand the complex mechanism through which active disinvestment may have an effect on reducing low-value care.<sup>##REF##28712620##16##, ####REF##31006390##17##, ##REF##29490647##18####29490647##18##</sup> Theoretical frameworks that may facilitate understanding how active disinvestment influences (clinical) decision-making of different stakeholders for specific interventions are lacking but needed to guide future active disinvestment initiatives.<sup>##REF##29490647##18##,##UREF##3##19##</sup> Therefore, we investigated how the active disinvestment initiative of subacromial decompression (SAD) surgery for subacromial pain syndrome (SAPS) in the Netherlands influenced clinical decision-making around surgery, including perspectives of hospital sales managers and orthopedic surgeons, to increase our understanding on how active disinvestment initiatives may exercise their effect on clinical decision-making.</p>" ]	[ "<title>Methods</title>", "<title> Study Design </title>", "<p> A qualitative study was conducted with semi-structured interviews among both hospital healthcare sales managers as well as orthopedic surgeons treating SAPS patients. We used a qualitative research approach as this provides more in-depth insights into processes that numerical data cannot capture and is able to fully explore the perspectives of relevant stakeholders.<sup>##REF##23968140##20##</sup> All results were reported according to the COnsolidated criteria for REporting Qualitative research (COREQ) checklist.<sup>##REF##17872937##21##</sup></p>", "<title> Setting</title>", "<p> The Netherlands has a private-public financed healthcare system, with mandatory standard private healthcare insurance for all Dutch citizens from healthcare insurance companies and optional additional insurance (eg, special dental care).<sup>##REF##18474971##22##</sup> The insurance market is dominated by four large insurers who together have a total market share of approximately 85%.<sup>##UREF##4##23##</sup> Most insurers operate nationally, but market shares vary per region and each region has a different market leader.<sup>##UREF##4##23##</sup> The government has given healthcare insurers an essential role in quality assurance by allowing them to selectively contract healthcare providers (eg, hospitals) and specific interventions.<sup>##REF##26278627##24##</sup> This selective contracting by healthcare insurers aims to reduce overall healthcare costs and improve the hospitals’ quality of care. Periodically (mostly each year), healthcare insurers negotiate with hospitals (through their hospital sales managers) on prices and volumes of specific interventions. The latter gives the healthcare insurer the opportunity to apply active disinvestment initiatives for low-value care interventions and thereby reduce their costs.</p>", "<title> Description of Intervention</title>", "<p> SAD surgery for SAPS is considered a low-value care intervention as high-quality literature found no overall clinical benefit of surgical treatment for SAPS compared to non-operative treatment.<sup>##REF##29169668##25##, ####REF##31144999##26##, ##REF##28566400##27##, ##REF##30728120##28####30728120##28##</sup> Nevertheless, in 2016 still approximately 10 000 patients underwent SAD surgery for SAPS in the Netherlands.<sup>##REF##30931669##29##</sup> Therefore, one of the four largest Dutch healthcare insurers introduced an active disinvestment initiative from January 2020 onwards to reduce SAD surgery in SAPS patients. This healthcare insurer considered 80% of all currently performed surgical procedures for SAPS to be low-value care. To reduce the use of this low-value procedure, this insurer decided to contract 30% fewer surgical procedures for SAPS from each contracted hospital compared with the number of procedures in the previous year. The insurer informed hospitals about this specific active disinvestment by email and during the annual healthcare contract negotiations with hospital sales managers.</p>", "<title> Participant Selection </title>", "<p> As the active disinvestment initiative of the healthcare insurer primarily targeted hospitals, we approached a purposive sample of 25 different relevant stakeholders working withing these hospitals (ie, hospital sales managers and orthopedic surgeons) to participate in the semi-structured interviews. In the Netherlands, hospital sales managers form the direct link between hospitals and healthcare insurers. They are responsible for making financial arrangements on reimbursement of healthcare services provided to patients by a hospital. In addition, they are accountable for communicating healthcare insurers’ policy changes within the hospital, including active disinvestment initiatives. Therefore, they are considered key players in making the process of active disinvestment work in daily practice. The orthopedic (shoulder) surgeons treating SAPS patients were interviewed as they are ultimately responsible for clinical decision-making together with the patient.</p>", "<p> We purposively sampled participants from different types of hospitals, ie, academic and non-academic teaching and non-teaching hospitals or independent treatment centers (ITCs), and different geographical regions because the impact of active disinvestment may vary significantly between types of hospitals and regions, depending on which part of their patients is insured by the healthcare insurer applying the active disinvestment initiative. The relevant stakeholders were recruited from the authors’ professional network. All stakeholders were invited to participate and received information about the interview by email. Twenty of the 25 contacted stakeholders (80%) agreed to participate. One orthopedic surgeon did not agree to be interviewed due to a lack of time, while four approached stakeholders (ie, one hospital sales manager and three orthopedic surgeons) did not respond to the invitation, despite several reminders by email.</p>", "<title> Data Collection</title>", "<p> Given their different role in the decision-making process, separate interview guides were created for hospital sales managers and orthopedic surgeons (##SUPPL##0##Supplementary file 1##). All interviews started with the question whether the participant was familiar with the active disinvestment for SAD surgery among SAPS patients from the particular healthcare insurer. The interviewer (THG) explained the active disinvestment initiative if they were unfamiliar with this. From this point, the interviews for hospital sales managers included the following topics: (<italic toggle=\"yes\">i</italic>) the negotiation process between healthcare insurers and healthcare providers, (<italic toggle=\"yes\">ii</italic>) the attention given to the active disinvestment initiative for SAPS during these negotiations, (<italic toggle=\"yes\">iii</italic>) the consequences of this active disinvestment for the hospital, and (<italic toggle=\"yes\">iv</italic>) the perceived effect of this active disinvestment on clinical decision-making. The interviews with orthopedic surgeons covered the following topics: (<italic toggle=\"yes\">i</italic>) their treatment strategy for SAPS, (<italic toggle=\"yes\">ii</italic>) the surgeons’ perspectives about the active disinvestment initiative, and (<italic toggle=\"yes\">iii</italic>) the perceived effect of the active disinvestment on clinical decision-making. Potentially relevant factors (related to organizational context or individual professional) that might influence how the active disinvestment worked were taken from a study by van Dulmen et al evaluating barriers and facilitators to reduce low-value care, and added to the interview guide as topics to discuss during the interview.<sup>##UREF##5##30##</sup> Participants were actively stimulated to say everything that came to mind and share their experiences and opinion. At the end of the interview, all participants had the opportunity to provide additional feedback.</p>", "<p> Since the COVID-19 pandemic hindered face-to-face contact all semi-structured interviews were conducted and video-recorded (after verbal consent was obtained) via secured video calls (Microsoft Teams) by the same interviewer between November 2020 and October 2021. The interviewer (THG, male), a physician with additional qualitative interviewing training, did not have an established relationship with the participants before the interview nor was involved in clinical care. Two pilot interviews were conducted with one orthopedic surgeon and one hospital sales manager to test relevance and refine the interview questions. Because the pilot interviews did not result in significant changes in the interview guide, both interviews were included in the analysis. The interviews continued until data saturation was reached, defined as at least three consecutive interviews revealing no new insights.<sup>##REF##20204937##31##</sup> The median interview duration was 34 minutes (interquartile range: 30-39 minutes). During the interviews, the interviewer took notes to direct further questioning. Repeat interviews were not conducted and transcripts were not returned to the participants for comment or correction. Participants did not receive any financial compensation for their time.</p>", "<title> Data Analysis</title>", "<p> All interviews were transcribed verbatim and entered into ATLAS.ti (version 7.0). THG and LvBV verified transcript accuracy. Interview transcripts were analysed using inductive thematic analysis. Inductive thematic analysis was applied to increase our understanding how the active disinvestment strategy may exercise its effect on clinical decision making in daily practice, thereby contributing to further development of theory rather than testing an existing theory. Thematic analysis is a flexible approach that identifies patterns within qualitative data, which is especially useful for describing processes that lack an existing theoretical framework.<sup>##UREF##6##32##</sup> After familiarizing with the data, initial codes were identified and a coding tree was developed into which the data was assigned. All interviews were independently coded by two authors (THG and LvBV). Discrepancies were discussed until a consensus was reached. Coded text segments were searched for and grouped into overarching themes by THG and LvBV. Overarching themes were defined as a group of factors that might influence how active disinvestment would affect clinical decision-making on SAD surgery for SAPS. The analysis of overarching themes was iterative and continuous throughout data collection. The overarching themes were inspected and discussed by THG, PJMvdM, and LvBV for recurring themes and influencing factors on the disinvestment process until consensus was reached. Participants did not receive the results of the analyses and were not asked to provide feedback on the findings.</p>" ]	[ "<title>Results</title>", "<p> Ten hospital sales managers and 10 orthopedic surgeons from 12 different hospitals were interviewed, with data saturation achieved after respectively nine and eight interviews. The healthcare insurer applying the active disinvestment initiative had the largest market share in three (25%) hospitals. Most (55%) interviewed participants worked in non-academic teaching hospitals. Three hospital sales managers (30%) and four orthopedic surgeons (40%) were familiar with the active disinvestment initiative for SAPS patients prior to the interview. Descriptive characteristics of the respondents are shown in ##TAB##0##Table 1##.</p>", "<p> Thematic analysis resulted in the identification of two overarching themes which negatively influenced the support for the active disinvestment of SAD surgery for SAPS patients. The first theme was that the active disinvestment represented a ‘Too small piece of the pie’ for the hospitals. Particularly hospital sales managers stated that the active disinvestment initiative for SAPS (<italic toggle=\"yes\">i</italic>) had little financial consequences for the total hospital budget, (<italic toggle=\"yes\">ii</italic>) was only part of the negotiation process in the sense of that healthcare insurance companies used it merely to lower the overall pricing of the hospital’s overall contract agreement, (<italic toggle=\"yes\">iii</italic>) required too much effort from hospital staff to accomplish only a slight reduction in overall costs, and (<italic toggle=\"yes\">iv</italic>) was not clearly defined. For these reasons the active disinvestment did not influence hospital-level decision making and information regarding the active disinvestment was not communicated within the hospital to orthopedic surgeons (see Figure).</p>", "<p> The second overarching theme was ‘They [the healthcare insurer] got it wrong.’ This theme was mainly highlighted by orthopedic surgeons who disagreed with the active disinvestment by the healthcare insurer. More specifically, the surgeons reported that the active disinvestment initiative was (<italic toggle=\"yes\">i</italic>) the result of misinterpretation of scientific evidence and clinical guidelines, (<italic toggle=\"yes\">ii</italic>) at odds with physician experience and beliefs, and (<italic toggle=\"yes\">iii</italic>) reduced the professional autonomy of clinicians. With regard to physician experience and beliefs, the general obligation as a physician to provide care was highlighted, as well as that SAD surgery could still be beneficial for specific patients and should therefore remain as a treatment option. For these reasons the active disinvestment did not influence patient-level decision making (see Figure).</p>", "<p> Besides these two overarching themes, several other contextual factors were identified that also influenced the effectiveness of the active disinvestment, such as a lack of communication between relevant stakeholders, patient preferences, fear of losing revenues and simultaneous other interventions that rewarded rather than penalized hospitals for not performing specific procedures. The overarching themes, subthemes and contextual factors are described in the following section, with representative quotes supporting each theme shown in ##TAB##1##Table 2##. Although most participants indicated they were not against active disinvestment initiatives, we did not identify any facilitating factors for the active disinvestment initiative to work as intended to reduce SAD surgery for SAPS.</p>", "<title> Too Small Piece of the Pie</title>", "<title> Little Financial Consequences for the Hospital Budget</title>", "<p> Both hospital sales managers and orthopedic surgeons stated that SAD surgery for SAPS reflects an insignificant part of the total care provided by the hospital. As a result, the active disinvestment for one specific procedure represented little financial value compared to the overall costs of care provided by the hospital (Quote 1-2). The active disinvestment initiative in its current form was considered to have no financial consequences for the hospitals’ budget, especially in hospitals where this healthcare insurer only had a small market share (Quote 3-4).</p>", "<title> Only Part of the Negotiations</title>", "<p> Hospital sales managers mentioned that the active disinvestment was only a tiny part of the negotiation process between the healthcare insurer and hospitals. They believed it merely aimed to lower the price of the overall contract agreement rather than explicitly reducing the number of performed surgeries for SAPS patients (Quote 5-7). At the end of the negotiation process, a contract is drawn up that includes the total volume of procedures (not only SAD for SAPS, but one overall agreement containing all procedures within the hospital) together with an overall price (Quote 8). Within this agreement, the active disinvestment no longer receives any particular attention, thereby leaving the possibility to perform SAD surgery for SAPS and receive reimbursement for it (Quote 9).</p>", "<title> Too Much Effort for a Slight Reduction in Costs</title>", "<p> Related to the first sub-theme that SAD surgery for SAPS had little financial consequences for the hospital, both hospital sales managers and orthopedic surgeons believed the amount of effort they had to put into reducing SAD surgery was disproportionate to the saving-potential (Quote 10-11). They also indicated that efforts by hospital staff to reduce low-value care procedures are likely to be the same for low-volume procedures as high-volume procedures. From an efficiency perspective, hospital staff should therefore better focus on high-volume procedures (Quote 12). In addition, hospitals often already have initiatives that aim to reduce the use of low-value care procedures so that such initiatives from healthcare insurers lead to unnecessary duplication of work (Quote 13).</p>", "<title> Active Disinvestment Not Clearly Defined</title>", "<p> A final sub-theme was that the active disinvestment was unclear (eg, the use of relative outcome measures without adequate baseline measurement), not specific enough and still allowed to perform surgery for SAPS as part of the surgeries were still reimbursed (Quote 14-15). Hospital sales managers argued that surgeons would only stop performing SAD surgery for SAPS when there would be no reimbursement at all (Quote 16).</p>", "<title> They Got it Wrong</title>", "<title> Misinterpretation of Scientific Evidence and Clinical Guidelines</title>", "<p> Orthopedic surgeons felt the healthcare insurer had misinterpreted the existing scientific evidence and clinical guidelines on which the active disinvestment was based. In general, they supported the reduction of low-value care. Still, they highlighted that healthcare insurers often lack the knowledge, skills and clinical experience to correctly interpret the scientific evidence and guidelines, so that active disinvestment initiatives cannot be based on their interpretation (Quote 17-18). Given that SAPS is an umbrella diagnosis covering a heterogeneous group of etiologies with different treatment needs, they felt that too many diagnoses and procedure codes were included in this particular active disinvestment. As consequence, the active disinvestment did not correctly reflect the SAPS population for which surgery is or is not appropriate, nor which surgical procedures were not appropriate for these patients (Quote 19-22). In addition, clinical guidelines aim only to guide clinical decision-making, and do not dictate treatment for specific patient groups. After all, it is the health professional’s decision to decide on an individual patient’s treatment given the specific input of clinical information of an individual patient in conjunction with the clinical experience of the orthopedic surgeon. Thus, surgeons felt that clinical guidelines should not be used to formulate active disinvestment initiatives (Quote 23).</p>", "<title> At Odds With Physician Experience and Beliefs</title>", "<p> Orthopedic surgeons argued that withholding treatment options resulting from active disinvestment initiatives, is at odds with their general obligation to provide care (Quote 24). They also declared that healthcare insurers have a similar obligation, to reimburse care needed by the patient, which is also violated by this active disinvestment. In addition, surgeons disagreed with the active disinvestment initiative as they believed that some patients could still benefit from surgery, often based on previous individual experience (Quote 25-26). They were not convinced that such a disinvestment initiative would result in a reduction of surgery for SAPS as surgeons would still decide to perform surgery when deemed appropriate by changing their coding practices rather than not doing the surgery anymore (Quote 27).</p>", "<title> Reduced Professional Autonomy</title>", "<p> Orthopedic surgeons argued they had extensive training to weigh different treatment options appropriately, to best care for their patients. Applying such active disinvestment initiatives, the healthcare insurer intervenes in the physician’s work by limiting clinical treatment options and thereby diminishes their professional autonomy. The surgeons mentioned that healthcare insurers should not take over the role of physicians (Quote 28) and felt that such initiatives expose an underlying mistrust of healthcare insurers in the professional autonomy of physicians (Quote 29). In general, they stated that healthcare insurers should not initiate such initiatives, but that these should be initiated by the orthopedic professional association (Quote 30-31).</p>", "<title> Contextual Factors</title>", "<p> Four contextual factors were identified that influenced the effectiveness of the active disinvestment initiative for SAPS. First, both hospital sales managers and orthopedic surgeons mentioned the lack of communication between relevant stakeholders. More communication was needed between the healthcare insurer and hospitals as sales managers needed additional explanation about the active disinvestment by the healthcare insurer (Quote 32). Increased communication was also required among the relevant stakeholders within hospitals as orthopedic surgeons indicated not being informed about the active disinvestment by neither the sales managers nor the healthcare insurer (Quote 33-34). Second, patient preferences may persuade orthopedic surgeons to perform surgery for SAPS (Quote 35-36). Third, fear of losing revenues was suggested as a contextual factor as orthopedic surgeons may have financial benefit from performing surgery, which might reduce the impact of the active disinvestment (Quote 37-39). Striking was that these were only suggested to apply to others (eg, sales managers about orthopedic surgeons, or orthopedic surgeons working in general hospitals about surgeons working in ITCs) and therefore it remains unclear whether this really affects active disinvestment. Finally, simultaneous other interventions (either national or within hospitals) aiming to reduce low-value care may also influence how well the active disinvestment will work (Quote 40-41). Some of these interventions financially rewarded hospitals for not performing low-value care procedures anymore. Sales managers thought that such initiatives would be more successful than active disinvestment as this would be more motivating for hospitals (Quote 42).</p>" ]	[ "<title>Discussion</title>", "<p> The present study showed that two overarching themes negatively influenced the impact of the active disinvestment regarding SAD surgery for SAPS in the Netherlands, as both hospital sales managers and orthopedic surgeons did not support the active disinvestment from the healthcare insurer. Particularly hospital sales managers felt it represented a “Too small piece of the pie” where it was merely used in negotiations to reduce costs but had little financial consequences for the hospital budget while requiring a lot of effort, and was not clearly defined nor enforced in the overall agreements between healthcare insurers and hospitals. As a result, they did not communicate the information on the active disinvestment initiative to orthopedic surgeons. Additionally, orthopedic surgeons felt “They got it wrong” as the active disinvestment had incorrectly interpreted the evidence and guidelines, was at odds with physicians’ experiences and beliefs, and perceived it as a reduction in professional autonomy. As a result, it did not affect their clinical decision-making regarding surgical or non-surgical treatment of these patients. Contextual factors that influenced the impact of the active disinvestment were lack of communication between stakeholders, others being afraid to lose revenue, patient preferences and other simultaneous interventions.</p>", "<p> A strength of this study is that we investigated how this active disinvestment exercises its effects in daily practice from both organizational and clinical perspectives. As we interviewed all study participants within two years after the active disinvestment was put into place, the results of the present study represent the topical opinions and experiences of key players involved in this process. Our findings add to existing theories on the effect of active disinvestment, which was suggested as a promising alternative to reduce low-value care, regarding the various factors through which the impact in daily practice may be considerably reduced. Limitations of our study include the fact that we did not interview SAPS patients themselves, even though they are important stakeholders in clinical decision-making who are likely to be affected by the active disinvestment initiative.<sup>##REF##33794869##12##</sup> In that context, it is relevant to note that the preferences of patients were identified as a contextual factor influencing the clinical decision process and indirectly also as factor influencing the effect of the active disinvestment because patients bypass the systems to get their preferred SAD surgery (see Quote 36). Secondly, since we only investigated the active disinvestment initiative for one specific procedure in a Dutch healthcare setting, the results are not necessarily generalizable to other contexts as other factors may be relevant in different circumstances because such initiatives are deemed context-specific.<sup>##REF##24290335##14##</sup> On the other hand, the overarching themes may still apply, ie, that it should have financial consequences for a hospital to make it worth their effort and that evidence on which it is based should be correctly interpreted, for which it is essential to engage clinicians with relevant expertise. Thirdly, we recruited participants from our professional networks to ensure a diverse sample. It is possible that our professional network does not adequately reflect the views of all sales managers and orthopedic surgeons from the Netherlands. For example, stakeholders who strongly disagree with such active disinvestment initiatives may have been more willing to participate. Furthermore, no orthopedic surgeons from ITCs agreed to participate, while it has been suggested that non-teaching hospitals deliver more low-value care.<sup>##REF##34570170##33##</sup> We did include participants from non-teaching hospitals as well as a sales manager from an ITC, who will likely capture the main views from ITCs although there may be some context-dependent differences. Additionally, our results may have been biased as the active disinvestment initiative started during the COVID-19 pandemic, so that the active disinvestment may have received less attention from relevant stakeholders within the hospital. Since we provided a clear explanation of the active disinvestment initiative to participants not familiar with the active disinvestment, we do not believe that this had a significant influence.</p>", "<p> Many studies have been published on priority setting and resource allocation in healthcare and de-implementation strategies for low-value care procedures.<sup>##REF##33411161##34##,##REF##34819122##35##</sup> Hardly any studies have, however, previously evaluated the outcome of an active disinvestment initiative on low-value care.<sup>##REF##32040158##11##,##REF##33794869##12##</sup> Despite its potentially powerful effect, only few initiatives have shown to result in actual disinvestment.<sup>##REF##33794869##12##</sup> More frequently, active disinvestment initiatives are preliminary terminated. Rotteveel et al evaluated commonalities between factors influencing the outcomes of active disinvestment initiatives in five recent cases in the Netherlands.<sup>##REF##33794869##12##</sup> Consistent with the results of the present study, they found that the degree of support from relevant stakeholders largely determined the success of an active disinvestment initiative. Rotteveel et al mainly evaluated the active disinvestment initiatives from a macro-level policy-makers perspective (eg, governmental institutions, health insurers) and concluded that policy-makers should search for interventions for which there is support from relevant stakeholders when applying an active disinvestment initiative. The present study therefore adds evaluating an active disinvestment initiative from a more meso/micro-level perspective (highlighting eg, local institutional factors<sup>##REF##30976197##36##</sup>) and identified several factors at meso/micro-level that contributed to the limited support for active disinvestment from relevant stakeholders. This adds to our understanding how support for active disinvestment initiatives by relevant stakeholders is needed to affect clinical practice, rather than only issuing an active disinvestment by policy-makers without any additional strategies targeting behavioural factors.</p>", "<p> Healthcare providers frequently disagree on how disinvestment initiatives should be prioritized as more than one low-value care practice is often considered suitable for disinvestment. Previous studies on priority setting and de-implementation strategies in healthcare state that the prioritization of such initiatives should also be based on the potential financial impact (ie, cost-saving potential), which is consistent with basic economic theory principles.<sup>##REF##26444862##37##,##REF##15104792##38##</sup> Our findings are in line with this, as we found that there was no support for the active disinvestment initiative because it had too little financial consequences for the hospital budget given the small number of SAPS patients for most hospitals. Hence, they highlighted the importance of looking for bigger hits with more significant saving potential proportional to the required effort from hospital staff. The importance of a proportional ratio between financial impact and required effort (eg, from hospital staff) is also described by Conrad et al. who explored the effect of monetary incentives on healthcare quality improvement.<sup>##REF##19296779##39##</sup> They concluded that larger financial incentives are more likely to result in improved quality of care and cover the costs of additional efforts and care process changes.<sup>##REF##19296779##39##</sup> They also suggested that financial penalties may elicit an even stronger response due to “loss aversion.” However, lack of financial impact may contra wisely limit its effectiveness as it will not motivate healthcare providers to change behaviour nor cover the costs of additional efforts. Furthermore, sales managers related the lack of financial impact of the active disinvestment to it only being a partial reimbursement stop and the active disinvestment being unclear (eg, the use of relative outcome measures) and not specifically enforced. Consequently, orthopedic surgeons could still perform surgery for SAPS and receive reimbursement. It is possible that active disinvestment initiatives would only work in situations with a complete reimbursement stop, as was the case with the successful Vitamin D reimbursement stop in Canada.<sup>##REF##32040158##11##</sup> Such a complete reimbursement stop makes it impossible to circumvent the active disinvestment. Additionally, it may be that an absolute performance target would have worked better than the relative performance measure used in the active disinvestment regarding SAPS as it is known from literature that these have better incentive properties than relative performance targets.<sup>##REF##19296779##39##</sup> A difficulty of relative performance targets is that they need adequate baseline measurements, which make clear what proportion of care is of low-value. However, in the active disinvestment regarding SAPS hospitals only knew how many surgical procedures they performed but not whether those were low-value care. Consequently, they did not have a clear view of their improvement potential.</p>", "<p> Orthopedic surgeons felt the healthcare insurer had misinterpreted existing scientific evidence and guidelines on treatment in SAPS patients even though literature suggests that disinvestment initiatives should be based on the strength of evidence supporting the lack of effectiveness.<sup>##REF##26444862##37##</sup> The construction of evidence in a disinvestment context is a very complex process as the results of scientific evidence are often not “black or white” and subject to between-subject variation in interpretation. Hodgetts et al stated that selection and interpretation of evidence in a disinvestment decision is necessarily framed such that it better fits the disinvestment initiative.<sup>##REF##22963922##40##</sup> Therefore, they highlighted the need for physician engagement within this process as they can add vital nuance to the debate on what evidence counts in a disinvestment decision and avoid any misinterpretations arising from this ‘fitting it in the disinvestment initiative.’ Additionally, policy-makers often present their disinvestment initiatives as being “black or white” which leaves little room for clinical judgment (it is either low-value care or not) even though it is more nuanced in clinical practice.<sup>##REF##34841821##41##</sup> Although sometimes there may be clear-cut candidates for disinvestment initiatives, ie, interventions that are entirely ineffective, these are generally scarce as most interventions will have at least some effect or in some situations, as otherwise they would likely have been abandoned already.<sup>##REF##34841821##41##</sup> Orthopedic surgeons believed that the active disinvestment initiative did not adequately distinguish in the heterogeneous group of etiologies that make up SAPS patients and felt that some patients could still benefit from surgery, which implies that they do not see SAPS as a good disinvestment candidate (ie, may not entirely be low-value care). Although the concept of low-value care is well-known, a clear definition of what constitutes low-value care is missing as well as who decides what constitutes low-value care, which may depend on the perspective taken.<sup>##REF##35297239##42##</sup> Hence, different stakeholders may have different views on what constitutes low-value care for their situation, as also found in our interviews. In this case, the healthcare insurer decided that most surgery for SAPS patients is low-value care and believed that costs related to this procedure could be saved or should be allocated to other procedures providing more value. The orthopedic surgeons, however, stated that it was not as clear-cut as some patients may benefit from surgery. The latter highlights the tension in perspectives between physicians that want to do as much as possible for their patients and healthcare policy-makers that need to make trade-offs in priority setting in the context of scarcity in healthcare spending.</p>", "<p> There are important implications for future active disinvestment initiatives based on the results from this study, increasing our understanding how active disinvestment initiatives may or may not exercise their effect. The first is that an active disinvestment initiative initiated from a macro-level perspective needs to go together with additional strategies for implementation at micro-level. A crucial step for this implementation at micro-level is to create support from relevant stakeholders,<sup>##REF##33499854##43##</sup> with the present study identifying several specific factors that may inhibit stakeholders’ support. Although the present study investigated only the perspectives of hospital sales managers and orthopedic surgeons, support from other relevant stakeholders (eg, patients, general public) also have been shown to be essential for successful active disinvestment.<sup>##REF##33794869##12##,##REF##34953417##44##, ####REF##33516087##45##, ##UREF##7##46####7##46##</sup> Gaining support of all relevant stakeholders is, however, extremely difficult as there are often contrasting viewpoints so it will be very complex to design an active disinvestment initiative incorporating all of these views.<sup>##REF##34841821##41##</sup> In our study, most participants were not against active disinvestment. Still, they highlighted several reasons why they should have been involved from the start in a policy change to (partially) stop reimbursement eg, to ensure correct interpretation of scientific evidence and prioritize initiatives with the most significant cost-saving potential. Such early engagement of relevant stakeholders and transparency of the designing process will therefore create a more nuanced strategy that will enhance the degree of support, thus increasing the possibility of successful active disinvestment.<sup>##REF##34841821##41##,##REF##23083894##47##</sup> The necessity of stakeholder engagement also has been emphasized in various other studies on eg, priority setting and other de-implementation strategies.<sup>##UREF##2##8##,##REF##33499854##43##</sup></p>", "<p> Another implication is that contextual factors will affect the impact of any active disinvestment initiative, such as fear of losing revenues and patient preferences as found in the present study. As a policy change to stop reimbursement will not influence such factors, active disinvestment initiatives should always be paired with other initiatives appealing to the more intrinsic motivation of clinicians such as clinical decision support, performance feedback, patient-oriented educational materials and other interventions that aim to change clinician behaviour.<sup>##REF##27402662##48##, ####REF##32264926##49##, ##REF##25880152##50####25880152##50##</sup> Therefore, future “top-down” policy changes, such as an active disinvestment initiative, should always be combined with “bottom-up” (eg, physician-oriented) co-interventions in order to maximize its effectiveness and increase to possibility for success.<sup>##UREF##8##51##,##REF##36190815##52##</sup> Additionally, future active disinvestment initiatives must be aligned with pre-existing theories, such as basic economic theory, and consider theoretical frameworks on eg, priority setting and/or de-implementation<sup>##REF##34819122##35##,##REF##31874742##53##</sup> as their implications largely overlap. Future research should further explore the effectiveness of active disinvestment initiatives, while taking into account these co-interventions, incorporate the perspectives of patients and develop more specific theoretical frameworks to facilitate understanding how active disinvestment influences (clinical) decision-making. Additionally, future studies must focus on creating a shared view on low-value care and the process around active disinvestment, so that all stakeholders have a uniform perspective in approaching this concept and can start working on initiatives to reduce low-value care.</p>" ]	[ "<title>Conclusion</title>", "<p> In conclusion, this study showed that two overarching themes negatively influenced the support for and effect of the active disinvestment regarding SAD surgery for SAPS. Hospital sales managers in particular felt it represented a “Too small piece of the pie” while orthopedic surgeons believed “They got it wrong.” Future active disinvestment initiatives should engage all relevant stakeholders at an early stage to gain support, ensure correct interpretation of the evidence and clear definition of the targeted procedures and should target low-value procedures that have sufficient saving-potential to increase the possibility of success.</p>" ]	[ "<p>\n<bold>Background:</bold> Withdrawal of reimbursement for low-value care through a policy change, ie, active disinvestment, is considered a potentially effective de-implementation strategy. However, previous studies have shown conflicting results and the mechanism through which active disinvestment may be effective is unclear. This study explored how the active disinvestment initiative regarding subacromial decompression (SAD) surgery for subacromial pain syndrome (SAPS) in the Netherlands influenced clinical decision-making around surgery, including the perspectives of orthopedic surgeons and hospital sales managers.\n</p>", "<p><bold>Methods:</bold> We performed 20 semi-structured interviews from November 2020 to October 2021 with ten hospital sales managers and ten orthopedic surgeons from twelve hospitals across the Netherlands as relevant stakeholders in the active disinvestment process. The interviews were video-recorded and transcribed verbatim. Inductive thematic analysis was used to analyse interview transcripts independently by two authors and discrepancies were resolved through discussion. </p>", "<p><bold>Results:</bold> Two overarching themes were identified that negatively influenced the effect of the active disinvestment initiative for SAPS. The first theme was that the active disinvestment represented a \"Too small piece of the pie\" indicating little financial consequences for the hospital as it was merely used in negotiations with healthcare insurers to reduce costs, required a disproportionate amount of effort from hospital staff given the small saving-potential, and was not clearly defined nor enforced in the overall healthcare insurer agreements. The second theme was \"They [healthcare insurer] got it wrong,\" as the evidence and guidelines had been incorrectly interpreted, the active disinvestment was at odds with clinician experiences and beliefs and was perceived as a reduction in their professional autonomy. </p>", "<p><bold>Conclusion:</bold> The two overarching themes and their underlying factors highlight the complexity for active disinvestment initiatives to be effective. Future de-implementation initiatives including active disinvestment should engage relevant stakeholders at an early stage to incorporate their different perspectives, gain support and increase the probability of success.</p>", "<p>\n<bold>Citation:</bold> Geurkink TH, Marang-van de Mheen PJ, Nagels J, Poolman RW, Nelissen RGHH, van Bodegom-Vos L. Impact of active disinvestment on decision-making for surgery in patients with subacromial pain syndrome: a qualitative semi-structured interview study among hospital sales managers and orthopedic surgeons. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7710. doi:10.34172/ijhpm.2023.7710</p>" ]	[ "<title>Acknowledgements</title>", "<p> We would like to thank all experts who volunteered their time and participated in the interviews.</p>", "<title>Ethical issues</title>", "<p> The study protocol (N20.127) was presented to the Medical Ethical Committee of the Leiden University Medical Center (METC-LDD, Code 058, Leiden, the Netherlands), who waived the need for ethical approval under Dutch law.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This work was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development [grant number: 80-83920-98-803]. ZonMW did not influence the study in any way nor the writing of the manuscript.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nFactors negatively Influencing the Effectiveness of the Active Disinvestment Initiative on Clinical Decision-Making. Abbreviations: SAD, subacromial decompression; SAPS, subacromial pain syndrome.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Baseline Characteristics of Study Participants\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Participant Characteristics</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Hospital Sales Managers (n = 10)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Orthopedic Surgeons (n = 10)</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Mean Age (SD)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">46 (8.1)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">50 (7.8)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">% Female</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">50</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">20</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean years of experience as orthopedic surgeon (SD)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">NA</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13 (7.2)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean number of SAPS patients per week (SD)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">NA</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13 (9.1)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Hospitals </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Academic</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Non-academic teaching</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Non-academic non-teaching</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Independent treatment center</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Healthcare insurer market leader in hospital </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Familiar with active disinvestment for SAPS patients </td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">4</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Representative Quotations Supporting Each Theme\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Subtheme</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quote Number</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Representative Quotations</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>“Too Small Piece of the Pie”</bold>\n</td></tr><tr><td rowspan=\"4\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Little financial consequences for the hospital budget</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“I mean: there is so much money involved. So let’s then focus on the big groups, on the mass and on the good things. This incentive to me comes across as a specialization within a specialization within a sub-specialization” (SM 3).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Look, with the healthcare insurer we negotiate about 100 million euros. Yes, you know, then you are not going to talk about one specific diagnosis treatment combination, that does not happen” (SM 8).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“I am not going into details, because that would go beyond what I am allowed to do. I cannot describe the details of such an agreement here. But it had no real financial impact on the total of the agreement” (SM 4). </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“According to me is that not our large group [of patients] but I don’t know that myself. In other words, then you will not notice that at all, if you only have a fraction of [patients insured by] [Name insurer]” (OS 2).</td></tr><tr><td rowspan=\"5\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Only part of the negotiations</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Sometimes it seems as if you have a lot of conversations, where there is only push to knock off a little of the overall price” (SM 4).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">6</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Because you have to realize that during the negotiation this is only one part of the total amount on the table. In the end, after exchanging a lot of arguments, you come to an agreement with each other, which is often painful on all fronts. You have to leave certain things to be able to come to an agreement. This is also to the case for the healthcare insurer. They too cannot achieve everything from their dreamed mandate” (SM 4).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“It is often under one big insurance ceiling, so then you get sort of a waterbed effect. So if you say: we want you to do this much fewer procedures and if you don’t entirely exclude that from the contract, so take it out from the ceiling in a separate financial agreement, then it may be possible that you can fill it up with for instance acute care or birth care. So the only way a healthcare insurer can say that you cannot do it anymore and we are going to enforce it, is that they cut out the entire block and really make it a separate part of the agreement. With a clear ceiling on the procedure so that it is really impossible to reimburse it anymore” (SM 6).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“There is often discussion about this during negotiations, with a lot in plus and a lot in minus, then these die individually so to speak and you come to an overall deal, 30, 40, 50, 60 million, in which everything is quasi intertwined” (SM 7).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“And with that (with the active disinvestment) you are actually forced to stop performing that procedure as you don’t get paid for it. That works I think only limited because what you do is that you often agree on one big pocket of money in which you apply the reduction. But if you secretly keep performing that procedure and instead do not perform something else where you have not talked about, then you will still receive the money but for the wrong things” (SM 1).</td></tr><tr><td rowspan=\"4\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Too much effort for a slight reduction in costs</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">10</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“You are talking about a legitimate 420 people, that is a very small number [of patients] and if you also take off the ones with the two other indications then that leaves so few, that yes, is it really worth the effort to spend time on it?” (OS 9).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">11</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“And let’s then mainly talk about the good things and not about a few niches which will take 80 percent of the energy, but only account for 2% of the costs” (SM 3).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">12</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“At the moment that you would you want to take steps towards efficiency, then you are looking for the big hits. Because you have to look at it this way, the commitment of people and resources is probably just as much to improve a certain procedure where we do only a small amount, compared- to where we do large amounts …. But more from the perspective: how do I invest my resources that are limited, human capacity too, to monitor [this]” (SM 1).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">13</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“All the topics that are now on the orthopedics agenda. Yes, these have passed here in the last few years. Still I am forced to catch up on a certain indexation and to make a plan. For which I actually need to hire someone, who would write than plan for me. Whilst we are already doing this…. you are almost forced to go along in that flow. While in the end it often doesn’t lead to the intended goal, or that goal has already been achieved. It involves a lot of effort” (SM 10).</td></tr><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Active disinvestment not clearly defined</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">14</td><td style=\"vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“But what we find very difficult about that information from [Name healthcare insurer] to which you just referred. That is that they indeed say: yes, 80 percent [of these procedures] you should no longer- do. But you don’t really know what 100 percent is. That I find very difficult as you only see what you do, maybe that is already very little, that you have left already that 20 percent [of the procedures that is of value to the patients].... So yes, what has actually been your baseline measurement?” (SM 5).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">15</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“We expect that next year you only do one-third of this [number of procedures]. What kind of discussion is that?” (SM 9).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">16</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“If a healthcare insurer would really shut it down with us and would say: you just cannot reimburse this [procedure] anymore, because it is not meaningful and that has been proven in so much literature. You should not do this anymore. Then we would send out a very clear signal [to the clinicians] you are not allowed to do this anymore” (SM 6).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Subtheme</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quote Number</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Representative Quotations</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>“They Got it Wrong”</bold>\n</td></tr><tr><td rowspan=\"7\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Misinterpretation of scientific evidence and clinical guidelines</italic>\n</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">17</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Yes, I’m fine with that [active disinvestment strategy by insurer] as long as they are well-founded and that’s where it goes wrong. They don’t have the knowledge, of course they have some medical advisors, but they don’t have substantive knowledge to enter a discussion with me. They don’t have the clinical experience with these patients and can’t interpret scientific research” (OS 1).</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">18</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Regardless of the situation, I don’t think the overall trend is good. Maybe it’s typical doctors reasoning but they [healthcare insurers] can’t gauge the true value of the science. They are good with numbers and at negotiating but not in valuing scientific research and its relation with clinical practice” (OS 8). </td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">19</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“And certainly the SAPS complaint, that is such a diverse group of patients so that you can hardly draw any conclusions about SAPS treatment in general” (OS 2).</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">20</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“They [healthcare insurer] include all kinds of things under the SAPS diagnosis…. So medically speaking, those are all very different things. But the healthcare insurer, the layman, includes everything under the same as if it is one big umbrella diagnosis, covering everything” (OS 4).</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">21</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“I know that they have been working on that for a long time, to stop reimbursing this care, however, they classify everything under one diagnosis. I think that you can’t do that, an acromioclavicular resection is suddenly a part of SAPS. That’s not in our guideline, that’s just not right” (OS 5).</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">22</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“In line with this, my biggest fear is that they will also stop reimbursement for cuff repair as they will say it is the same. But it’s not the same. They classify everything under the SAPS syndrome, one collective term for every diagnosis. Yes, before you know it you can’t perform any surgery anymore. Not that that’s what this is about, but I think it’s a worrying development” (OS 8).</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">23</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Guidelines remain guidelines and it is not the case that this means that these interventions must absolutely not be performed and it is also not said that it’s a medical error when you perform this procedure. Therefore, I don’t understand why this policy is used by the healthcare insurer” (OS 7).</td></tr><tr><td rowspan=\"4\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">At odds with physician experience and beliefs</italic>\n</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">24</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“When they say: it is not allowed anymore, it will no longer be reimbursed. Yes, then I’ll use a different [reimbursement] code as I still have a patient who is crying out in pain. I have a general duty of care to help the patient. It is very strange that they say that I can’t do this. They should not be able to do this. They also have a general obligation to provide care” (OS 9).</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">25</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“When I notice that my treatments don’t have any effect, than I’m not going to offer it. The majority of patients that we treat are eventually happy and have less pain. I don’t care whether this is the result of surgery, an injection or some explanation. If I can treat patients well with conservative treatment then I will be happy to do so. But I still think there is a role for surgical treatments” (OS 2).</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">26</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“But when there is a persistent problem and the patient has had adequate treatment for at least one year, our physical therapists cannot do anything anymore, the diagnosis is confirmed on echo and a subacromial injection provides temporary pain relief, and everything points towards that direction [SAPS]. Yes, then I think you should still have the option to perform surgery” (OS 5).</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">27</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“When I think there is a medical indication, then that’s it and then I’m going to do that. I can still justify this for myself from the medical evidence. But on the other hand, it’s so artificial to say: we stop reimbursement. Look, orthopedic surgeons are smart enough to use another code [diagnosis and procedure code combination]. So yeah, this is not a good way to regulate something at all” (OS 7).</td></tr><tr><td rowspan=\"4\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Reduced professional autonomy</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">28</td><td style=\"vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Well, I think that the healthcare insurer should not take the place of the doctor…. I know for sure that we, orthopedic surgeons, are not waiting for healthcare insurers that tell us what we should and shouldn’t do” (OS 7).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">29</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Speaking for myself, I have the feeling that they think that we want to fool someone or to get financial gain out of something. The more subacromial decompressions we do, a simple procedure, the more money we earn. But nobody, at least none of my colleagues, thinks about this while doing consultations at the outpatient clinic” (OS 6).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">30</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“I think that the incentive should be initiated by the professional association…. In the end, I think that clinicians should decide and that the treatment policy should not be determined by the health insurer” (OS 8). </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">31</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“You get people in the right direction more quickly if they are intrinsically motivated, instead of extrinsic matters. I think that the social control in the Netherlands is also large enough. At a certain point, you know from colleagues if they still do it [procedures] or if they do it a lot and you come across them and you will see their patients for a second opinion. So, I think the circuit also works well and you don’t want to be seen as the one who is still performing these operations. I think everyone has his own pride in that. I think that this might work better than a healthcare insurer interfering in this, as they are not seen as a partner. And then I’m putting it mildly” (OS 1).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Subtheme</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quote Number</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Representative Quotations</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Contextual Factors</bold>\n</td></tr><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Lack of communication between relevant stakeholders</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">32</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“What I sometimes find rather peculiar about [name healthcare insurer], they are, in my opinion, very good at just throwing things over the fence…. If you really want to change something, then start a conversation” (SM 3). </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">33</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“We are never told about this by sales or the medical manager, that we need to change certain things in our working procedure” (OS 2).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">34</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Within our group [orthopedic surgeons] we have discussed this extensively and I also formulated a response [for the healthcare insurer], which was checked by the others.… The stupid thing is, I don’t hear anything about it. I know that this now also is a point of concern nationally, so that it will also be tackled nationally after that discussion in the shoulder elbow working group. But I haven’t heard back what’s going to happen now, whether the care we provide will be reimbursed or not” (OS 5).</td></tr><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Patient preferences</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">35</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“People who have had the [same] surgery in the past, had good results on that side and now have similar pain or shoulder complaints on the other side. They want surgery” (OS 3).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">36</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“By the way, then people will sometimes just go to Belgium. And that will subsequently also be reimbursed by the insurers. So there are patients who bypass the system” (SM 4).</td></tr><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Fear of losing revenues</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">37</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“But the projects [reducing low-value procedures] don’t run themselves as the surgeons are financially rewarded for their volume [of performed procedures]. Therefore, at the moment you remove volumes, they will not be the first ones applauding for you” (SM 2).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">38</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“We are a hospital in which incomes and honoraria are highly correlated with production. So yes, I dare to state that these kind of desired movements will not be helped by the way in which hospitals like ours work and that such incentives could be very tricky in that context.” (SM 5).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">39</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“I understand that there are still clinics where they [surgeons] just do everything: hips, knees, shoulders, and that subacromial pain leads to a subacromial decompression…. Because they make their living with this. An arthroscopy will give you a lot of money. So if you just do a bursectomy or a Neer acromioplasty, that will yield a lot of money” (OS 9).</td></tr><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">Simultaneous other interventions</italic>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">40</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“For example, there is now also the ZE&GG program<sup>a</sup>, we actively started with this last year…. Last year this was a bit more noncommittal and you could see this in the varying degree of involvement between departments. This year we are going to make it mandatory as there are financial agreements linked to this for the hospitals” (SM 3).</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">41</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“I’m not familiar with the example [active disinvestment strategy for SAPS], that’s how I should phrase it. However, the general tendency and the conversations, we are constantly working on this. Patients a day shorter. They used to spend three days in a room after surgery, now only two or sometimes one. So in general, we are already working on similar trajectories” (SM 8). </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">42</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">“Then we’re talking again about the ZE&GG agenda. The hospitals get a certain additional compensation for increases in wages and collective labor agreement, and for that they have agreed to actively participate with that ZE&GG agenda…. So in that sense this works with an incentive. Apparently, the hospitals were interested and have agreed with this. Because they get their money, but also do something in return. We all get it. I think this might be relevant for you to consider, to what extent would incentives work better than disincentives” (SM 1).</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Based on the results of this study, the effectiveness of an active disinvestment initiative seems to be largely dependent on the support for active disinvestment by relevant stakeholders. </p></list-item><list-item><p>To gain support for active disinvestment and improve the probability of success, policy-makers should actively engage relevant stakeholders early on in the development of the disinvestment strategy. </p></list-item><list-item><p>In specific, active disinvestment initiatives must have sufficient saving-potential and a required effort from hospital staff that is proportionate to the financial impact, need to be clearly defined and enforced in overall hospital agreements, and be supported by evidence and guidelines. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> The withdrawal of reimbursement for low-value procedures through a policy change, ie, active disinvestment, is considered a potentially effective but underused strategy to reduce low-value care. This study found that the effectiveness of such initiatives seems to be largely dependent on the support for active disinvestment from relevant stakeholders (eg, hospital sales managers and orthopedic surgeons). Therefore, policy-makers should engage relevant stakeholders early on in the development of an active disinvestment initiative to improve the possibility for success. Furthermore, several specific factors were identified within this study that may contribute to the limited support for active disinvestment by relevant stakeholders.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Semi-structured Interview Guides.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: SAPS, subacromial pain syndrome; SD, standard deviation; NA, not available.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: SM, hospital sales manager; OS, orthopedic surgeon; SAPS, subacromial pain syndrome.</p><p>\n<sup>a</sup> The ZE&GG program is a program for the evaluation and appropriate use of care from Zorginstituut Nederland. Within this program, hospitals work together with healthcare insurers and the Dutch government in order to actively reduce the use of low-value care. The hospitals receive a financial incentive for their participation.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7710-g001\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7710-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["5"], "mixed-citation": [" Smith M, Saunders R, Stuckhardt L, McGinnis JM. Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Washington, DC: National Academies Press; 2013. "], "pub-id": ["10.17226/13444"]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Levinson", "Kallewaard", "Bhatia", "Wolfson", "Shortt", "Kerr"], "given-names": ["W", "M", "RS", "D", "S", "EA"], "article-title": ["\u2018Choosing Wisely\u2019: a growing international campaign"], "source": ["BMJ Qual Saf"], "year": ["2015"], "volume": ["24"], "issue": ["2"], "fpage": ["167"], "lpage": ["174"], "pub-id": ["10.1136/bmjqs-2014-003821"]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Grimshaw", "Patey", "Kirkham"], "given-names": ["JM", "AM", "KR"], "article-title": ["De-implementing wisely: developing the evidence base to reduce low-value care"], "source": ["BMJ Qual Saf"], "year": ["2020"], "volume": ["29"], "issue": ["5"], "fpage": ["409"], "lpage": ["417"], "pub-id": ["10.1136/bmjqs-2019-010060"]}, {"label": ["19"], "mixed-citation": [" Hollingworth W, Rooshenas L, Busby J, et al. Using Clinical Practice Variations as a Method for Commissioners and Clinicians to Identify and Prioritise Opportunities for Disinvestment in Health Care: A Cross-Sectional Study, Systematic Reviews and Qualitative Study. Southampton, UK: NIHR Journals Library; 2015. "], "pub-id": ["10.3310/hsdr03130"]}, {"label": ["23"], "mixed-citation": [" Jeurissen P, Maarse H. The Market Reform in Dutch Health Care: Results, Lessons and Prospects. Copenhagen: European Observatory on Health Systems and Policies; 2021. "]}, {"label": ["30"], "person-group": ["\n"], "surname": ["van Dulmen", "Naaktgeboren", "Heus"], "given-names": ["SA", "CA", "P"], "article-title": ["Barriers and facilitators to reduce low-value care: a qualitative evidence synthesis"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["10"], "fpage": ["e040025"], "pub-id": ["10.1136/bmjopen-2020-040025"]}, {"label": ["32"], "person-group": ["\n"], "surname": ["Braun", "Clarke"], "given-names": ["V", "V"], "article-title": ["Using thematic analysis in psychology"], "source": ["Qual Res Psychol"], "year": ["2006"], "volume": ["3"], "issue": ["2"], "fpage": ["77"], "lpage": ["101"], "pub-id": ["10.1191/1478088706qp063oa"]}, {"label": ["46"], "person-group": ["\n"], "surname": ["Born", "Coulter", "Han"], "given-names": ["KB", "A", "A"], "article-title": ["Engaging patients and the public in Choosing Wisely"], "source": ["BMJ Qual Saf"], "year": ["2017"], "volume": ["26"], "issue": ["8"], "fpage": ["687"], "lpage": ["691"], "pub-id": ["10.1136/bmjqs-2017-006595"]}, {"label": ["51"], "person-group": ["\n"], "surname": ["Patey", "Soong"], "given-names": ["AM", "C"], "article-title": ["Top-down and bottom-up approaches to low-value care"], "source": ["BMJ Qual Saf"], "year": ["2023"], "volume": ["32"], "issue": ["2"], "fpage": ["65"], "lpage": ["68"], "pub-id": ["10.1136/bmjqs-2022-014977"]}]	{ "acronym": [], "definition": [] }	53	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 13; 12:7710	oa_package/66/99/PMC10590240.tar.gz
PMC10590241	0	[ "<title>Background</title>", "<p> The rise of the for-profit business corporation (hereafter corporation, unless otherwise specified) has been described as one of the most fundamental global transformations of the past three centuries.<sup>##UREF##0##1##,##UREF##1##2##</sup> Corporations are entities that owe the legal basis for their mandate and powers to pursue private profits to a combination of state concessions granted upon incorporation (see ##BOX##0##Box 1##).<sup>##UREF##2##3##,##UREF##3##4##</sup> In general, it is the <italic toggle=\"yes\">combination</italic> of these concessions that give corporations considerable financial, economic, and political advantages over non-corporate business forms (eg, sole proprietorships) and non-business corporate forms (eg, incorporated universities).<sup>##UREF##3##4##</sup></p>", "<p> Dating back at least to the 16th century when European states began to attach a special set of rights and privileges to business entities in the pursuit of national, imperial or public interest objectives,<sup>##UREF##1##2##,##UREF##7##8##</sup> corporations have greatly impacted on the health of many populations.<sup>##UREF##1##2##,##UREF##6##7##,##UREF##8##9##</sup> Corporations have been lauded by many for contributing to economic prosperity and development, job creation, and meaningful technological progress.<sup>##UREF##9##11##, ####UREF##10##12##, ##UREF##11##13####11##13##</sup> However, many concerns have been raised about the myriad ways by which many corporations negatively impact on population health and health inequity.<sup>##UREF##1##2##,##UREF##6##7##,##UREF##8##9##,##UREF##12##14##,##UREF##13##15##</sup> In recent years, an increasing body of research on the influence of corporations and other commercial actors on health and equity has fallen under the banner of the <italic toggle=\"yes\">commercial determinants of health</italic>, referring to the ‘<italic toggle=\"yes\">systems, practices, and pathways through which commercial actors drive health and equity</italic>.’<sup>##REF##36966782##16##</sup></p>", "<p> Public health stakeholders have long sought to expose and hold powerful business actors, especially corporations, to account for harmful practices.<sup>##REF##34878875##17##</sup> Many approaches to address harmful business practices have focused on the products and practices of particular industries, especially health-harming commodity industries and those related to essential healthcare products or services. Since the harms of cigarette smoking were exposed in the 1940s and 1950s, for instance, public health stakeholders have led international efforts for stricter regulation of tobacco products and of various practices conducted by tobacco corporations.<sup>##UREF##0##1##,##REF##13174399##18##, ####REF##14772469##19##, ##REF##13160495##20##, ##REF##19298423##21##, ##REF##27628857##22####27628857##22##</sup> As another example, public health campaigns targeting pharmaceutical corporations that jeopardise efforts to make medicines (eg, antiretrovirals against the human immunodeficiency virus) and vaccines (eg, against SARS-CoV-2) accessible and affordable for all have made some inroads into improving health equity for various populations.<sup>##REF##22789043##23##,##REF##33131225##24##</sup> Industry-specific approaches to holding powerful corporations to account are important, and, in many cases, have played a substantial role in improving health outcomes. Nevertheless, many of the most pressing public health challenges of our time, including climate breakdown and widening socio-economic inequalities, are driven and reinforced by large corporations in diverse sectors and contexts. It follows, then, that cross-sectoral actions that seek to address the root causes of these problems are needed.<sup>##REF##36966782##16##,##REF##32563223##25##, ####UREF##14##26##, ##UREF##15##27####15##27##</sup></p>", "<p> The concept of ‘excessive corporate power’ offers a potentially crucial entry point for identifying and linking such cross-sectoral approaches to improving and protecting population health and health equity.<sup>##UREF##16##28##, ####REF##33619932##29##, ##REF##30024808##30####30024808##30##</sup> Albeit a contested term, excessive corporate power can refer to the capacity of corporate actors to ‘interfere’ on an ‘arbitrary’ basis with the real or perceived choices of other actors or groups (eg, workers, consumers, citizens, other businesses, legislators, and researchers).<sup>##UREF##17##31##</sup> This definition draws from both Lukes’ (1974, 2005) definition of power and Pettit’s (1997) definition of domination, with the latter author referring to ‘arbitrary’ interference as interfering for the purpose of self-interest (eg, profit maximisation) with minimal regard to the interests of others affected.<sup>##UREF##17##31##, ####UREF##18##32##, ##UREF##19##33####19##33##</sup> Several public health scholars have described how excessive corporate power, conceptualised as above or in a similar way, can influence health. These conceptualisations often cover relatively direct or instrumental mechanisms of influence, including by subjecting workers to harmful working conditions or poor wages, or by shaping the preferences of disadvantaged individuals and social groups via aggressive and predatory marketing practices.<sup>##REF##34020657##34##,##REF##29448968##35##</sup> The conceptualisations of excessive corporate power also cover more indirect mechanisms of influence, such as the way in which corporations shape markets, supply chains, the distribution of wealth and income, public policy, regulation, science, the mainstream media, and public opinion, thereby <italic toggle=\"yes\">structuring</italic> the real or perceived choices that particular actors can make to the detriment of their health or the health of others.<sup>##UREF##16##28##, ####REF##33619932##29##, ##REF##30024808##30####30024808##30##,##REF##34020657##34##, ####REF##29448968##35##, ##REF##33276385##36##, ##REF##32198290##37####32198290##37##</sup> These dynamics take play within broader systems that, in recent decades, have become increasingly neoliberalised and financialised (albeit to varying degrees), characterised by a suite of policies, norms and governance arrangements that have accommodated, rather than confronted, corporate power.<sup>##REF##31657174##38##, ####REF##34192622##39##, ##UREF##20##40##, ##REF##36631805##41##, ##UREF##21##42##, ##UREF##22##43####22##43##</sup></p>", "<p> A few notable exceptions notwithstanding,<sup>##UREF##6##7##,##UREF##15##27##,##REF##34192622##39##,##UREF##23##44##, ####REF##35150415##45##, ##REF##36966784##46##, ##UREF##24##47##, ##REF##36764315##48####36764315##48##</sup> discussions and research on how to curb excessive corporate powerremain relatively underdeveloped in the public health literature. With this in mind, this paper aimed to identify a diverse range of actions with the potential to address excessive corporate power. The underlying premise for the review was that <italic toggle=\"yes\">any </italic>action that addresses excessive corporate power, at least as conceptualised above, has the <italic toggle=\"yes\">potential</italic> to positively influence population health and health equity.</p>" ]	[ "<title>Methods</title>", "<p> Given the complex and interdisciplinary nature of the subject at hand, we chose to conduct a scoping review of diverse social science and legal literature. We describe our theoretical and organising framework below, along with the scoping review methods used.</p>", "<title> Theoretical and Organising Framework</title>", "<p> We drew from Meagher’s ‘3Ds’ heuristic device to guide our framing of identified accounts and prescriptions on how to address excessive corporate power.<sup>##UREF##8##9##,##UREF##25##49##</sup> This heuristic categorises actions to address excessive corporate power into three groups — <italic toggle=\"yes\">dispersion</italic>, <italic toggle=\"yes\">democratisation</italic>, and <italic toggle=\"yes\">dissolution</italic>.<sup>##UREF##8##9##,##UREF##25##49##</sup>\n<italic toggle=\"yes\">Dispersion</italic> refers to the decentralisation and redistribution of concentrations of corporate wealth and power. Within this domain, Meagher focuses mostly on antitrust (competition law) measures designed to prevent future monopolies and break up existing monopolies. <italic toggle=\"yes\">Democratisation</italic> refers to ensuring that corporate decision-makers take into account the interests of all actors subject to excessive corporate power within their control (eg, via diverse stakeholder representation on corporate boards). Lastly, <italic toggle=\"yes\">dissolution</italic> refers to dissolving excessive corporate power that cannot be dispersed or democratised, largely through revoking corporate privileges granted upon incorporation.</p>", "<p> We chose Meagher’s ‘3Ds’ heuristic to be our organising framework as we felt it was broad enough in scope to inform the categorisation of a wide range of potential actions. Nevertheless, we maintained flexibility during our categorisation process by allowing for the development of new categories in cases where identified actions did not neatly fit within the three original groups (further details below). We also chose Meagher’s heuristic because we felt it appropriately recognises the complex relationship that typically exists between states and corporations. In particular, the heuristic does not assume that states and corporations are always in contest, that the general rise in corporate power seen in recent decades has come at the expense of state power, nor that the boundaries between states and corporations are always distinct. Rather, in accordance with the concession and political theories of the corporation,<sup>##UREF##2##3##,##UREF##3##4##</sup> it assumes that corporations cannot exist without states, and that, in principle, states have the power to regulate corporations within their jurisdiction.</p>", "<title> Scoping Review Methods</title>", "<p> Following the process set out by Arksey and O’Malley,<sup>##UREF##26##50##</sup> we conducted a scoping review to identify actions that have the potential to address excessive corporate power (see ##SUPPL##0##Supplementary file 1## for search terms used). Searches were completed across four databases: Scopus, Web of Science, HeinOnline, and EBSCO (encompassing Medline Complete, Business Source Complete, EconLit, Environment Complete, Global Health, Legal Source, and Political Science Complete). Databases were searched in January 2022. Search results (n = 327 studies) were downloaded and imported into Endnote citation software where duplicates (n = 92) were removed. Backwards citation searching was undertaken to identify additional studies (see Figure). Following Godin and colleagues’ approach to systematically analyse grey literature,<sup>##REF##26494010##51##</sup> two advanced Google Scholar and Google searches were completed (limited to English language), with the first conducted in January and the second in February 2022. The first 100 results for each search were scanned. The websites of organisations and think tanks identified through the Google searches were also examined for relevant documents. Finally, the list of included documents was supplemented with: (<italic toggle=\"yes\">i</italic>) the authors’ knowledge of relevant documents, including some published after the literature searches were completed; and (<italic toggle=\"yes\">ii</italic>) expanded searches on illustrative examples found during the review process that warranted further information to inform analysis.</p>", "<p> No specific limits were placed on dates or geography, although documents not published in English were excluded. We screened the titles and abstracts (or table of contents and executive summaries where relevant) for all search results (see ##TAB##0##Table 1##). Following screening, full texts were retrieved and tabulated by one of the authors in excel. From the documents that fulfilled the inclusion criteria, we extracted the title, authors, date of publication, the identified or prescribed action(s), and the corresponding country or region (where relevant).</p>", "<title> Data Analysis and Framework Development</title>", "<p> Identified actions were thematically grouped into strategies in an iterative manner. Guided by Meagher’s ‘<italic toggle=\"yes\">3Ds</italic>’ heuristic,<sup>##UREF##8##9##,##UREF##25##49##</sup> these strategies were grouped into overarching strategic objectives via a process of deductive coding. During the analysis, additional actions and strategies were identified that did not neatly fit within the heuristic. After discussion amongst all authors, two additional strategic objectives were developed to encompass these additional actions and strategies: ‘<italic toggle=\"yes\">strengthen countervailing power structures</italic>’ and ‘<italic toggle=\"yes\">reform and democratise the global governance of corporations.’</italic> We documented examples in which the identified actions had been implemented, including, in some cases, the key actors involved.</p>" ]	[ "<title>Results</title>", "<p> We identified 178 documents that collectively describe a broad range of actions to address excessive corporate power. ##TAB##1##Table 2## outlines the five strategic objectives and 18 strategies identified in this study, as well as illustrative examples of actions. The strategic objectives, strategies, and actions discussed in this section are interlinked and, in general, complementary to one another.</p>", "<title> Disperse Concentrated Corporate Wealth and Power</title>", "<title> Strengthen Antitrust Regulation to Protect and Promote the Welfare of All Citizens </title>", "<p> In many jurisdictions, antitrust or competition law represents one of the most powerful levers a state has at its disposal to disperse excessive corporate power, including through addressing high market concentration and abuses of market dominance.<sup>##UREF##8##9##,##UREF##27##52##, ####UREF##28##53##, ##UREF##29##54####29##54##</sup></p>", "<p> The US antitrust model has been one of the most influential globally, both due to US influence over other national antitrust models, as well as the global influence of US corporations subjected in some way to US antitrust law. With one of the longest antitrust traditions, the US passed its first federal antitrust law in 1890 to supposedly preserve open markets and economic opportunities, as well as to safeguard society and democracy against extreme concentrations of wealth and power.<sup>##UREF##27##52##, ####UREF##28##53##, ##UREF##29##54####29##54##</sup> Many contend, however, that US antitrust regulation has weakened considerably since the 1970s and 1980s, largely underpinned by a shift in thinking, led by the Chicago School and sponsored by big business, about the normative purpose of antitrust policy.<sup>##UREF##8##9##,##UREF##30##55##, ####UREF##31##56##, ##UREF##32##57####32##57##</sup> The Chicago School contended that the sole objective of antitrust should be to advance ‘consumer welfare,’ a concept they considered synonymous with ‘economic efficiency,’ and one that is often narrowly interpreted as low consumer prices.<sup>##UREF##8##9##,##UREF##31##56##</sup> Many antitrust agencies and courts around the world today continue to recognise ‘consumer welfare’ in such narrow terms as one of the primary goals of antitrust policy.<sup>##UREF##33##58##,##UREF##34##59##</sup></p>", "<p> Some jurisdictions, however, have wider antitrust policy objectives than those prescribed by <italic toggle=\"yes\">consumer welfarists</italic>, or at least are in the process of widening such objectives, that are arguably better aligned with the strategic objective of dispersing corporate power.<sup>##UREF##35##60##, ####UREF##36##61##, ##UREF##37##62##, ##UREF##38##63####38##63##</sup> For instance, one of the stated objectives of the Republic of Korea’s Monopoly Regulation and Fair Trade Act is to prohibit the excessive concentration of economic power.<sup>##UREF##39##64##</sup> South Africa, as another example, has a model in which its antitrust agencies and courts must consider a set of public interest considerations, some which relate to the social and economic welfare of its so-called ‘Historically Disadvantaged Persons,’ that was reportedly established to help restore a society deeply divided along racial and socio-economic lines.<sup>##UREF##40##65##</sup> In 2021, South Africa’s antitrust regulators blocked a merger <italic toggle=\"yes\">solely</italic> on the grounds that it would have drastically reduced the shares held by ‘Historically Disadvantaged Persons’ in the target company.<sup>##UREF##41##66##</sup> Moreover, at the time of writing, the European Commission was in the process of considering the integration of environmental sustainability objectives into the antitrust policy of the European Union.<sup>##UREF##36##61##</sup></p>", "<p> In the United States, President Biden signed an executive order in 2021 that provides the statutory basis for stronger whole-of-government approach to antitrust policy to better protect democratic accountability and the welfare of diverse groups across society.<sup>##UREF##42##67##</sup> Perhaps even more indicative of Biden’s intent to challenge Chicago School-style antitrust regulation was his appointment of Lina Khan as chair of the Federal Trade Commission and Jonathan Kanter as head of the US Department of Justice’s Antitrust Division.<sup>##UREF##35##60##</sup> Khan, a key figure of the anti-monopolist ‘New Brandeisian’ antitrust movement, pledged among other things to use the power of antitrust law to curb the power of ‘<italic toggle=\"yes\">Big Tech</italic>’ in a dramatically new way.<sup>##UREF##43##68##</sup> Under the leadership of Kanter, the US Department of Justice’s Antitrust Division reportedly litigated more mergers in 2022 than any fiscal year on record.<sup>##UREF##44##69##</sup></p>", "<title> Limit Corporate Rent-Seeking and Cost Externalisation</title>", "<p> An important means of dispersing corporate power is to limit corporate rent-seeking – the generation of income that is unearned (eg, through owning a scarce asset, such as a patent) or generated in an extractive manner (eg, by externalising costs onto society; by abusing a dominant market position). The generation of excessive profits by virtue of holding and misusing a position of market dominance, in principle, can be addressed via antitrust law (discussed in the previous section).<sup>##UREF##8##9##</sup></p>", "<p> Cost externalisation is an important form of corporate rent-seeking, wherein corporations effectively generate rents by not being held financially accountable for the harms they cause.<sup>##UREF##8##9##</sup> In many jurisdictions today, well-established regulations have been implemented to restrict how certain harmful products are made, packaged, and labelled, as well as marketed to specified population groups.<sup>##REF##34982584##70##,##UREF##45##71##</sup> Similarly, fiscal policy has also been recognised as an important tool to limit health-related cost externalisation, including through measures such as ‘sin taxes’ to reduce the population-level consumption of harmful commodities.<sup>##REF##34982584##70##,##UREF##46##72##,##UREF##47##73##</sup></p>", "<p> Fiscal policy can also play a key role in targeting and redistributing excessive corporate rents and externalised costs more broadly. Many people, for instance, have called for ‘windfall profit’ taxes targeting certain fossil fuel and COVID-19 vaccine manufacturing corporations in light of their recent record profits.<sup>##UREF##48##74##,##UREF##49##75##</sup> As perhaps a more radical example, we identified a proposal to reform tax law to disincentivise all forms of aggressive advertising, including by ensuring that corporations cannot offset the cost of advertising against the profits they generate to reduce their taxable income.<sup>##UREF##50##76##</sup></p>", "<p> International agreements and conventions have, in some cases, played an important role in facilitating the spread of national regulations targeting harmful commodity industries. In the 1970s, for example, public health and civil society actors drove the development of the International Code of Marketing of Breast-Milk Substitutes (the BMS Code), endorsed by the World Health Assembly in 1981, in an attempt to address the role played by the infant milk formula industry in undermining health and human rights.<sup>##UREF##51##77##,##REF##33035126##78##</sup> Notwithstanding its relatively poor implementation and enforcement, the BMS Code provides provisions targeting the harmful marketing of infant milk formula and similar products that states can incorporate into national laws.<sup>##REF##34020657##34##</sup> As an another example, after decades of internationalised efforts to strengthen regulation of the tobacco industry, the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) entered in force as binding law in 2005 for all parties to the treaty.<sup>##REF##33533185##79##</sup> The FCTC has reportedly facilitated a drop in both tobacco smoking prevalence and exposure to second-hand tobacco smoke around the world.<sup>##REF##33533185##79##</sup> It has also contributed to the resolution of legal challenges put forward by the tobacco industry in favour of governments, including by providing a legal and evidential basis for such regulatory measures.<sup>##REF##29860233##80##</sup></p>", "<p> The exploitation of intellectual property rights has been described as a particularly harmful form of corporate rent-seeking.<sup>##UREF##52##81##, ####UREF##53##82##, ##UREF##54##83####54##83##</sup> Such behaviour can be particularly problematic when corporations exploit their monopoly rights over particular technologies in a way that denies access to essential goods (eg, seeds, medicines, vaccines) on the basis of the ability to pay.<sup>##REF##33173259##84##,##UREF##55##85##</sup> Our review identified that some countries have challenged this form of exploitation. For instance, during the 1990s and early 2000s, Brazil and Thailand successfully pursued the goal of universal access to antiretroviral therapy against HIV/AIDS, in part through legislating free access to such treatment and scaling domestic capacity to produce generic medicines.<sup>##UREF##56##86##</sup> At the international level, and largely though the organised efforts of public health, civil society and some state actors, World Trade Organisation (WTO) member states adopted the Doha Declaration on Trade-Related Aspects and Intellectual Property Rights (TRIPS) and Public Health in 2001, which provides national governments some agency to take measures to protect their public’s health within the relatively restrictive TRIPS framework.<sup>##REF##33131225##24##</sup></p>", "<p> Further examples of corporate rent-seeking identified in the literature include tax minimisation, tax evasion, and corporate welfare (ie, money or aid given to a corporation from a government).<sup>##UREF##57##87##, ####UREF##58##88##, ##UREF##59##89####59##89##</sup> In this respect, important measures suggested include mandating that corporations apportion tax to countries according to the location of their assets, employment, and sales<sup>##UREF##60##90##</sup>; implementing a fair and adequate global minimum corporate tax rate<sup>##UREF##61##91##</sup>; strengthening tax collection and enforcement<sup>##UREF##62##92##</sup>; and strictly controlling which corporations receive tax incentives, exemptions, and subsidies.<sup>##UREF##58##88##,##UREF##62##92##</sup> With respect to the last measure, 197 countries formally agreed to speed up efforts to eliminate ‘inefficient’ fossil fuel subsidies, which now exceed US$500 billion every year, at the 2021 United Nations (UN) Climate Change Conference.<sup>##UREF##63##93##</sup></p>", "<title> Redistribute Concentrations of Corporate Wealth and Income Through Progressive Tax Policy</title>", "<p> On top of redistributing corporate rents, tax policy has an important role in curbing excessive corporate power through restricting concentrations of excess wealth and income.<sup>##UREF##64##94##,##UREF##65##95##</sup> Measures such as raising corporate statutory tax rates, or taxing a corporations’ stock, fall within this strategy.<sup>##UREF##64##94##</sup> Relatedly, it has been argued that tax policy should encompass the regulation of the use of corporations by shareholders and company executives to maximise their own private wealth and income. In this respect, measures could include taxing share repurchases,<sup>##UREF##66##96##</sup> strengthening capital income and gains tax policies,<sup>##UREF##62##92##</sup> implementing or strengthening financial transaction taxes to disincentivise high-frequency trading,<sup>##UREF##62##92##,##UREF##67##97##</sup> and penalising corporations that exceed a certain threshold for the ratio of payments their Chief Executive Officer receives relative to median employee pay.<sup>##UREF##68##98##</sup></p>", "<title> Strengthen Regulation of Political Contributions, Corruption, and Conflicts of Interest </title>", "<p> It has been argued that, in many contexts, political contribution (including campaign finance) and anti-corruption reforms will be required to restrain corporate influence in policy-making and politics.<sup>##UREF##59##89##,##UREF##69##99##, ####UREF##70##100##, ##UREF##71##101##, ##UREF##72##102####72##102##</sup> Important measures identified during the review include bans, limits, and real-time disclosure of political contributions from corporations<sup>##UREF##73##103##,##UREF##74##104##</sup>; tightly regulating, through bans, waiting periods, and disclosure laws, the ‘revolving door’ between legislators and regulators and high-level positions in corporations<sup>##REF##31569204##105##</sup>; and the implementation of mandatory lobby registers and ‘ministers’ diaries’ that require detailed real-time disclosures for corporate engagement with public officials.<sup>##UREF##75##106##,##UREF##76##107##</sup> In the United States, many commentators have specifically called for an overruling of the 2010 <italic toggle=\"yes\">Citizens United v. Federal Election Commission</italic> decision, which permits unlimited election spending by corporations using treasury funds.<sup>##UREF##77##108##,##REF##21421946##109##</sup></p>", "<p> Public health actors have called on governments, academic institutions, the media, and civil society to strictly regulate their interaction with corporations, especially those active in health-harming commodity industries, to better manage conflicts of interest.<sup>##REF##36966784##46##,##UREF##78##110##</sup> The FCTC is often portrayed as an exemplar instrument in this respect. FCTC’s Article 5.3 establishes rules at the international level to ban engagement between public health officials and the vested interests of the tobacco industry.<sup>##REF##36966784##46##,##REF##34982584##70##</sup> Article 5.3 also calls for the protection of public health policies from the vested interests of the tobacco industry, stating that: ‘<italic toggle=\"yes\">Parties shall act to protect [public health] policies from commercial and other vested interests of the tobacco industry in accordance with national law</italic>.’<sup>##REF##36966784##46##</sup> Calls have been made for similar treaties to be applied to other health-harming industries, such as alcohol and ultra-processed foods.<sup>##UREF##78##110##</sup> One proposal takes this further by calling for a broader international convention on the <italic toggle=\"yes\">commercial determinants of health</italic> that would focus on coordinating policy responses to a range of commercial practices, political processes, and related norms.<sup>##REF##36966784##46##</sup></p>", "<p> Efforts made by the Australian Government to manage conflicts of interest during the ongoing review of the Australian Dietary Guidelines, including a dedicated governance committee and a commitment to publishing a summary of meetings, correspondence, and relevant phone calls from external stakeholders during the review process, provides an example of innovation in this area at the national level.<sup>##UREF##79##111##</sup></p>", "<title> Strengthen Countervailing Power Structures</title>", "<title> Strengthen the Countervailing Power of Workers and Consumers </title>", "<p> In line with arguments put forward by North American economist John Galbraith,<sup>##UREF##80##112##</sup> the power of workers and consumers can help to countervail excessive corporate power. Workers can exercise countervailing power, for instance, by joining unions, taking part in strikes and sit-ins, and by whistle-blowing. We identified several examples of governments supporting the countervailing power of workers, including by strengthening labour and unionisations laws, protecting the right to strike and to collectively bargain, and ensuring adequate protections for whistle-blowers.<sup>##UREF##81##113##, ####REF##31504470##114##, ##UREF##82##115##, ##UREF##83##116##, ##UREF##84##117##, ##UREF##85##118##, ##UREF##86##119####86##119##</sup></p>", "<p> Consumers can exercise countervailing power in various forms, including by joining consumer movements, as well as by taking part in consumer boycotts. A well-known case of this in action was the consumer boycott of Nestlé — triggered by exposés of the company’s undermining of child and maternal rights in disadvantaged parts of the world – which contributed to multiple forms of meaningful change, including the development of the WHO BMS Code described earlier.<sup>##REF##33035126##78##</sup> Robust consumer laws, including the strict regulation of aggressive and predatory marketing practices, and privacy laws (especially with respect to ‘Big Tech’) are recognised as important ways by which governments can support consumers.<sup>##REF##34982584##70##,##REF##33035126##78##,##UREF##70##100##,##UREF##87##120##,##UREF##88##121##</sup></p>", "<title> Promote Socially Responsible Shareholding</title>", "<p> Shareholders have access to certain rights and entitlements that can be leveraged to influence corporate decision-making. ‘<italic toggle=\"yes\">Shareholder activism</italic>,’ where individuals or organisations acquire corporate shares and thus the right to participate in voting on particular corporate policies and strategies, represents a market-based action with the potential to influence corporate decision-making in the public interest.<sup>##REF##34982584##70##,##UREF##89##122##,##UREF##90##123##</sup> As an example, in response to shareholder pressure led by the non-governmental organisation ShareAction, Unilever announced commitment in 2022 to set a new benchmark for public reporting with respect to the healthfulness of its food products.<sup>##UREF##91##124##</sup> In some cases, divestment campaigns have called on shareholders to divest from corporations active in harmful industries (eg, fossil fuels, tobacco, and certain weapons), as well as those active or based in controversial regions (eg, Israel, Russia, and Myanmar).<sup>##UREF##92##125##,##UREF##93##126##</sup></p>", "<p> As governments and government agencies at different levels are often corporate shareholders, they can support these shareholder activism campaigns and divestment initiatives. In 2021, for instance, Boston Mayor’s Michelle Wu prohibited the use of public funds within her jurisdiction to invest in corporations that derive more than 15% revenue from fossil fuel, tobacco, and private prison operations.<sup>##UREF##94##127##</sup></p>", "<title> Strengthen Transparency Mechanisms to Promote Corporate Accountability </title>", "<p> Strong corporate transparency mechanisms, among other things, can provide civil society and state actors with the necessary evidence to trigger or reinforce efforts (eg, litigation, consumer boycotts, legislative reforms) to hold dominant corporations to account.<sup>##REF##36966784##46##,##UREF##62##92##,##REF##25703108##128##</sup></p>", "<p> Increasing corporate tax transparency is recognised as one particularly important component in ensuring corporate accountability, especially given the non-transparent and often secretive nature of corporate tax minimisation and avoidance.<sup>##UREF##95##129##</sup> In this respect, public country-by-country reporting has been proposed as a tool to better monitor and address the tax minimisation and avoidance-related activities of transnational corporations, such as transfer pricing.<sup>##UREF##95##129##</sup> More broadly, mandatory corporate disclosure on social and environmental issues has been described as an important means for civil society and governments to hold corporations to account.<sup>##REF##36966784##46##,##REF##25703108##128##,##UREF##96##130##,##REF##35080755##131##</sup> The Corporate Sustainability Reporting Directive recently proposed by the European Commission serves as a notable example of what would be a mandatory reporting framework that, in principle, aims to broaden what large corporations must disclose with respect to the implementation of their environmental, social, and governance policies.<sup>##UREF##96##130##</sup></p>", "<title> Support Legal Remediation for Citizens Harmed by Corporations </title>", "<p> Supporting and promoting access to justice for citizens harmed by corporations can act as an important countervailing power structure for citizens insofar as it can help to redress harmful and exploitative practices that enable some corporations to generate profits and consolidate power.</p>", "<p> Litigation in particular has been widely used to curb the production of harmful commodities, recover externalised costs, and hold corporations to account for the harms they have caused to individuals or groups of individuals.<sup>##REF##34982584##70##</sup> Especially since the 1990s, it has been noted that litigation of the tobacco industry in the United States has been somewhat successful, at least relative to earlier periods. One particularly momentous settlement took place in 1998, in which four of the largest tobacco corporations were required to, inter alia, stop engaging in marketing practices that target children, and pay an annual compensation to the states for health-care related costs associated with tobacco smoking.<sup>##UREF##97##132##</sup> In recent years, the fossil fuel industry has been increasingly targeted by lawsuits.<sup>##UREF##98##133##</sup> It was even noted in a 2022 Intergovernmental Panel on Climate Change report that climate-change related litigation had become one of several important new avenues for shaping climate and environmental policy worldwide.<sup>##UREF##99##134##</sup></p>", "<p> Compared to private lawsuits, <italic toggle=\"yes\">qui tam</italic> lawsuits, referring to suits in which private individuals or organisations assist a prosecution on behalf of the government, have been described as having greater potential to prompt broader regulatory changes relating to dominant corporations.<sup>##UREF##100##135##</sup> It was suggested that, in order to support and scale up this hybrid private-public enforcement approach, states could define a wider range of regulatory laws in which <italic toggle=\"yes\">qui tam</italic> lawsuits could be used to seek compensation related to particular harmful corporate actions, such as those in violation of public health, human rights, and environmental laws.<sup>##UREF##100##135##</sup></p>", "<title> Organise Alternative Modes of Business and Systems of Production and Distribution</title>", "<p> An important strategy to challenge excessive corporate power is to promote and organise alternative modes of business that allow communities to bypass systems of production and distribution dominated by corporations (especially those primarily concerned with the short-term interests of their shareholders).<sup>##UREF##101##136##, ####UREF##102##137##, ##UREF##103##138##, ##UREF##104##139####104##139##</sup> Important examples include co-operatives and mutual enterprises, which are collectively owned by various actors such as consumers or workers, and are often driven by principles including mutual aid, equity, solidarity, and community development.<sup>##REF##36966784##46##</sup> It has been noted that business co-operatives managed and owned by workers, such as Mondragon in the Basque region of Spain and Cooperation Jackson in the U.S, can provide meaningful living wage jobs and foster community development.<sup>##UREF##105##140##,##UREF##106##141##</sup> Renewable energy co-operatives, which are playing a key role in renewable energy transition in a number of European countries, have also been described as important enablers of community development.<sup>##UREF##107##142##</sup></p>", "<p> We identified several examples of communities around the world redesigning local modes of food production and distribution in their quest for ‘<italic toggle=\"yes\">food sovereignty</italic>,’ often under the leadership of the 200-million strong <italic toggle=\"yes\">Via Campesina</italic> movement.<sup>##UREF##104##139##,##UREF##108##143##,##UREF##109##144##</sup> Notably, the worldwide expansion of programs and policies instituting ‘<italic toggle=\"yes\">food sovereignty’</italic> highlights the political salience of reconfiguring local food systems to benefit the livelihoods, health, and food security of citizens and communities.<sup>##UREF##109##144##</sup> As an illustration, local government policy-makers in the Brazilian city of Belo Horizonte, a city considered to be a pioneer in addressing food insecurity, have implemented a set of integrated local-level policies and programs that seek to promote access to safe, quality, and nutritious food.<sup>##UREF##110##145##</sup></p>", "<p> National governments can play an important role in supporting business alternatives to shareholder-oriented corporations, including via scaling-up social enterprises through sufficient public investment initiatives, progressive public procurement policies, and implementing supportive legal frameworks.<sup>##REF##36966784##46##</sup> In 2006, as a notable example, South Korea’s parliament introduced its Social Enterprise Promotion Act, which, among other things, reportedly inspired the Ministry of Agriculture, Food and Rural Affairs to introduce and support a business scheme designed to support rural communities.<sup>##UREF##111##146##</sup> Similarly, in 2014, France’s parliament implemented a ‘Social and Solidarity Economy’ law to better support social enterprises in promoting and achieving sustainable local development.<sup>##UREF##112##147##</sup></p>", "<title> Democratise Corporate Decision-Making </title>", "<title> Improve Stakeholder Representation on Corporate Boards</title>", "<p> To democratise corporate decision-making, many scholars have advocated for mandating stakeholder representation on corporate boards in order to allow stakeholders subject to corporate power a say in how such power is exercised and distributed.<sup>##UREF##113##148##, ####UREF##114##149##, ##UREF##115##150####115##150##</sup> This idea partly builds on existing corporate law models of co-determination, such as in Germany, wherein workers of large companies have the legal right to elect representatives to almost half of all supervisory board positions.<sup>##UREF##116##151##,##UREF##117##152##</sup> Corporate law has also been used to achieve gender parity on corporate boards in Norway.<sup>##UREF##118##153##</sup> More broadly, a number of scholars have suggested that a potential way to improve the representation of the general public in corporate decision-making could be to mandate the inclusion of public representatives on the boards of large corporations.<sup>##UREF##119##154##</sup></p>", "<title> Mandate the Pursuit of Stakeholder Value </title>", "<p> Voluntary ‘<italic toggle=\"yes\">stakeholder value</italic>’ corporate models, in which corporate decision-makers voluntarily commit to take into account the interests of a broad range of their stakeholders, have recently become available as a legal form in several jurisdictions.<sup>##UREF##8##9##,##UREF##120##155##, ####UREF##121##156##, ##UREF##122##157####122##157##</sup> However, despite the emergence of these newer corporate forms, many argue that the prevailing view of corporate purpose in many contexts continues to be that publicly listed corporations should extract and distribute value for the primary benefit of their shareholders.<sup>##UREF##3##4##,##UREF##8##9##,##UREF##62##92##,##UREF##123##158##,##UREF##124##159##</sup></p>", "<p> The considerable shortcomings of voluntary corporate pledges that claim to address escalating social and ecological crises have led to mounting calls for states to obligate corporate directors to internalise the interests of <italic toggle=\"yes\">all</italic> stakeholders in their decision-making.<sup>##UREF##113##148##,##UREF##114##149##,##UREF##124##159##,##UREF##125##160##</sup> Some scholars, for instance, have called for corporate purpose to be redefined under law,<sup>##UREF##8##9##,##UREF##124##159##,##UREF##126##161##</sup> with an example text as follows: ‘[to create] <italic toggle=\"yes\">sustainable value within the planetary boundaries while respecting the interests of its investors and other involved parties</italic>.’<sup>##UREF##124##159##</sup> Similarly, corporate charters, which detail the rights and obligations of corporations,<sup>##UREF##3##4##</sup> have been described as an instrument that could be operationalised by states to ensure corporations pursue stakeholder value.<sup>##UREF##70##100##,##UREF##74##104##,##UREF##127##162##</sup> In the United States, pertinent examples of federal chartering proposals that would require large corporations to pursue stakeholder value are included in the Nader Group Report of 1976,<sup>##UREF##128##163##</sup> Elizabeth Warren’s proposed Accountable Capitalism Act,<sup>##UREF##129##164##</sup> and Bernie Sander’s Corporate Accountability and Democracy Plan.<sup>##UREF##130##165##</sup></p>", "<title> Mandate Corporate Decision-Makers to Identify and Mitigate Adverse Social and Environmental Impacts </title>", "<p> The review identified several studies in which it was noted that corporate due diligence laws have the potential to regulate the corporate pursuit of stakeholder value through requiring corporate directors to identify and mitigate actual and potential adverse social and environmental impacts related to their decisions.<sup>##UREF##96##130##,##UREF##131##166##, ####UREF##132##167##, ##UREF##133##168##, ##REF##33948049##169##, ##UREF##134##170##, ##UREF##135##171####135##171##</sup> A number of countries, such as Germany and France, have implemented corporate due diligence laws with respect to human rights, with France also expanding such laws to encompass environmental harms.<sup>##UREF##96##130##,##UREF##136##172##</sup> In a recent development, the European Commission set out a proposal in early 2022 for a new directive on corporate <italic toggle=\"yes\">sustainability</italic> due diligence, which would, in principle, legally hold directors of large European Union-based corporations to account for the adverse human rights, climate change and environmental consequences of their decisions.<sup>##UREF##96##130##</sup></p>", "<p> Many scholars have argued that an important way to safeguard the rights and interests of citizens around the world from corporate violations is to subject transnational corporations to a legally binding international instrument on human rights.<sup>##UREF##133##168##, ####REF##33948049##169##, ##UREF##134##170##, ##UREF##135##171####135##171##,##UREF##137##173##, ####UREF##138##174##, ##UREF##139##175##, ##UREF##140##176##, ##UREF##141##177####141##177##</sup> Drafted in 2003, the ‘<italic toggle=\"yes\">Norms on the Responsibilities of Transnational Corporations and Other Business Enterprises with Regards to Human Rights</italic>’ (the Norms) provides an example of such an instrument, although this was ultimately rejected by the UN Commission on Human Rights.<sup>##UREF##131##166##,##UREF##142##178##</sup></p>", "<p> One innovative proposal identified during the review largely based on the principle of ‘restorative justice’ involved requiring all corporations above a certain size to prepare and continuously improve a ‘justice plan,’ referring to a plan developed via a deliberative process between corporate decision-makers and stakeholders to determine what must be done to prevent and repair injustices caused by the corporation.<sup>##UREF##143##179##</sup> Under this proposal, large corporations would be required to improve their justice plans each year, and to monitor whether the citizens they affect are receiving just treatment.<sup>##UREF##143##179##</sup></p>", "<title> Increase the Public Takeover of Privatised “Public Goods”</title>", "<p> Many scholars have called for the ownership and control of privatised and outsourced ‘public good’ industries (eg, public utilities such as water) to be retransferred to communities or the relevant level of government through the processes of remunicipalisation, renationalisation, and rebuilding public sector capacities.<sup>##UREF##59##89##,##UREF##144##180##, ####UREF##145##181##, ##UREF##146##182##, ##UREF##147##183####147##183##</sup> A recent report from the Transnational Institute provides more than 800 examples of the remunicipalisation of public services, including water, energy, housing, transport, security, finance, and school canteens, in 1600 cities and 45 countries.<sup>##UREF##148##184##</sup> A well-documented case occurred in 2000 in Bolivia, where, in response to large-scale and coordinated protests, the Bolivian government reversed the privatisation of Cochabamba’s water supply and handed back control to the city.<sup>##UREF##149##185##</sup> As part of the ‘<italic toggle=\"yes\">energy democracy’</italic> movement, as another illustration, an increasing number of cities across the world are calling for, and in some cases achieving, a transition towards the public ownership of their energy utilities.<sup>##UREF##150##186##,##UREF##151##187##</sup></p>", "<p> The potential benefits of public control of technology, including the ways in which socially meaningful technologies and their associated benefits are distributed, are also well described.<sup>##UREF##52##81##</sup> While not necessarily publicly owned, Cuba’s state-owned biotechnology and pharmaceutical sector has been lauded for successfully supporting its national health system, as well as fostering technology transfer among low- and middle-income countries (LMICs), providing somewhat of a contrast to the highly financialised biotechnology and pharmaceutical sectors in countries like the United States.<sup>##UREF##52##81##,##UREF##152##188##,##UREF##153##189##</sup></p>", "<p> It was argued that governments and universities have an important role to play in promoting the public ownership of science, including as a means of protecting the processes of generating, disseminating, and using evidence to inform public policy from being captured by powerful corporate interests.<sup>##REF##36966784##46##,##UREF##74##104##</sup> In this respect, suggested measures included increasing government support for publicly-funded research (especially critical social science research), as well as strengthening the management of conflicts of interests that invariably arise from corporate-sponsored research (as alluded to in an earlier section).<sup>##REF##36966784##46##,##UREF##74##104##</sup></p>", "<title> Reform and Democratise the Global Governance of Corporations</title>", "<title> Reform and Democratise Existing International Organisations and Institutional Arrangements That Sustain Corporate Power</title>", "<p> We identified a number of proposals relating to reforming existing international organisations and arrangements to shift decision-making power from powerful states and their corporations back to elected governments and civil societies.<sup>##UREF##0##1##,##REF##33948049##169##,##UREF##154##190##, ####UREF##155##191##, ##UREF##156##192##, ##UREF##157##193####157##193##</sup> Chimni, for example, proposes a suite of measures, including assigning a greater role to national parliaments in the negotiation and ratification of WTO agreements to ensure that the consent of the representatives of citizens in the respective country, where relevant, is adequately sought.<sup>##UREF##154##190##</sup> To initiate such a measure, it was suggested that national parliaments could pass a law requiring consultation and consent as a precondition for ratification of any significant international agreement, including but not limited to those related to trade and investment.<sup>##UREF##154##190##</sup> In its report entitled ‘A Fair Globalization,’ the International Labour Organisation called for greater flexibility to be given to countries for entering or opting out of proposed disciplines or issues in the WTO, including by allowing greater policy space for countries to pursue diverse national policy objectives.<sup>##UREF##155##191##</sup> The Doha Declaration introduced earlier shows that some concessions, albeit limited, have been made under the auspices of WTO to protect national policy space in certain areas relating to public health (eg, access to medicines).</p>", "<p> The Investor State Dispute Settlement (ISDS) mechanism has come under considerable criticism for readily allowing transnational corporations to sue governments for implementing public health regulations.<sup>##REF##34819083##194##,##UREF##158##195##</sup> Several LMICs — including Argentina, Bolivia, Venezuela, Ecuador, South Africa, and Indonesia — have taken action on this issue, including by withdrawing from trade and investment agreements that have facilitated ISDS.<sup>##REF##34819083##194##,##UREF##158##195##</sup> Under the auspices of the UN Commission on International Trade Law, discussions on reforming the system of ISDS are currently under negotiation amid calls by some experts for its abolition.<sup>##UREF##159##196##,##UREF##160##197##</sup></p>", "<p> With respect to the International Monetary Fund (IMF) and the World Bank, the International Trade Union Confederation recently published reports calling for these organisations to stop their structural reform programs that promote economic policies and processes, such as liberalisation and privatisation, that often sustain the power of corporations headquartered in wealthy countries.<sup>##UREF##161##198##,##UREF##162##199##</sup> Among other things, International Trade Union Confederation made the case that the current conditionality policies of the IMF should be changed to better align with priority sustainable development goals.<sup>##UREF##161##198##</sup></p>", "<title> Develop New International Organisations and Institutional Arrangements to Constrain Corporate Power</title>", "<p> Our review identified numerous proposals for the development of new international organisations and institutional arrangements to constrain the power of transnational corporations. As a pertinent example, it was noted that during the 1970s a collective project of many countries, referred to as the New International Economic Order (NIEO), started to call for, among other things, the development of new international institutions to govern transnational corporations.<sup>##UREF##163##200##,##UREF##164##201##</sup> The NIEO project produced some mixed results, at least initially. In 1974, not long after then-Chilean President Salvador Allende called for the international community to address the ‘<italic toggle=\"yes\">economic power, political influence and corrupting action</italic>’ of corporations, the UN Centre on Transnational Corporations was formed.<sup>##UREF##165##202##</sup> Largely due to US and corporate opposition, however, the UN Centre on Transnational Corporations failed to build consensus for a legally binding Code of Conduct for Transnational Corporations, and was eventually abolished in 1992.<sup>##UREF##165##202##</sup> In early 2023, nearly 50 years from when the project first emerged, delegates from over 25 countries met in Havana, Cuba, in an attempt to revive discussions about a NIEO in the UN General Assembly.<sup>##UREF##164##201##</sup></p>", "<p> Perhaps the most comprehensive proposal to democratise the global governance of corporations identified during the review entailed the development of a Second Assembly of the UN directly elected by the citizens of the world.<sup>##UREF##166##203##</sup> This Second Assembly, it was suggested, could be given the authority to organise international committees of democratically elected representatives to oversee the work of international organisations (eg, the WTO, the IMF, and the World Bank).<sup>##UREF##0##1##</sup> The committees could be mandated to hear complaints made against these international organisations by citizen groups, and have the authority to take cases to the International Court of Justice or the International Criminal Court as required.<sup>##UREF##0##1##</sup></p>", "<title> Dissolve Excessive and Harmful Corporate Power</title>", "<title> Dissolve Harmful Corporations </title>", "<p> Corporations that consistently breach the public interest can be disempowered through the revocation of some or all privileges granted via incorporation.<sup>##UREF##25##49##,##UREF##71##101##,##UREF##146##182##</sup> While such an idea may appear radical in many contemporary contexts, it is worth noting that corporations were regularly dissolved in the United States and Europe prior to the 20<sup>th</sup> century.<sup>##UREF##8##9##</sup> More recently, several companies in the United Kingdom were dissolved for fraudulently claiming COVID-19 pandemic related business support.<sup>##UREF##167##204##</sup> The recent dissolution of Purdue Pharma, a corporation that fuelled the US opioid epidemic, also offers a glimpse of this approach in action.<sup>##UREF##168##205##</sup></p>", "<title> Wind-Down Harmful Industries</title>", "<p> When breaches of the public interest apply more broadly to an industry, some argue that measures to ‘wind down’ the industry in question should be considered.<sup>##UREF##169##206##,##REF##30654860##207##</sup> Through innovative industrial policy, public investment strategies, and corporate law, corporations active in industries in direct conflict with public and planetary health (eg, fossil fuels, tobacco, certain pesticides) could, in principle, be forced to be redesigned so that their operations specific to the industry in question are reduced, substituted, and, when necessary, prohibited.<sup>##UREF##170##208##,##UREF##171##209##</sup> As an illustration, many states, including the United Kingdom, Canada, and France, have recently made public pledges to phase out the use of coal as a source of energy.<sup>##UREF##172##210##</sup> As another example, New Zealand recently moved to ban the sale of cigarettes to people born after the year 2010.<sup>##UREF##173##211##</sup> At the local and municipal levels of government, an increasing number of political leaders are reportedly taking part in planning a prompt and systematic transition from energy dependence on fossil fuels towards clean and renewable energy sources within their jurisdictions.<sup>##UREF##58##88##,##UREF##174##212##</sup></p>", "<p> International coordination, however, is required to prevent harmful industries that have been wound down in one context from investing more heavily in other contexts with weaker regulatory arrangements. The global elimination of leaded petroleum in 2021 shows that sufficient international coordination can be achieved to ‘wind down’ an industry at the global level.<sup>##UREF##175##213##</sup></p>", "<title> Reform/transform the Corporate Form</title>", "<p> Many historical and contemporary commentators have called for stricter control and, in some cases, systematic revocation of the legal, political, and economic privileges of corporations. In the United States, for instance, hundreds of local and municipal governments have in recent times issued ordinances supporting the revocation of ‘corporate personhood’ (ie, the legal notion that a corporation is an entity separate from the people associated with it).<sup>##UREF##77##108##</sup> Corporate chartering reforms have also been proposed that challenge the right of perpetual existence, including by requiring corporations to apply for the renewal of their privileges granted upon incorporation at the completion of a defined period (eg, ten years).<sup>##UREF##70##100##,##UREF##176##214##</sup></p>", "<p> A number of scholars have argued for a systematic rethink of limited liability, contending that it promotes corporate irresponsibility and the externalisation of costs as a core profit-maximising strategy.<sup>##UREF##177##215##,##UREF##178##216##</sup> To address this issue, measures such as revoking limited liability for large corporations and implementing a system of ‘equity’ fines (wherein offending corporations would be required to issue shares that would be controlled by a compensation fund) have been suggested.<sup>##UREF##146##182##,##UREF##177##215##,##UREF##179##217##, ####UREF##180##218##, ##UREF##181##219####181##219##</sup> Relatedly, some scholars have recognised the need to strengthen corporate law to ensure that parent corporations hiding behind a corporate ‘veil’ — that is, controlling a subsidiary by being a major shareholder, and thereby being protected under limited liability — can still be held liable for gross misconduct.<sup>##UREF##182##220##,##UREF##183##221##</sup> The case of James Hardie, a transnational corporation that manufactured and distributed the majority of asbestos in Australia, provides one illustration of how some corporations seek to avoid liability through complex restructuring. In this case, though, James Hardie was challenged by the state of New South Wales and the High Court of Australia, with the corporation subsequently required to establish and fund a charitable trust to cover relevant claims.<sup>##UREF##183##221##</sup></p>" ]	[ "<title>Discussion</title>", "<title> Overview</title>", "<p> This study identified a wide range of implemented and proposed actions, across multiple levels of governance (eg, subnational, national, and international) and regulatory domains, that have the potential to challenge excessive corporate power. We categorised these actions into 18 strategies and five strategic objectives to provide insight into how they might be able to work synergistically. Notwithstanding the preponderance of literature originating from high-income countries, many of the identified actions have been implemented in diverse contexts. However, we recognise that most actions have not been widely adopted, and, in many contexts, there are considerable political, institutional, and cultural barriers to their implementation.</p>", "<p> Many of the strategies largely fall under the purview of democratically elected governments. This is particularly the case for the strategies largely contingent on law (eg, those related to antitrust regulation, corporate purpose and form, and tax), as well as government policy and intergovernmental relations (eg, reforming and democratising the global governance architecture). While government action is required for many strategies, there are nevertheless opportunities for other actors to support and reinforce these government actions. Such opportunities are perhaps most explicit for the strategies that fall under the strategic objective of ‘strengthen[ing] countervailing power structures.’ Workers, for instance, can take part in organised labour actions<sup>##UREF##85##118##</sup>; shareholders can use their privileged positions ‘within’ the corporation to shape corporate policy and strategy in the public’s interest<sup>##UREF##91##124##</sup>; and citizens, non-corporate business actors and communities can contribute to the scaling up of alternative forms of business.<sup>##UREF##105##140##,##UREF##106##141##,##UREF##109##144##</sup> Furthermore, while it was beyond the scope of this paper to provide explanations of the factors that led to the implementation of identified actions, civil society actors (eg, health organisations, labour unions, consumer organisations, grassroots movements, activist academics, citizens and citizen groups) likely played important roles in driving many of the identified actions — both state and collective. Civil society actors can present a considerable countervailing force vis-à-vis excessive corporate power, such as by exposing and raising awareness of harmful corporate practices, advocating for government policy and law reforms, and challenging ideas and norms that sustain corporate power.<sup>##UREF##0##1##,##REF##36966784##46##,##REF##34982584##70##,##REF##31504470##114##</sup> As part of mobilised civil society efforts, actors in the field of public health have often played a key role in challenging excessive corporate power, at least in some contexts.<sup>##REF##33131225##24##,##REF##36966784##46##,##REF##34982584##70##</sup> Testament to this is the implementation of many national public health regulations against harmful corporate products and practices, the successful litigation against health-harming industries, and the development of numerous public health-oriented international frameworks and conventions (eg, FCTC).</p>", "<p> Many of the identified actions and proposals represent a reversal or response to neoliberal policies and programs (eg, remunicipalisation and other public ownership initiatives to counter privatisation), the contemporary neoliberal-style international economic order (eg, challenging the ISDS mechanism to protect national sovereignty), and shifts in corporate governance towards ‘maximising shareholder value’ (eg, laws mandating corporate-decision makers to consider and balance a broad range of interests). The effects of these policies, governance arrangements and norms vary considerably around the world, which perhaps partly explains why state and collective efforts to address excessive corporate power are piecemeal and highly diverse. Several other proposals instead seek to fundamentally reconfigure the relationship between business corporations and capitalist society — a relationship that has evolved substantially in recent centuries.<sup>##UREF##0##1##</sup> In some cases these proposals draw from historical laws and regulatory frameworks, such as some of the prescriptions relating to corporate law (eg, changes to the privileges that corporations received upon incorporation). In other cases, including the proposal to develop a Second Assembly of the UN directly elected by the citizens of the world, they represent radical ideas yet to be enacted.</p>", "<p> The proposed framework supports and links existing work in the public health literature that outlines and seeks to develop integrated approaches to the <italic toggle=\"yes\">commercial determinants</italic> of ill-health and health inequity.<sup>##UREF##14##26##,##REF##36966784##46##,##REF##36764315##48##,##REF##34982584##70##,##UREF##74##104##,##UREF##123##158##,##UREF##184##222##,##REF##35508319##223##</sup> Similar to Wiist and Freudenberg, for instance, the proposed framework engages with a set of government levers, such as those related to corporate and antitrust laws, not often discussed in the public health literature despite their <italic toggle=\"yes\">potential</italic> to protect and promote population health and health equity.<sup>##UREF##24##47##,##UREF##123##158##</sup> In line with the recent Lancet series on the <italic toggle=\"yes\">commercial determinants of health,</italic> the framework also considers the role of cross-sectoral national policies and regulations, international frameworks and conventions, and the scaling up of alternative business models to systematically reduce the social and environmental harms caused by powerful commercial actors.<sup>##REF##36966784##46##</sup></p>", "<p> There are several opportunities for public health researchers to take part in supporting the implementation of this paper’s prescribed agenda. Public health researchers, for instance, could seek to collaborate with key actors (eg, researchers, government actors, business actors) from diverse regulatory domains and geographical contexts to explore the political, cultural, and institutional feasibility of implementing some of the identified actions and proposed strategies. Such work could be facilitated by intergovernmental organisations such as WHO and the UN Conference on Trade and Development, both of which have experience in supporting and coordinating government responses to particular issues pertaining to excessive corporate power. As noted by Friel et al, WHO’s new focus on addressing the commercial determinants of ill-health and health inequity could help to promote greater and more cohesive action on these determinants.<sup>##REF##36966784##46##</sup> Among other benefits, this type of work could help public health researchers and advocates develop key competencies and sensitivities to better understand and engage with a range of technical and epistemic communities. It might also provide an opportunity for public health researchers to voice and infuse public health ideas and objectives into policy discussions in which they might not otherwise be explicitly considered. Nevertheless, it is important to recognise that some of the identified actions might be feasible and culturally appropriate in one context, but not another. Further research is needed to understand the context-specific opportunities and barriers for implementing the proposed strategies and actions identified in this review.</p>", "<p> In recognition of the key role that civil societies play in driving social and political change, a related opportunity for public health researchers to contribute to efforts to address excessive corporate power could be to support and engage with a broad range of civil society actors. For example, future public health advocacy could seek to increase engagement with diverse actors — such as representatives of movements related to climate change, degrowth, feminism, anti-monopoly, food and energy sovereignty, feminism, indigenous rights, and tax and debt justice, as well as consumer organisations and trade unions — to identify common goals and potential ways to pool capacities and resources to achieve these shared goals in different contexts. As we have argued in this paper, the goal of curbing excessive corporate power to promote health and equity could serve as an entry point to identify common objectives among such civil society actors, as well as a potentially powerful way to frame advocacy campaigns pushing for government intervention. These advocacy efforts could help to generate enabling environments for governments to act on some of the strategies proposed in this review.</p>", "<title> Strengths and Limitations</title>", "<p> A strength of this paper is that it includes a review of a diverse range of literature, and integrated findings and discussions from multiple fields and disciplines. The normative and theoretical basis of the paper, and its organising framework, also drew upon well-established theories of the corporation.<sup>##UREF##2##3##,##UREF##3##4##</sup></p>", "<p> This paper has several limitations. First, given the broad-ranging nature of the topic, the search terms used in the scoping review were relatively narrow, and, as such, the review would not have identified all the actions that have previously been identified as having the potential to address excessive corporate power. This is particularly likely to be the case for actions taken in many LMICs, given that the data we extracted were skewed towards high-income countries.</p>", "<p> Second, we acknowledge that the process of grouping and classifying actions identified during the review would have been influenced by the concepts of the theoretical framework adopted, as well as our own perspectives. We did use an iterative approach to allow for some flexibility in categorising identified actions that we felt did not neatly fit under the organising framework. Nevertheless, the use of a different organising framework may have led to the identification of different strategies and strategic objectives.</p>", "<p> Third, it was beyond the scope of this paper to identify and examine how each action has translated or could potentially translate into positive health and equity outcomes. The way in which particular actions may be implemented in different contexts and how their impact may vary based on local factors was not considered. These represent important avenues for future examination.</p>", "<p> Furthermore, the focus of this study was on the impact of for-profit business corporations on health, because it is this particular business form that has emerged to dominate economies and politics around much of the world.<sup>##UREF##0##1##,##UREF##1##2##</sup> We recognise, though, that non-corporate businesses can also negatively influence health and equity.<sup>##REF##36966783##224##</sup> We also recognise that for many corporations, such as certain state-owned corporations, political objectives of the corporation and/or the state in which it is headquartered may trump the objective of generating profits. In such instances, especially if the state in question is not a representative democracy, some of the proposed strategies would become largely inapplicable.</p>", "<p> Lastly, it was beyond the scope of this paper to examine the factors and processes that have led to, or could facilitate, the adoption of the identified actions in diverse contexts. We recognise that many of these actions have not been widely adopted, and that, in many contexts, there are likely to be substantial barriers to their implementation. For instance, many state, corporate and private actors benefit from excessive corporate power, and are likely to take steps to sustain and protect such power.<sup>##UREF##20##40##,##UREF##21##42##</sup> Relatedly, some have argued that efforts to reform many state instruments, including some of those discussed in this paper, in ways that give increased prominence to broader social and environment objectives will likely fail because these instruments are primarily designed to serve the interests of large corporations and their major beneficiaries.<sup>##UREF##101##136##,##UREF##185##225##</sup> Nevertheless, this paper highlights a range of complementary ‘top-down’ and ‘bottom-up’ actions that have been implemented in practice. The proposed framework can guide future research and advocacy efforts as part of a solutions-oriented <italic toggle=\"yes\">commercial determinants of health </italic>agenda.</p>" ]	[ "<title>Conclusion</title>", "<p> The proposed framework presented in this paper consists of a range of measures that can change the regulatory context in which corporations operate so that broader societal goals, including health and equity, are given much greater prominence and consideration vis-à-vis powerful corporate interests. As such, the framework provides guidance for those seeking to identify upstream and integrated solutions to many pressing and complex societal challenges, including unhealthy diets, climate breakdown, and widening socio-economic inequalities. Many of the identified actions and proposed strategies require direct involvement from democratically elected governments, but such involvement will only likely come about through strong civil society advocacy and collective action.</p>" ]	[ "<p>\n<bold>Background:</bold> In many sectors of the economy, for-profit business corporations hold excessive power relative to some governments and civil society. These power imbalances have been recognised as important contributors to many pressing and complex societal challenges, including unhealthy diets, climate change, and widening socio-economic inequalities, and thus pose a major barrier to efforts to improve public health and health equity. In this paper, we reviewed potential actions for addressing excessive corporate power.\n</p>", "<p><bold>Methods:</bold> We conducted a scoping review of diverse literature (using Scopus, Web of Science, HeinOnline, and EBSCO databases), along with expanded searches, to identify state and collective actions with the potential to address excessive corporate power. Actions were thematically classified into overarching strategic objectives, guided by Meagher’s ‘3Ds’ heuristic, which classifies actions to curb corporate power into three groups: dispersion, democratisation, and dissolution. Based on the actions identified, we proposed two additional strategic objectives: reform and democratise the global governance of corporations, and strengthen countervailing power structures.\n</p>", "<p><bold>Results:</bold> We identified 178 documents that collectively cover a broad range of actions to address excessive corporate power. In total, 18 interrelated strategies were identified, along with several examples in which aspects of these strategies have been implemented.\n</p>", "<p><bold>Conclusion:</bold> The proposed framework sheds light on how a diverse set of strategies and actions that seek to address excessive corporate power can work synergistically to change the regulatory context in which corporations operate, so that broader societal goals, including health and equity, are given much greater prominence and consideration vis-à-vis powerful corporate interests.</p>", "<p>\n<bold>Citation:</bold> Wood B, Lacy-Nichols J, Sacks G. Taking on the corporate determinants of ill-health and health inequity: a scoping review of actions to address excessive corporate power to protect and promote the public’s health. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7304. doi:10.34172/ijhpm.2023.7304</p>" ]	[ "<title>Acknowledgements</title>", "<p> We are very grateful to Michelle Meagher for some very helpful comments on an earlier draft of this paper.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nPRISMA Flow Diagram. Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Inclusion and Exclusion Criteria\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Inclusion</bold>\n</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Exclusion</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Published in English.</td><td style=\"border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Not published in English (due to the language background and skills of the authors).</td></tr><tr><td style=\"border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Provided an account of a realised action(s), or the prescription for a potential action(s), to address excessive corporate power. The author(s) needed to have problematised or conceptualised excessive corporate power in a manner consistent with our own conceptualisation described earlier. Actions could be state actions (eg, reforming or strengthening state instruments), private market-based actions (eg, consumer boycotts, shareholder activism), or any other collective action (eg, promotion of alternative business forms).</td><td style=\"border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Did not include an account or prescription of ways to address excessive corporate power (problematised or conceptualised in a manner consistent with our own conceptualisation described earlier).</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Strategic Objectives, Strategies, and Illustrative Examples of Actions to Curb Excessive Corporate Power, Adapted From Meagher<sup>##UREF##8##9##,##UREF##25##49##</sup>\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Strategic Objective</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Strategy</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Illustrative Example of Action</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"4\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Disperse concentrated corporate wealth and power </td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Strengthen antitrust regulation to protect and promote the welfare of all citizens</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Widen objectives of antitrust policy to consider broader welfare concerns</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Limit corporate rent-seeking and cost externalisation</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Legislate free access to essential medicines and healthcare services</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Redistribute concentrations of corporate wealth and income through progressive tax policy</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Implement a robust tax on share repurchases</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Strengthen regulation of political contributions, corruption, and conflicts of interest </td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Regulate corporate contributions to political candidates and parties</td></tr><tr><td rowspan=\"5\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Strengthen countervailing power structures</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Strengthen the countervailing power of workers and consumers</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Strengthen labour and unionisation laws</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Strengthen transparency mechanisms to promote corporate accountability</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Implement public country-by-country reporting requirements for transnational corporations</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Promote socially responsible shareholding</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Support divestment campaigns targeting harmful industries</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Support legal remediation for citizens harmed by corporations</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Support the use of <italic toggle=\"yes\">qui tam</italic> suits by citizens against corporations</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Organise alternative modes of business and systems of production and distribution</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Scale-up alternative forms of enterprise, such as worker co-operatives and mutual enterprises</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"4\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Democratise corporate decision-making </td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Improve stakeholder representation on corporate boards</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mandate stakeholder representation requirements on corporate boards </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mandate the pursuit of stakeholder value </td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Amend the objectives of the corporation under the law </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mandate corporate decision-makers to identify and mitigate adverse social and environmental impacts </td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Implement robust corporate due diligence laws that consider human rights and environmental sustainability</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Increase public takeover of privatised ‘public goods’</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">(Re)municipalise public goods and services, such as water, energy, housing, and transport</td></tr><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Reform and democratise the global governance of corporations</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Reform and democratise existing international organisations and institutional arrangements that sustain corporate power</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Assign a greater role to national parliaments in the negotiation and ratification of WTO agreements</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Develop new international organisations and institutional arrangements that constrain corporate power</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Revive plans to develop global institutions to govern transnational corporations </td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Dissolve excessive and harmful corporate power</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Dissolve excessive and harmful corporate power</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Revoke the privileges granted via incorporation of corporations that repeatedly violate regulations and/or human rights</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Wind-down harmful industries</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Scale-up industrial policy that drives systematic transition from non-renewable to renewable energy sources</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Reform/transform the corporate form</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Revoke limited liability for all corporations above a certain size in terms of assets or revenue</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title><bold>Box 1.</bold> Key Rights and Privileges Conferred to Business Corporations Upon Incorporation in Many Jurisdictions, Adapted From Multiple Sources<sup>##UREF##1##2##,##UREF##3##4##, ####UREF##4##5##, ##UREF##5##6##, ##UREF##6##7####6##7##</sup></title><list list-type=\"bullet\"><list-item><p>Legal separation of ownership and control </p></list-item><list-item><p>Limited liability for shareholders </p></list-item><list-item><p>Joint-stock mechanism allowing for the accumulation of pools of capital from multiple parties </p></list-item><list-item><p>Right to an unlimited lifespan </p></list-item><list-item><p>Right to own shares in other business entities </p></list-item><list-item><p>Right to pursue multiple lines of business </p></list-item><list-item><p>Right to operate in multiple jurisdictions </p></list-item><list-item><p>A range of political rights, including the right to challenge legislation </p></list-item></list></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Search Terms Used.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviation: WTO, World Trade Organisation.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7304-g001\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7304-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" Braithwaite J, Drahos P. Global Business Regulation. Cambridge University Press; 2000. "]}, {"label": ["2"], "mixed-citation": [" Bakan J. The Corporation: The Pathological Pursuit of Profit and Power. Toronto: Viking Canada; 2004. "]}, {"label": ["3"], "person-group": ["\n"], "surname": ["Padfield"], "given-names": ["SJ"], "article-title": ["Rehabilitating concession theory"], "source": ["Oklahoma Law Rev"], "year": ["2013"], "volume": ["66"], "issue": ["2"], "fpage": ["327"], "lpage": ["361"]}, {"label": ["4"], "person-group": ["\n"], "surname": ["Ciepley"], "given-names": ["D"], "article-title": ["Beyond public and private: toward a political theory of the corporation"], "source": ["Am Polit Sci Rev"], "year": ["2013"], "volume": ["107"], "issue": ["1"], "fpage": ["139"], "lpage": ["158"], "pub-id": ["10.1017/s0003055412000536"]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Davoudi", "McKenna", "Olegario"], "given-names": ["L", "C", "R"], "article-title": ["The historical role of the corporation in society"], "source": ["J Br Acad"], "year": ["2018"], "volume": ["6"], "issue": ["s1"], "fpage": ["17"], "lpage": ["47"], "pub-id": ["10.5871/jba/006s1.017"]}, {"label": ["6"], "mixed-citation": [" Nace T. Superpowers: the corporation acquires nine powerful attributes. In: Gangs of America: The Rise of Corporate Power and the Disabling of Democracy. San Francisco: Berrett-Koehler Publishers; 2003. "]}, {"label": ["7"], "mixed-citation": [" Wiist WH. The Bottom Line or Public Health: Tactics Corporations Use to Influence Health and Health Policy, and What We Can Do to Counter Them. New York: Oxford University Press; 2010. "]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Hurst"], "given-names": ["J"], "article-title": ["The legitimacy of the business corporation"], "source": ["Indiana Law J"], "year": ["1971"], "volume": ["46"], "issue": ["3"], "fpage": ["10"]}, {"label": ["9"], "mixed-citation": [" Meagher M. Competition is Killing Us: How Big Business is Harming Our Society and Planet - and What to Do About it. London: Penguin Group; 2020. "]}, {"label": ["11"], "mixed-citation": [" Harford T. How a Creative Legal Leap Helped Create Vast Wealth. BBC News; 2017. "], "uri": ["https://www.bbc.com/news/business-40674240"]}, {"label": ["12"], "mixed-citation": [" Berger PL. Capitalism and Development. In: The Capitalist Revolution: Fifty Propositions About Prosperity, Equality, and Liberty. New York: Basic Books; 1986. "]}, {"label": ["13"], "mixed-citation": [" Schumpeter JA. Capitalism, Socialism and Democracy. Taylor & Francis; 2003. "]}, {"label": ["14"], "mixed-citation": [" Freudenberg N. The corporate consumption complex. In: Lethal but Legal: Corporations, Consumption, and Protecting Public Health. Oxford: Oxford University Press; 2014. "]}, {"label": ["15"], "mixed-citation": [" Maani N, Petticrew M, Galea S, eds. The Commercial Determinants of Health. Oxford University Press; 2022. "]}, {"label": ["26"], "mixed-citation": [" Northcott T, Lawrence M, Parker C, Baker P. Ecological regulation for healthy and sustainable food systems: responding to the global rise of ultra-processed foods. Agric Human Values. 2023. "], "pub-id": ["10.1007/s10460-022-10412-4"]}, {"label": ["27"], "person-group": ["\n"], "surname": ["Lencucha", "Thow"], "given-names": ["R", "AM"], "article-title": ["Intersectoral policy on industries that produce unhealthy commodities: governing in a new era of the global economy?"], "source": ["BMJ Glob Health"], "year": ["2020"], "volume": ["5"], "issue": ["8"], "fpage": ["e002246"], "pub-id": ["10.1136/bmjgh-2019-002246"]}, {"label": ["28"], "person-group": ["\n"], "surname": ["Lacy-Nichols", "Marten"], "given-names": ["J", "R"], "article-title": ["Power and the commercial determinants of health: ideas for a research agenda"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["2"], "fpage": ["e003850"], "pub-id": ["10.1136/bmjgh-2020-003850"]}, {"label": ["31"], "mixed-citation": [" Pettit P. Republicanism: A Theory of Freedom and Government. Oxford: Oxford University Press; 1997. "]}, {"label": ["32"], "mixed-citation": [" Lukes S. Power: A Radical View. 2nd ed. London: Palgrave Macmillan; 2005. "]}, {"label": ["33"], "mixed-citation": [" Lukes S. Power: A Radical View. London: Macmillan; 1974. "]}, {"label": ["40"], "mixed-citation": [" Watson M. The Market. Newcastle upon Tyne: Agenda Publishing Limited; 2018. "]}, {"label": ["42"], "mixed-citation": [" Crouch C. The Strange Non-Death of Neoliberalism. Cambridge, UK: Polity Press; 2011. "]}, {"label": ["43"], "mixed-citation": [" Christophers B. Rentier Capitalism: Who Owns the Economy, and Who Pays for it? Verso Books; 2022. "]}, {"label": ["44"], "mixed-citation": [" Freudenberg N. At What Cost: Modern Capitalism and the Future of Health. Oxford University Press; 2021. "]}, {"label": ["47"], "mixed-citation": [" Freudenberg N. Lethal But Legal: Corporations, Consumption, and Protecting Public Health. Oxford: Oxford University Press; 2014. "]}, {"label": ["49"], "person-group": ["\n"], "surname": ["Meagher"], "given-names": ["M"], "article-title": ["Winner takes all"], "source": ["RSA J"], "year": ["2020"], "volume": ["166"], "issue": ["3"], "fpage": ["32"], "lpage": ["34"]}, {"label": ["50"], "person-group": ["\n"], "surname": ["Arksey", "O\u2019Malley"], "given-names": ["H", "L"], "article-title": ["Scoping studies: towards a methodological framework"], "source": ["Int J Soc Res Methodol"], "year": ["2005"], "volume": ["8"], "issue": ["1"], "fpage": ["19"], "lpage": ["32"]}, {"label": ["52"], "person-group": ["\n"], "surname": ["Khan"], "given-names": ["LM"], "article-title": ["The ideological roots of America\u2019s market power problem"], "source": ["Yale Law J"], "year": ["2017"], "volume": ["127"], "fpage": ["960"], "lpage": ["979"]}, {"label": ["53"], "person-group": ["\n"], "surname": ["Stucke"], "given-names": ["ME"], "article-title": ["Reconsidering antitrust\u2019s goals"], "source": ["Boston Coll Law Rev"], "year": ["2012"], "volume": ["53"], "issue": ["4"], "fpage": ["551"], "lpage": ["629"]}, {"label": ["54"], "person-group": ["\n"], "surname": ["Flynn"], "given-names": ["JJ"], "article-title": ["The Reagan administration\u2019s antitrust policy, \u201coriginal intent\u201d and the legislative history of the Sherman Act"], "source": ["Antitrust Bull"], "year": ["1988"], "volume": ["33"], "issue": ["2"], "fpage": ["259"], "lpage": ["307"], "pub-id": ["10.1177/0003603x8803300204"]}, {"label": ["55"], "person-group": ["\n"], "surname": ["Bogus"], "given-names": ["CT"], "article-title": ["The new road to serfdom: the curse of bigness and the failure of antitrust"], "source": ["Univ Mich J Law Reform"], "year": ["2015"], "volume": ["49"], "issue": ["1"], "fpage": ["1"], "lpage": ["120"], "pub-id": ["10.36646/mjlr.49.1.new"]}, {"label": ["56"], "mixed-citation": [" Bork R. The Antitrust Paradox: A Policy at War with Itself. New York: Basic Books; 1978. "]}, {"label": ["57"], "person-group": ["\n"], "surname": ["Bogus"], "given-names": ["CT"], "article-title": ["Books and olive oil: why antitrust must deal with consolidated corporate power"], "source": ["Univ Mich J Law Reform"], "year": ["2019"], "volume": ["52"], "issue": ["2"], "fpage": ["265"], "lpage": ["342"], "pub-id": ["10.36646/mjlr.52.2.books"]}, {"label": ["58"], "mixed-citation": [" Organization for Economic Co-operation and Development (OECD). Executive Summary of the Roundtable on Public Interest Considerations in Merger Control. Paris: OECD; 2017. "]}, {"label": ["59"], "mixed-citation": [" Fair Trade Advocacy Office (FTAO). EU Competition Law and Sustainability in Food Systems: Addressing the Broken Links. Brussels: FTAO; 2019. "]}, {"label": ["60"], "mixed-citation": [" Open Markets Institute. With Kanter, Khan, Wu, and the Rest of Biden\u2019s Trustbusting Team, We\u2019re Looking at a New Era of Democracy for All Americans, From the Bottom Up. Open Markets Institute; 2021. "], "uri": ["https://www.openmarketsinstitute.org/publications/with-kanter-khan-wu-and-the-rest-of-bidens-trustbusting-team-were-looking-at-a-new-era-of-democracy-for-all-americans-from-the-bottom-up"]}, {"label": ["61"], "mixed-citation": [" European Commission. Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions. Brussels: European Commission; 2021. "]}, {"label": ["62"], "mixed-citation": [" Stiglitz J. Towards a broader view of competition policy. In: Bonakele T, Fox EM, Mncube L, eds. Competition Policy for the New Era: Insights from the BRICS Countries. Oxford: Oxford University Press; 2017:4-21. "]}, {"label": ["63"], "mixed-citation": [" Holmes S, Meagher M. A Sustainable Future: How Can Control of Monopoly Power Play a Part? 2022. "], "uri": ["https://ssrn.com/abstract=4099796"]}, {"label": ["64"], "mixed-citation": [" United Nations Conference on Trade and Development (UNCTAD). Model Law on Competition - Revised Chapter 1. UNCTAD; 2015. "]}, {"label": ["65"], "mixed-citation": [" Njisane Y, Ratshisusu H. Public interest issues in cross-border mergers. In: Bonakele T, Fox EM, Mncube L, eds. Competition Policy for the New Era: Insights from the BRICS Countries. Oxford: Oxford University Press; 2017. "]}, {"label": ["66"], "mixed-citation": [" Crane A, Baiphaphele L. Burger King \u2014 The Growing Importance of Public Interest Factors on Merger Control in South Africa. 2021. "], "uri": ["https://za.andersen.com/news/insights/2021/06/burger-king-the-growing-importance-of-public-interest-factors-on-merger-control-in-south-africa#"]}, {"label": ["67"], "mixed-citation": [" The White House. Executive Order on Promoting Competiton in the American Economy. The White House; 2021. "], "uri": ["https://www.whitehouse.gov/briefing-room/presidential-actions/2021/07/09/executive-order-on-promotingcompetition-in-the-american-economy"]}, {"label": ["68"], "mixed-citation": [" Kang C. FTC Chair Upends Antitrust Standards with Meta Lawsuit. The New York Times. July 28, 2022. "], "uri": ["https://www.nytimes.com/2022/07/28/technology/ftc-lina-khan-meta.html"]}, {"label": ["69"], "mixed-citation": [" Kanter J. Respecting the Antitrust Laws and Reflecting Market Realities. Assistant Attorney General Jonathan Kanter Delivers Keynote Speech at Georgetown Antitrust Law Symposium. "], "uri": ["https://www.justice.gov/opa/speech/assistant-attorney-general-jonathan-kanter-delivers-keynote-speech-georgetown-antitrust"]}, {"label": ["71"], "mixed-citation": [" Freudenberg N. Optimism past, present, and future: the building blocks for a movement. In: Lethal but Legal: Corporations, Consumption, and Protecting Public Health. Oxford: Oxford University Press; 2014. "]}, {"label": ["72"], "mixed-citation": [" Chaloupka F, Drope J, Siu E, et al. Tobacconomics Cigarette Tax Scorecard. 2nd ed. Chicago: Health Policy Center, Institute for Health Research and Policy, University of Illinois Chicago; 2021. "]}, {"label": ["73"], "mixed-citation": [" WHO. WHO Calls on Countries to Tax Sugar-Sweetened Beverages to Save Lives. 2022. "], "uri": ["https://www.who.int/news/item/13-12-2022-who-calls-on-countries-to-tax-sugar-sweetened-beverages-to-save-lives#:~:text=The%20WHO%20manual%20highlights%20the,Africa%2C%20and%20the%20United%20Kingdom"]}, {"label": ["74"], "mixed-citation": [" Baunsgaard T, Vernon N. Taxing Windfall Profits in the Energy Sector. Washington, DC: International Monetary Fund; 2022. "]}, {"label": ["75"], "mixed-citation": [" Topham G. Fresh Calls for Windfall Tax on Companies that Prospered During COVID. The Guardian. September 20, 2021. "], "uri": ["https://www.theguardian.com/politics/2021/sep/20/fresh-calls-for-windfall-tax-on-companies-that-prospered-during-covid"]}, {"label": ["76"], "mixed-citation": [" Murphy R. The Courageous State: Rethinking Economics, Society and the Role of Government. Searching Finance Limited; 2011. "]}, {"label": ["77"], "mixed-citation": [" WHO. International Code of Marketing of Breast-Milk Substitutes. 1981. "], "uri": ["https://www.who.int/nutrition/publications/code_english.pdf"]}, {"label": ["81"], "mixed-citation": [" Mazzucato M. Extracting value through the innovation economy. In: The Value of Everything: Making and Taking in the Global Economy. Hachette UK; 2018. "]}, {"label": ["82"], "mixed-citation": [" Food Ethics Council (FEC). TRIPS with Everything? London, UK: FEC; 2002. "]}, {"label": ["83"], "person-group": ["\n"], "surname": ["Magaisa"], "given-names": ["AT"], "article-title": ["Indigenous peoples, corporate power and the knowledge economy: the law and politics of knowledge protection"], "source": ["Law Democr Dev"], "year": ["2003"], "volume": ["7"], "issue": ["2"], "fpage": ["269"], "lpage": ["284"]}, {"label": ["85"], "person-group": ["\n"], "surname": ["Gill", "Benatar"], "given-names": ["SR", "SR"], "article-title": ["Reflections on the political economy of planetary health"], "source": ["Rev Int Polit Econ"], "year": ["2020"], "volume": ["27"], "issue": ["1"], "fpage": ["167"], "lpage": ["190"], "pub-id": ["10.1080/09692290.2019.1607769"]}, {"label": ["86"], "person-group": ["\n"], "surname": ["Ford", "Wilson", "Costa Chaves", "Lotrowska", "Kijtiwatchakul"], "given-names": ["N", "D", "G", "M", "K"], "article-title": ["Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand"], "source": ["AIDS"], "year": ["2007"], "volume": ["21 Suppl 4"], "fpage": ["S21"], "lpage": ["29"], "pub-id": ["10.1097/01.aids.0000279703.78685.a6"]}, {"label": ["87"], "person-group": ["\n"], "surname": ["Sikka"], "given-names": ["P"], "article-title": ["Why combatting tax avoidance means curbing corporate power"], "source": ["Crim Justice Matters"], "year": ["2013"], "volume": ["94"], "issue": ["1"], "fpage": ["16"], "lpage": ["17"], "pub-id": ["10.1080/09627251.2013.865495"]}, {"label": ["88"], "mixed-citation": [" United Nations Conference on Trade and Development (UNCTAD). Trade and Development Report 2021: From Recovery to Resilience: The Development Dimension. Geneva: UNCTAD; 2021. "]}, {"label": ["89"], "mixed-citation": [" Barak G. Halting corporate harm. In: Unchecked Corporate Power: Why the Crimes of Multinational Corporations Are Routinized Away and What We Can Do About it. New York: Routledge; 2017:141-186. "]}, {"label": ["90"], "person-group": ["\n"], "surname": ["Clausing"], "given-names": ["KA"], "article-title": ["The US"], "source": ["state experience under formulary apportionment: are there lessons for international reform? Natl Tax J"], "year": ["2016"], "volume": ["69"], "issue": ["2"], "fpage": ["353"], "lpage": ["385"]}, {"label": ["91"], "mixed-citation": [" Global Alliance for Tax Justice (GATJ). Global Minimum Tax of 15% Would Only Benefit Developed Countries. GATJ; 2021. "], "uri": ["https://globaltaxjustice.org/news/global-minimum-tax-of-15-would-only-benefit-developed-countries/"]}, {"label": ["92"], "mixed-citation": [" Abernathy N, Hamilton D, Morgan JM. New Rules for the 21st Century: Corporate Power, Public Power, and the Future of the American Economy. New York, NY: Roosevelt Institute; 2019. "]}, {"label": ["93"], "mixed-citation": [" International Monetary Fund (IMF). Fossil Fuel Subsidies. Climate Change 2021. "], "uri": ["https://www.imf.org/en/Topics/climate-change/energy-subsidies"]}, {"label": ["94"], "mixed-citation": [" Saez E, Zucman G. Top Incomes and Tax Policy. Institute for Fiscal Studies; 2022. "]}, {"label": ["95"], "mixed-citation": [" Christensen MB, Hallum C, Maitland A, Parrinello Q, Putaturo C. Survival of the Richest: How We Must Tax the Super-Rich Now to Fight Inequality. Oxford, UK: Oxfam International; 2023. "]}, {"label": ["96"], "mixed-citation": [" Lazonick W, Sakin\u00e7 ME, Hopkins M. Why Stock Buybacks Are Dangerous for the Economy. 2020. "], "uri": ["https://hbr.org/2020/01/why-stock-buybacks-are-dangerous-for-the-economy#:~:text=When%20companies%20do%20these%20buybacks,2017%2C%20according%20to%20JPMorgan%20Chase"]}, {"label": ["97"], "person-group": ["\n"], "surname": ["Berentsen", "Huber", "Marchesiani"], "given-names": ["A", "S", "A"], "article-title": ["The societal benefit of a financial transaction tax"], "source": ["Eur Econ Rev"], "year": ["2016"], "volume": ["89"], "fpage": ["303"], "lpage": ["323"], "pub-id": ["10.1016/j.euroecorev.2016.08.003"]}, {"label": ["98"], "mixed-citation": [" Rogoway M. Portland Expects up to $3.5 Million from Unique CEO Tax. 2019. "], "uri": ["https://www.oregonlive.com/business/2019/02/portland-expects-up-to-35-million-from-unique-ceo-tax.html"]}, {"label": ["99"], "person-group": ["\n"], "surname": ["Teachout"], "given-names": ["Z"], "article-title": ["The problem of monopolies & corporate public corruption"], "source": ["Daedalus"], "year": ["2018"], "volume": ["147"], "issue": ["3"], "fpage": ["111"], "lpage": ["126"]}, {"label": ["100"], "mixed-citation": [" Danaher K, Mark J. Conclusion: Building a Movement for Global Democracy. In: Insurrection: Citizen Challenges to Corporate Power. New York: Routledge; 2003. "]}, {"label": ["101"], "mixed-citation": [" Nace T. Fighting Back. In: Gangs of America: The Rise of Corporate Power and the Disabling of Democracy. Oakland, CA: Berrett-Koehler Publishers; 2003. "]}, {"label": ["102"], "mixed-citation": [" Corporate Europe Observatory (CEO). Captured States: When EU Governments Are a Channel for Corporate Interests. Brussels: CEO; 2019. "]}, {"label": ["103"], "mixed-citation": [" Nader R. How to Curb Corporate Power. 2005. "], "uri": ["https://www.thenation.com/article/archive/how-curb-corporate-power/"]}, {"label": ["104"], "mixed-citation": [" Freudenberg N. Wanted: a movement for a healthier, more sustainable future. In: Lethal but Legal: Corporations, Consumption, and Protecting Public Health. Oxford: Oxford University Press; 2014. "]}, {"label": ["106"], "mixed-citation": [" Democracy International. Lobby Transparency. 2019. "], "uri": ["https://www.democracy-international.org/eu-transparency"]}, {"label": ["107"], "mixed-citation": [" OECD. Lobbying in the 21st Century: Transparency, Integrity and Access. Paris: OECD Publishing; 2021. "]}, {"label": ["108"], "person-group": ["\n"], "surname": ["Ripken"], "given-names": ["SK"], "article-title": ["Citizens United, corporate personhood, and corporate power: the tension between constitutional law and corporate law"], "source": ["J Law Public Policy"], "year": ["2012"], "volume": ["6"], "issue": ["2"], "fpage": ["285"], "lpage": ["316"]}, {"label": ["110"], "person-group": ["\n"], "surname": ["Mialon", "Vandevijvere", "Carriedo-Lutzenkirchen"], "given-names": ["M", "S", "A"], "article-title": ["Mechanisms for addressing and managing the influence of corporations on public health policy, research and practice: a scoping review"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["7"], "fpage": ["e034082"], "pub-id": ["10.1136/bmjopen-2019-034082"]}, {"label": ["111"], "mixed-citation": [" National Health and Medical Research Council (NHMRC). Communicating with Our Stakeholders. 2021. "], "uri": ["https://www.nhmrc.gov.au/health-advice/nutrition/australian-dietary-guidelines-review/communicating"]}, {"label": ["112"], "mixed-citation": [" Galbraith JK. American Capitalism: The Concept of Countervailing Power. Vol 619. 1st ed. New York: Routledge; 1993. "]}, {"label": ["113"], "person-group": ["\n"], "surname": ["Farber", "Herbst", "Kuziemko", "Naidu"], "given-names": ["HS", "D", "I", "S"], "article-title": ["Unions and inequality over the twentieth century: new evidence from survey data"], "source": ["Q J Econ"], "year": ["2021"], "volume": ["136"], "issue": ["3"], "fpage": ["1325"], "lpage": ["1385"], "pub-id": ["10.1093/qje/qjab012"]}, {"label": ["115"], "person-group": ["\n"], "surname": ["MacDonald", "MacDonald"], "given-names": ["K", "T"], "article-title": ["Democracy in a pluralist global order: corporate power and stakeholder representation"], "source": ["Ethics Int Aff"], "year": ["2010"], "volume": ["24"], "issue": ["1"], "fpage": ["19"], "lpage": ["43"], "pub-id": ["10.1111/j.1747-7093.2010.00242.x"]}, {"label": ["116"], "mixed-citation": [" Rogers B. Can labor law reform encourage robust economic democracy? In: The Cambridge Handbook of U.S. Labor Law for the Twenty-First Century. Cambridge University Press. 2020:327-335. "]}, {"label": ["117"], "person-group": ["\n"], "surname": ["Witt", "Wilson"], "given-names": ["M", "R"], "article-title": ["The Teamsters\u2019 UPS strike of 1997: building a new labor movement"], "source": ["Labor Stud J"], "year": ["1999"], "volume": ["24"], "issue": ["1"], "fpage": ["58"], "lpage": ["72"]}, {"label": ["118"], "person-group": ["\n"], "surname": ["Tyler"], "given-names": ["G"], "article-title": ["Laboring to counterbalance concentrated capital"], "source": ["Challenge"], "year": ["1991"], "volume": ["34"], "issue": ["5"], "fpage": ["4"], "lpage": ["11"], "pub-id": ["10.1080/05775132.1991.11471529"]}, {"label": ["119"], "mixed-citation": [" Hamaji K, Deutsch R, Nicolas E. Unchecked Corporate Power: Forced Arbitration, the Enforcement Crisis, and How Workers Are Fighting Back. The Center for Popular Democracy, Economic Policy Institute; 2019. "]}, {"label": ["120"], "mixed-citation": [" Waters CP. Consumer Boycotts in the\u201d New Economy\u201d: How Should the Common Law Respond? Montreal, Canada: Institute of Comparative Law, McGill University; 1997. "]}, {"label": ["121"], "mixed-citation": [" Toscano J. Data Privacy Issues Are the Root of Our Big Tech Monopoly Dilemma. Forbes. 2021. "], "uri": ["https://www.forbes.com/sites/joetoscano1/2021/12/01/data-privacy-issues-are-the-root-of-our-big-tech-monopoly-dilemma/"]}, {"label": ["122"], "mixed-citation": [" Soederberg S. Corporate Power and Ownership in Contemporary Capitalism: The Politics of Resistance and Domination. London: Routledge; 2010. "]}, {"label": ["123"], "mixed-citation": [" ShareAction. Tesco Makes Further Health Commitments in Response to Investor Engagement. ShareAction; 2021. "], "uri": ["https://shareaction.org/news/tesco-makes-further-health-commitments-in-response-to-investor-engagement"]}, {"label": ["124"], "mixed-citation": [" ShareAction. Unilever Shareholder Campaign Secures Industry-Leading Transparency on Nutrition. ShareAction; 2022. "], "uri": ["https://shareaction.org/news/unilever-shareholder-campaign-secures-industry-leading-transparency-on-nutrition"]}, {"label": ["125"], "mixed-citation": [" Fossil Free. What is Fossil Fuel Divestment? Fossil Free; 2021. "], "uri": ["https://gofossilfree.org/divestment/what-is-fossil-fuel-divestment/"]}, {"label": ["126"], "mixed-citation": [" Tobacco Free Portfolios. Imagine a Tobacco-Free World. Tobacco Free Portfolios; 2020. "], "uri": ["https://tobaccofreeportfolios.org/"]}, {"label": ["127"], "mixed-citation": [" Chief Investment Officer. Boston to Divest from Fossil Fuels, Tobacco, Private Prisons. 2021. "], "uri": ["https://www.ai-cio.com/news/boston-to-divest-from-fossil-fuels-tobacco-private-prisons/"]}, {"label": ["129"], "mixed-citation": [" European Parliament. Proposal on Disclosure of Income Tax Information by Certain Undertakings and Branches - Public Country-by-Country Reporting. Brussels: European Parliament; 2015. "]}, {"label": ["130"], "mixed-citation": [" European Commission. Directive of the European Parliament and the Council on Corporate Sustainability Due Diligence and amending Directive (EU) 2019/1937. Brussels: European Commission; 2022. "]}, {"label": ["132"], "mixed-citation": [" Commonwealth of Massachusetts. The Tobacco Master Settlement Agreement. "], "uri": ["https://www.mass.gov/service-details/the-tobacco-master-settlement-agreement"]}, {"label": ["133"], "mixed-citation": [" Kaminski I. Fossil Fuel Industry Faces Surge in Climate Lawsuits. The Guardian. June 30, 2022. "], "uri": ["https://www.theguardian.com/environment/2022/jun/30/fossil-fuel-industry-surge-climate-lawsuits"]}, {"label": ["134"], "mixed-citation": [" Intergovernmental Panel on Climate Change (IPCC). Climage Change 2022: Mitigation of Climate Change. IPCC; 2022. "]}, {"label": ["135"], "mixed-citation": [" Braithwaite J. Regulatory Capitalism: How it Works, Ideas for Making It Work Better. Cheltenham, UK: Edward Elgar; 2008. "]}, {"label": ["136"], "mixed-citation": [" Schneiberg M. Resisting and Regulating Corporations through Ecologies of Alternative Enterprise: Insurance and Electricity in the US Case. In: Baars G, Spicer A, eds. The Corporation. Cambridge, UK: Cambridge University Press; 2017:512-526. "]}, {"label": ["137"], "person-group": ["\n"], "surname": ["Fernandez-Guada\u00f1o", "Lopez-Millan", "Sarria-Pedroza"], "given-names": ["J", "M", "J"], "article-title": ["Cooperative entrepreneurship model for sustainable development"], "source": ["Sustainability"], "year": ["2020"], "volume": ["12"], "issue": ["13"], "fpage": ["5462"], "pub-id": ["10.3390/su12135462"]}, {"label": ["138"], "mixed-citation": [" Mann S. What is to be Done? Bioethics in Perspective: Corporate Power, Public Health and Political Economy. Cambridge, UK: Cambridge University Press; 2010. "]}, {"label": ["139"], "mixed-citation": [" Kinezuka A, de Wit MM. Food Sovereignty in Japan and Beyond. In: Jayaraman S, De Master K, eds. Bite Back: People Taking on Corporate Food and Winning. California: University of California Press; 2020:192-202. "]}, {"label": ["140"], "mixed-citation": [" Cooperation Jackson. Who We Are. 2021. "], "uri": ["https://cooperationjackson.org/intro"]}, {"label": ["141"], "mixed-citation": [" Mondragon Corporation. About Us. 2021. "], "uri": ["https://www.mondragon-corporation.com/en/about-us/"]}, {"label": ["142"], "person-group": ["\n"], "surname": ["Wierling", "Schwanitz", "Zei\u00df"], "given-names": ["A", "V", "J"], "article-title": ["Statistical evidence on the role of energy cooperatives for the energy transition in European countries"], "source": ["Sustainability"], "year": ["2018"], "volume": ["10"], "issue": ["9"], "fpage": ["3339"], "pub-id": ["10.3390/su10093339"]}, {"label": ["143"], "mixed-citation": [" International Panel of Experts on Sustainable Food Systems (IPES-Food). Breaking Away from Industrial Food and Farming Systems: Seven Case Studies of Agroecological Transition. IPES-Food; 2018. "]}, {"label": ["144"], "mixed-citation": [" McMichael P. Political economy of the global food and agriculture system. In: Kassam A, Kassam L, eds. Rethinking Food and Agriculture. Woodhead Publishing. 2021:53-75. "], "pub-id": ["10.1016/b978-0-12-816410-5.00003-7"]}, {"label": ["145"], "mixed-citation": [" International Panel of Experts on Sustainable Food Systems (IPES-Food). What Makes Urban Food Policy Happen? Insights from Five Case Studies. IPES-Food; 2017. "]}, {"label": ["146"], "mixed-citation": [" Bidet E, Eum H. Social Enterprise in South Korea: General Presentation of the Phenomenon. International Comparative Social Enterprise Models; 2014. "]}, {"label": ["147"], "mixed-citation": [" Organisation for Economic Co-operation and Development, European Union. Boosting Social Enterprise Development: Good Practice Compendium. Paris: OECD Publishing; 2017. "]}, {"label": ["148"], "mixed-citation": [" Hitzig Z, Meagher M, Veiga A, Weyl G. Economic Democracy and Market Power. Antitrust Chronicle, Competition Policy International; 2020. "]}, {"label": ["149"], "mixed-citation": [" Greenfield K. Saving the World with Corporate Law? Boston, MA: Boston College Law School; 2007. "]}, {"label": ["150"], "mixed-citation": [" Parkinson JE. The Democratic Imperative: Beyond Social Responsibility. In: Corporate Power and Responsibility: Issues in the Theory of Company Law. Oxford: Oxford University Press; 1993. "]}, {"label": ["151"], "mixed-citation": [" Sandrock O, du Plessis J. The German system of supervisory codetermination by employees. In: German Corporate Governance in International and European Context. Berlin, Heidelberg: Springer; 2017: 167-242.\u2005"], "pub-id": ["10.1007/978-3-662-54198-2_5"]}, {"label": ["152"], "mixed-citation": [" Dammann J, Eidenmueller H. Codetermination and the Democratic State. 2020. Law Working Paper No. 536. "], "uri": ["https://ssrn.com/abstract=3680769"]}, {"label": ["153"], "mixed-citation": [" Seierstad C, Huse M. Gender quotas on corporate boards in Norway: ten years later and lessons learned. In: Seierstad C, Gabaldon P, Mensi-Klarbach H, eds. Gender Diversity in the Boardroom. Cham: Palgrave Macmillan; 2017. "]}, {"label": ["154"], "person-group": ["\n"], "surname": ["Bavoso"], "given-names": ["V"], "article-title": ["The corporate law dilemma and the enlightened sovereign control paradigm: in search of a new legal framework"], "source": ["Brooklyn Journal of Corporate, Financial & Commercial Law"], "year": ["2018"], "volume": ["12"], "issue": ["2"], "fpage": ["241"], "lpage": ["278"]}, {"label": ["155"], "mixed-citation": [" Alexander R. Benefit Corporation Law and Governance. Oakland, CA: Berrett-Koehler Publishers; 2017. "]}, {"label": ["156"], "mixed-citation": [" Abboud L. Danone Adopts a New Legal Status to Reflect Social Mission. Financial Times. June 26, 2020. "], "uri": ["https://www.ft.com/content/1eff9241-ef11-4a38-8b5c-bb825fa108ca"]}, {"label": ["157"], "mixed-citation": [" United Nations Global Compact. See Who\u2019s Involved: Our Participants. United Nations Global Compact; 2021. "], "uri": ["https://unglobalcompact.org/what-is-gc/participants"]}, {"label": ["158"], "mixed-citation": [" Wiist WH. The corporation: an overview of what it is, its tactics, and what public health can do. In: The Bottom Line or Public Health: Tactics Corporations Use to Influence Health and Health Policy, and What We Can Do to Counter Them. Oxford, UK: Oxford University Press; 2010. "]}, {"label": ["159"], "person-group": ["\n"], "surname": ["Sj\u00e5fjell", "Taylor"], "given-names": ["B", "MB"], "article-title": ["Clash of norms: shareholder primacy vs sustainable corporate purpose"], "source": ["International and Comparative Corporate Law Journal"], "year": ["2019"], "volume": ["13"], "issue": ["3"], "fpage": ["40"], "lpage": ["66"]}, {"label": ["160"], "person-group": ["\n"], "surname": ["Grossfeld", "Ebke"], "given-names": ["B", "W"], "article-title": ["Controlling the modern corporation: a comparative view of corporate power in the United States and Europe"], "source": ["Am J Comp Law"], "year": ["1978"], "volume": ["26"], "issue": ["3"], "fpage": ["397"], "lpage": ["433"], "pub-id": ["10.2307/839810"]}, {"label": ["161"], "mixed-citation": [" Cray C. Using Charters to Redesign Corporations in the Public Interest. In: Wiist WH, ed. The Bottom Line or Public Health. New York: Oxford University Press; 2010. "]}, {"label": ["162"], "person-group": ["\n"], "surname": ["Grossman", "Adams", "Levenstein"], "given-names": ["RL", "FT", "C"], "article-title": ["Taking care of business: citizenship and the charter of incorporation"], "source": ["New Solut"], "year": ["1993"], "volume": ["3"], "issue": ["3"], "fpage": ["7"], "lpage": ["18"], "pub-id": ["10.2190/NS3.3.c"]}, {"label": ["163"], "mixed-citation": [" Nader R, Green MJ, Seligman J. Constitutionalizing the Corporation: The Case for the Federal Chartering of Giant Corporations. Washington, DC: Corporate Accountability Research Group; 1976. "]}, {"label": ["164"], "mixed-citation": [" Warren E. Companies Shouldn\u2019t Be Accountable Only to Shareholders. The Wall Street Journal. 2018. "], "uri": ["https://www.wsj.com/articles/companies-shouldnt-be-accountable-only-to-shareholders-1534287687"]}, {"label": ["165"], "mixed-citation": [" Friends of Bernie Sanders. Issues: Corporate Accountability and Democracy. 2021. "], "uri": ["https://berniesanders.com/issues/corporate-accountability-and-democracy/"]}, {"label": ["166"], "mixed-citation": [" Office of the United Nations High Commissioner for Human Rights. Guiding Principles on Business and Human Rights: Implementing the United Nations \u201cProtect, Respect and Remedy\u201d Framework. New York, Geneva: United Nations; 2011. "]}, {"label": ["167"], "mixed-citation": [" Organization for Economic Co-operation and Development (OECD). OECD Guidelines for Multinational Enterprises. Paris: OECD; 2011. "]}, {"label": ["168"], "person-group": ["\n"], "surname": ["Grosser", "McCarthy"], "given-names": ["K", "L"], "article-title": ["Imagining new feminist futures: how feminist social movements contest the neoliberalization of feminism in an increasingly corporate-dominated world"], "source": ["Gend Work Organ"], "year": ["2019"], "volume": ["26"], "issue": ["8"], "fpage": ["1100"], "lpage": ["1116"], "pub-id": ["10.1111/gwao.12267"]}, {"label": ["170"], "person-group": ["\n"], "surname": ["Schuftan"], "given-names": ["C"], "article-title": ["Why power only yields to counter-power"], "source": ["Development"], "year": ["2017"], "volume": ["60"], "issue": ["3"], "fpage": ["206"], "lpage": ["212"], "pub-id": ["10.1057/s41301-018-0160-y"]}, {"label": ["171"], "person-group": ["\n"], "surname": ["Musindarwezo"], "given-names": ["D"], "article-title": ["The 2030 agenda from a feminist perspective: no meaningful gains without greater accountability for Africa\u2019s women"], "source": ["Agenda"], "year": ["2018"], "volume": ["32"], "issue": ["1"], "fpage": ["25"], "lpage": ["35"], "pub-id": ["10.1080/10130950.2018.1427693"]}, {"label": ["172"], "person-group": ["\n"], "surname": ["Savourey", "Brabant"], "given-names": ["E", "S"], "article-title": ["The French law on the duty of vigilance: theoretical and practical challenges since its adoption"], "source": ["Bus Hum Rights J"], "year": ["2021"], "volume": ["6"], "issue": ["1"], "fpage": ["141"], "lpage": ["152"], "pub-id": ["10.1017/bhj.2020.30"]}, {"label": ["173"], "mixed-citation": [" Bisch\u00f6fliches Hilfswerk Misereor e.V. Corporate Influence on the Business and Human Rights Agenda of the United Nations. Aachen: Bisch\u00f6fliches Hilswerk Misereor e.V.; 2014. "]}, {"label": ["174"], "person-group": ["\n"], "surname": ["Khan"], "given-names": ["W"], "article-title": ["Corporate power and the protection of human rights in equilibrium"], "source": ["Secur Hum Rights"], "year": ["2013"], "volume": ["24"], "issue": ["1"], "fpage": ["29"], "lpage": ["42"], "pub-id": ["10.1163/18750230-02401006"]}, {"label": ["175"], "person-group": ["\n"], "surname": ["Martin"], "given-names": ["M"], "article-title": ["Conflicted corporates: rethinking the role of business in global security"], "source": ["Glob Policy"], "year": ["2012"], "volume": ["3"], "issue": ["1"], "fpage": ["35"], "lpage": ["45"], "pub-id": ["10.1111/j.1758-5899.2011.00079.x"]}, {"label": ["176"], "mixed-citation": [" Augenstein D. The crisis of international human rights law in the global market economy. In: Bulterman MK, van Genugten W, eds. Netherlands Yearbook of International Law 2013: Crisis and International Law: Decoy or Catalyst? Vol 44. Springer; 2014. "]}, {"label": ["177"], "person-group": ["\n"], "surname": ["Bond"], "given-names": ["P"], "article-title": ["Social movements and corporate social responsibility in South Africa"], "source": ["Dev Change"], "year": ["2008"], "volume": ["39"], "issue": ["6"], "fpage": ["1037"], "lpage": ["1052"], "pub-id": ["10.1111/j.1467-7660.2008.00528.x"]}, {"label": ["178"], "mixed-citation": [" Khoury S, Whyte D. Conclusion: new mechanisms of accountability for corporate human rights violations? In: Corporate Human Rights Violations: Global Prospects for Legal Action. New York: Routledge; 2017. "]}, {"label": ["179"], "mixed-citation": [" Parker C. Just Lawyers. Oxford: Oxford University Press; 1999. "]}, {"label": ["180"], "mixed-citation": [" Kennedy P. No More Market Failure: The Economic Case for Nationalisation. 2017. "], "uri": ["https://www.opendemocracy.net/en/opendemocracyuk/no-more-market-failure-economic-case-for-nationalisation/"]}, {"label": ["181"], "person-group": ["\n"], "surname": ["Farazmand"], "given-names": ["A"], "article-title": ["Globalization and public administration"], "source": ["Public Adm Rev"], "year": ["1999"], "volume": ["59"], "issue": ["6"], "fpage": ["509"], "lpage": ["522"], "pub-id": ["10.2307/3110299"]}, {"label": ["182"], "mixed-citation": [" Tombs S, Whyte D. Conclusion: what is to be done about the corporate criminal. In: The Corporate Criminal: Why Corporations Must Be Abolished. New York: Routledge; 2015:157-182. "]}, {"label": ["183"], "mixed-citation": [" Global Working Group Beyond Development. Alternatives in a World of Crisis. Brussels: Rosa Luxembourg Stiftung, Universidad Andina Sim\u00f3n Bol\u00edvar; 2018. "]}, {"label": ["184"], "mixed-citation": [" Transnational Institute (TNI). The Future is Public: Towards Democratic Ownership of Public Services. Amsterdam, Paris: TNI; 2020. "]}, {"label": ["185"], "person-group": ["\n"], "surname": ["Assies"], "given-names": ["W"], "article-title": ["David versus Goliath in Cochabamba: water rights, neoliberalism, and the revival of social protest in Bolivia"], "source": ["Lat Am Perspect"], "year": ["2003"], "volume": ["30"], "issue": ["3"], "fpage": ["14"], "lpage": ["36"], "pub-id": ["10.1177/0094582x03252286"]}, {"label": ["186"], "mixed-citation": [" Energy Democracy. About Us. 2021. "], "uri": ["https://energy-democracy.net/about-us/"]}, {"label": ["187"], "mixed-citation": [" Angel J. Towards Energy Democracy: Discussions and Outcomes from an International Workshop. Amsterdam: Transnational Institute (TNI); 2016. "]}, {"label": ["188"], "mixed-citation": [" World Health Organization (WHO). Cuban Experience with Local Production of Medicines, Technology Transfer and Improving Access to Health. Geneva: World Health Organization, European Commission, Pan American Health Organization; 2015. "]}, {"label": ["189"], "mixed-citation": [" Reardon S. Cuba\u2019s Bet on Home-Grown COVID Vaccines is Paying Off. Nature; 2021. "], "uri": ["https://www.nature.com/articles/d41586-021-03470-x"]}, {"label": ["190"], "mixed-citation": [" Chimni B. WTO, democracy, and development: a view from the south. In: Birbeck CD, ed. Making Global Trade Governance Work for Development: Perspectives and Priorities from Developing Countries. Cambridge, UK: Cambridge University Press; 2011. "]}, {"label": ["191"], "mixed-citation": [" International Labour Organization (ILO). A Fair Globalization: Creating Opportunities for All. Geneva: ILO; 2004. "]}, {"label": ["192"], "mixed-citation": [" Kuper A. Transforming Global Institutions. In: Democracy Beyond Borders: Justice and Representation in Global Institutions. Oxford, UK: Oxford University Press; 2004. "]}, {"label": ["193"], "person-group": ["\n"], "surname": ["Clapp"], "given-names": ["J"], "article-title": ["The privatization of global environmental governance: ISO 14000 and the developing world"], "source": ["Glob Gov"], "year": ["1998"], "volume": ["4"], "issue": ["3"], "fpage": ["295"], "lpage": ["316"]}, {"label": ["195"], "person-group": ["\n"], "surname": ["Peinhardt", "Wellhausen"], "given-names": ["C", "RL"], "article-title": ["Withdrawing from investment treaties but protecting investment"], "source": ["Glob Policy"], "year": ["2016"], "volume": ["7"], "issue": ["4"], "fpage": ["571"], "lpage": ["576"], "pub-id": ["10.1111/1758-5899.12355"]}, {"label": ["196"], "mixed-citation": [" United Nations Commission on International Trade Law (UNCITRAL). The UNCITRAL Working Group III (ISDS Reform) - Informal Online Meeting on 6-10 December 2021. UNCITRAL; 2021. "], "uri": ["https://uncitral.un.org/en/content/uncitral-working-group-iii-isds-reform-informal-online-meeting-6-10-december-2021"]}, {"label": ["197"], "mixed-citation": [" de Zayas A. Statement by the Independent Expert on the Promotion of a Democratic and Equitable International Order, Alfred de Zayas, on the Upcoming Signing the Trans-Pacific Partnership. 2015. "], "uri": ["https://www.ohchr.org/EN/NewsEvents/Pages/DisplayNews.aspx?NewsID=17005"]}, {"label": ["198"], "mixed-citation": [" International Trade Union Confederation (ITUC). The IMF\u2019s Renewed Supply-Side Push: Four Decades of Structural Adjustment and Austerity Conditionality. ITUC; 2020. "]}, {"label": ["199"], "mixed-citation": [" International Trade Union Confederation (ITUC). Market Fundamentalism and the World Bank Group: From Structural Adjustment Programmes to Maximizing Finance for Development and Beyond. ITUC; 2020. "]}, {"label": ["200"], "mixed-citation": [" Laszlo E, Baker R, Eisenberg E, Raman V. The Objectives of the New International Economic Order. New York: Pergamon Press; 1978. "]}, {"label": ["201"], "mixed-citation": [" Sneyd A. The New International Economic Order Stumbled Once Before. Will it Succeed a Second Time Around? The Conversation; 2023. "], "uri": ["https://theconversation.com/the-new-international-economic-order-stumbled-once-before-will-it-succeed-a-second-time-around-198969"]}, {"label": ["202"], "person-group": ["\n"], "surname": ["Sauvant"], "given-names": ["KP"], "article-title": ["The negotiations of the United Nations code of conduct on transnational corporations: experience and lessons learned"], "source": ["J World Invest Trade"], "year": ["2015"], "volume": ["16"], "issue": ["1"], "fpage": ["11"], "lpage": ["87"], "pub-id": ["10.1163/22119000-01601002"]}, {"label": ["203"], "mixed-citation": [" Segall J. Building a More Democratic United Nations. London: Routledge; 1991. "]}, {"label": ["204"], "mixed-citation": [" The Insolvency Service. Press Release: Insolvency Service Takes Action Against Businesses Abusing COVID-19 Financial Support. The Insolvency Service; 2021. "], "uri": ["https://www.gov.uk/government/news/insolvency-service-takes-action-against-businesses-abusing-covid-19-financial-support"]}, {"label": ["205"], "mixed-citation": [" Hoffman J. Purdue Pharma is Dissolved and Sacklers Pay $4.5 Billion to Settle Opioid Claims. The New York Times; 2021. "], "uri": ["https://www.nytimes.com/2021/09/01/health/purdue-sacklers-opioids-settlement.html"]}, {"label": ["206"], "mixed-citation": [" SEI, IISD, ODI, E3G, UNEP. The Production Gap Report. Stockholm Environment Institute; 2021. "]}, {"label": ["208"], "mixed-citation": [" Kessler D. A Question of Interest: A Great American Battle with a Deadly Industry. New York: Public Affairs Press; 2002. "]}, {"label": ["209"], "mixed-citation": [" Thornton J. Pandora\u2019s Poison: Chlorine, Health and a New Environmental Strategy. Boston: MIT Press; 2000. "]}, {"label": ["210"], "mixed-citation": [" Ritchie H. When Will Countries Phase Out Coal Power? Our World in Data; 2021. "], "uri": ["https://ourworldindata.org/coal-phase-out"]}, {"label": ["211"], "mixed-citation": [" Ministry of Health of New Zealand. Smokefree Aotearoa 2025 Action Plan. Ministry of Health of New Zealand; 2021. "], "uri": ["https://www.health.govt.nz/our-work/preventative-health-wellness/tobacco-control/smokefree-aotearoa-2025-action-plan"]}, {"label": ["212"], "mixed-citation": [" Worldwatch Institute. State of the World: Can a City Be Sustainable. Washington, DC: Worldwide Institute; 2016. "]}, {"label": ["213"], "mixed-citation": [" Domonoske C. The World Has FInally Stopped Using Leaded Gasoline. Algeria Used the Last Stockpile. National Public Radio; 2021. "], "uri": ["https://www.npr.org/2021/08/30/1031429212/the-world-has-finally-stopped-using-leaded-gasoline-algeria-used-the-last-stockp"]}, {"label": ["214"], "mixed-citation": [" Lent J. Five Ways to Curb the Power of Corporations. 2018. "], "uri": ["https://www.opendemocracy.net/en/transformation/five-ways-to-curb-power-of-corporations/"]}, {"label": ["215"], "person-group": ["\n"], "surname": ["Ireland"], "given-names": ["P"], "article-title": ["Limited liability, shareholder rights and the problem of corporate irresponsibility"], "source": ["Cambridge J Econ"], "year": ["2010"], "volume": ["34"], "issue": ["5"], "fpage": ["837"], "lpage": ["856"], "pub-id": ["10.1093/cje/ben040"]}, {"label": ["216"], "mixed-citation": [" Parkinson JE. Strengthening the Constraints. In: Corporate Power and Responsibility. Oxford, UK: Oxford University Press; 1993. "]}, {"label": ["217"], "mixed-citation": [" Teachout Z. Corporate Rules and Political Rules: Antitrust as Campaign Finance Reform. Fordham Law Legal Studies Research Paper No. 2384182. 2014. "], "uri": ["https://ssrn.com/abstract=2384182"]}, {"label": ["218"], "person-group": ["\n"], "surname": ["Glasbeek"], "given-names": ["H"], "article-title": ["Missing the targets\u2014Bill C-45: reforming the status quo to maintain the status quo"], "source": ["Policy Pract Health Saf"], "year": ["2013"], "volume": ["11"], "issue": ["2"], "fpage": ["9"], "lpage": ["23"], "pub-id": ["10.1080/14774003.2013.11667787"]}, {"label": ["219"], "person-group": ["\n"], "surname": ["Coffee JC"], "given-names": ["Jr"], "article-title": ["\u201c No soul to damn: no body to kick\u201d: an unscandalized inquiry into the problem of corporate punishment"], "source": ["Mich Law Rev"], "year": ["1981"], "volume": ["79"], "issue": ["3"], "fpage": ["386"], "lpage": ["459"], "pub-id": ["10.2307/1288201"]}, {"label": ["220"], "mixed-citation": [" Rutkow L, Teret S. Limited liability and the public\u2019s health. In: Wiist WH, ed. The Bottom Line or Public Health. New York: Oxford University Press; 2010. "]}, {"label": ["221"], "person-group": ["\n"], "surname": ["Boggio"], "given-names": ["A"], "article-title": ["Linking corporate power to corporate structures: an empirical analysis"], "source": ["Soc Leg Stud"], "year": ["2013"], "volume": ["22"], "issue": ["1"], "fpage": ["107"], "lpage": ["131"], "pub-id": ["10.1177/0964663912458447"]}, {"label": ["222"], "mixed-citation": [" Casswell S. A policy agenda for the commercial determinants of health. In: Maani N, Petticrew M, Galea S, eds. The Commercial Determinants of Health. New York: Oxford University Press; 2023. "]}, {"label": ["225"], "person-group": ["\n"], "surname": ["Baars"], "given-names": ["G"], "article-title": ["\u201cIt\u2019s not me, it\u2019s the corporation\u201d: the value of corporate accountability in the global political economy"], "source": ["Lond Rev Int Law"], "year": ["2016"], "volume": ["4"], "issue": ["1"], "fpage": ["127"], "lpage": ["163"], "pub-id": ["10.1093/lril/lrw008"]}]	{ "acronym": [], "definition": [] }	225	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 9; 12:7304	oa_package/1b/b6/PMC10590241.tar.gz
PMC10590242	0	[ "<title>Background</title>", "<p> China’s rapidly aging population has created a growing demand for the long-term care (LTC) services.<sup>##REF##30720879##1##</sup> In China, the number of people aged 60 and above has been 267 million by 2021 and it is expected to reach 480 million by 2050.<sup>##UREF##0##2##</sup> Informal care provided by family members has long been the main source of care for older adults.<sup>##REF##26475654##3##</sup> However, as a result of reduced family size, large-scale domestic migration and a decline in cohabiting with older adults, fewer people are taking on informal care in households and the risk for unmet LTC needs is growing substantially in China.<sup>##REF##23213161##4##,##REF##25323978##5##</sup> About one-third of functionally disabled people age 45 and older who need help with one or more activities of daily living (ADLs) or instrumental ADLs have their needs unmet.<sup>##REF##28888126##6##</sup> Hence, the demands for formal LTC outside traditional informal networks are increasing.<sup>##REF##35093795##7##</sup></p>", "<p> To ensure that older disabled people receive affordable care services and alleviate the care burdens on family members, the Chinese government launched a long-term care insurance (LTCI) policy experimentation in 15 cities and 2 provinces in 2016.<sup>##REF##31385373##8##</sup> In the pilot phase, LTCI was mainly financed by existing public health insurance schemes to cover basic care costs for daily living and related medical expenses for eligible beneficiaries with long-term disabilities.<sup>##REF##35093795##7##</sup> LTC services can be broadly divided into three types, eg, home care, institutional care and hospital care. The types and frequencies of LTC services available to beneficiaries depends on the severity of their disability. Reimbursement rates vary depending on the type of LTC services provided and are usually higher for home care.<sup>##REF##35093795##7##</sup> Theoretically, an increase in formal LTC utilization could help maintain or improve the health status of disabled older adults, who are the primary recipients of LTCI benefits. More details of LTCI can be seen in Text S1 and Table S1 (##SUPPL##0##Supplementary file 1##).</p>", "<p> Most studies have examined the health effects of LTCI in developed countries. Previous studies assessing the effects of LTCI or different types of formal care on health outcomes of older adults produced mixed results. For example, an increase in public home care program generosity was associated with an improvement in self-reported health in Canada.<sup>##REF##16426689##9##</sup> In the context of Korea, the LTCI policy was associated with lower mortality risk among care beneficiaries,<sup>##REF##32066015##10##,##REF##27017418##11##</sup> and their cognitive function and disability declined less.<sup>##REF##30246886##12##</sup> Yet another study found that subsidies for LTC had no effects on mortality.<sup>##UREF##1##13##</sup> Several studies showed that LTCI had little effects on health outcomes of frail older adults,<sup>##REF##21885099##14##, ####REF##29040896##15##, ##UREF##2##16####2##16##</sup> or the decline in formal home healthcare had no adverse health effects,<sup>##UREF##3##17##</sup> but reduced independent living among older adults in the United States.<sup>##UREF##4##18##</sup> In the coming decades, developing countries with different social systems, cultures and socio-economic environments will be the main force of global population ageing.<sup>##UREF##5##19##</sup> Therefore, it is necessary to examine the health effects of LTCI in developing countries like China.</p>", "<p> Up to now, rigorous evaluations of the health effects of China’s LTCI pilots have been limited. Available evidence showed that the introduction of LTCI led to an improvement in overall health<sup>##REF##34983634##20##,##REF##32540515##21##</sup> and quality of life,<sup>##REF##35083471##22##</sup> including self-reported health,<sup>##REF##35093795##7##,##REF##35646763##23##</sup> the ADL,<sup>##REF##35646763##23##</sup> mental health,<sup>##REF##35646763##23##</sup> cognitive function,<sup>##REF##36403228##24##</sup> and a reduction in one-year mortality risk.<sup>##REF##35093795##7##</sup> However, the potential effects and heterogeneity of LTCI on comprehensive health outcomes of older adults are still unclear. Understanding the health impacts of LTCI is important given the aging population in China and the need for effective policies to support older adults’ health and well-being. This study is, to the best of our knowledge, one of the first to examine the health effects of China’s first pilots of the public LTCI program on older adults aged 60+, utilizing a quasi-experimental design of the LTCI policy. We included 15 pilot cities and also two provinces (ie, Jilin and Shandong provinces) as the study frame, which has never been done before. Our goal is to conduct a comprehensive health assessment of the LTCI policy and provide policy relevance to other middle-income or developing countries.</p>" ]	[ "<title>Methods</title>", "<title> Data and Sample</title>", "<p> We used data from the 2015 and 2018 waves of the China Health and Retirement Longitudinal Study (CHARLS), which covered the periods before and after the introduction of LTCI. CHARLS is a nationally representative longitudinal survey.<sup>##REF##24391298##25##</sup> So far, a total of four waves of surveys have been completed in 2011, 2013, 2015, and 2018, respectively. We targeted respondents aged 60+ years, who were the most relevant group to the LTCI policy. A total of 13 730 respondents aged 60+ were interviewed in the 2015 survey, of whom 9087 (66.18%) were interviewed again in 2018. 4643 (33.82%) respondents died or were lost to follow-up prior to the 2018 survey, and 47 respondents were dropped due to missing values in control variables. Our main study sample is a panel composed of 9040 older adults from 122 cities. Based on the pre-post treatment-control design, we included health insurance enrollees who were covered by the local LTCI pilot between 2015 and 2018 into the treatment group (N = 314). The remaining were assigned to the control group (N = 8726).</p>", "<p> Panel attrition may be a source of bias if respondents were lost to follow-up non-randomly and their sample attrition was systematically related to the treatment variable (ie, the LTCI coverage) conditional on the characteristics we controlled for in equation. The fixed-effects specification in our main analysis mitigated the concern regarding attrition due to time-invariant sources. To further examine whether the nonresponse was associated with the treatment, we used the full sample of CHARLS 2015 and constructed an indicator of whether the respondent was lost to follow-up in 2018. We then regressed this indicator on individual treatment status and a set of demographic and socioeconomic variables in 2015. In Table S2, the coefficients of the treatment variable were statistically insignificant, suggesting that the possibility of respondents lost to follow-up in 2018 was independent with the LTCI coverage, and that potential attrition bias was unlikely to be a concern.</p>", "<title> Outcome Variables</title>", "<p> We used multiple measures of health as outcome variables in CHARLS, including self-reported health, physical function, kinds of chronic diseases, cognitive function, and depression.</p>", "<p> Self-reported health was measured according to a five-category survey question: “How do you rate your health at present?” We constructed a continuous indicator with a value of 0 if the respondent reported “poor” health, a value of 1 for “fair” health, and a value of 2 for “good” health.</p>", "<p> ADLs based on the Barthel Index was used to access physical function: feeding, bathing, grooming, dressing, bowels, bladder, toilet use, transfers (bed to chair and back), mobility (on level surface), and stairs. Although the assessment of ADLs in CHARLS did not use Barthel Index, ADLs in CHARLS were converted to conform to the measurement of Barthel Index following previous literature (Table S3).<sup>##REF##31385373##8##</sup> The total score ranged from 0–100, with a higher score indicating a greater independence. 0–60 meant moderate or severe disability, and 61–100 meant mild disability or full independence.<sup>##REF##31385373##8##</sup></p>", "<p> Kinds of chronic diseases were calculated according to respondents’ answers to the question of whether they had at least one chronic disease diagnosed by a doctor, including hypertension, dyslipidemia, diabetes, cancer, chronic lung diseases, liver diseases, heart diseases, stroke, kidney diseases, digestive system diseases, arthritis, or asthma.</p>", "<p> Cognitive function measured respondents’ abilities of orientation, attention, episodic memory and mental intactness, which was presented as the total score in the following four aspects: (<italic toggle=\"yes\">a</italic>) naming the day, week, month, year, and the season (0 to 5 scores); (<italic toggle=\"yes\">b</italic>) subtracting a number by five times (0 to 5 scores); (<italic toggle=\"yes\">c</italic>) drawing a picture on the paper (0 to 1 score); (<italic toggle=\"yes\">d</italic>) memorizing and recalling ten words (average 0 to 10 scores). The range was 0-21, and higher score meant better cognitive function.<sup>##REF##31718564##26##</sup> A score of 6 or less was used as a cut point for having intellectual disability.<sup>##REF##21743047##27##</sup></p>", "<p> Depression was detected by using the 10-item Center for the Epidemiological Studies of Depression Short Form (CES-D-10).<sup>##REF##22212622##28##</sup> The subjects rated how often each emotion had occurred in the past week on a 4-point scale, ranging from 0 (“none”) to 3 (“most of the time”). A total score of CES-D-10 ranged from 0 to 30.</p>", "<title> Independent Variables</title>", "<p> We constructed an indicator of whether the respondent was covered by LTCI. LTCI coverage was based on the pilot timing at the city level and local requirements for public health insurance status (ie, Urban Employee Basic Medical Insurance, Urban Resident Basic Medical Insurance, and Urban and Rural Resident Basic Medical Insurance). In our sample, 15 cities had implemented the program by the 2018 survey, including 11 cities in the 2016 officially announced pilot list and 4 cities in which the local government launched the program during 2015-2018. All 15 pilot cities offered LTCI coverage for Urban Employee Basic Medical Insurance enrollees. 2 cities also covered urban and rural residents enrolled in Urban and Rural Resident Basic Medical Insurance.</p>", "<p> In the 2018 survey, 314 respondents were living in pilot cities and covered by the local LTCI, who were classified as the treated group. The remaining 8726 respondents uncovered by LTCI during 2015-2018 were classified as the control group, no matter whether they lived in pilot cities or not. That is, the specific groups of people included in the control group were (1) those uncovered by the local LTCI and living in pilot cities; (2) those uncovered by the local LTCI and living in non-pilot cities.</p>", "<title> Covariates</title>", "<p> Covariates included age (continuous), gender (male/female), marital status (single/married), education level (illiterate/literate/primary school/junior high school and above), residence (urban/rural), smoking (no/yes or ever), drinking (no/yes or ever), and the number of living children (continuous).</p>", "<title> Statistical Analysis</title>", "<p> To evaluate the health effects of LTCI and to avoid the confounding health effects of insurance coverage other than LTCI, we applied a difference-in-difference (DID) strategy with individual fixed effects (FE) to the two-year panel data: 2015 before LTCI and 2018 after LTCI. The DID approach compared the changes in health outcomes over time between those who had participated in the LTCI program (the treatment group) and those who had not (the control group) while controlling for other factors that might affect health outcomes. By comparing changes in health outcomes before and after the implementation of the LTCI program in the treatment group with the control group, the study could isolate the effects of LTCI coverage from other factors. DID is a well-established method in health policy research and has been shown to be effective in evaluating the impact of policy interventions. The following equation is estimated:</p>", "<p>\n<italic toggle=\"yes\">y</italic><sub>ict</sub>= <italic toggle=\"yes\">β</italic><sub>1</sub><italic toggle=\"yes\">Treat</italic><sub>ic</sub> × <italic toggle=\"yes\">Post</italic><sub>t</sub>+ <italic toggle=\"yes\">β</italic><sub>2</sub><italic toggle=\"yes\">X</italic><sub>ict</sub>+ <italic toggle=\"yes\">τ</italic><sub>t</sub>+ <italic toggle=\"yes\">a</italic><sub>i</sub>+ <italic toggle=\"yes\">ε</italic><sub>ict</sub></p>", "<p> where <italic toggle=\"yes\">y</italic><sub>ict</sub> denotes the health outcomes of individual <italic toggle=\"yes\">i</italic> living in city <italic toggle=\"yes\">c</italic> in year <italic toggle=\"yes\">t</italic>. In the independent variable <italic toggle=\"yes\">Treat</italic><sub>ic</sub> × <italic toggle=\"yes\">Post</italic><sub>t</sub>, <italic toggle=\"yes\">Post</italic><sub>t</sub> is a dichotomous variable that is 0 for 2015 and 1 for 2018, and <italic toggle=\"yes\">Treat</italic><sub>ic</sub> is a dummy variable for individual treatment status. <italic toggle=\"yes\">X</italic><sub>ict</sub> is a vector of individual time-varying characteristics that includes the respondent’s age, marital status, residence, smoking, drinking, and the number of living children. <italic toggle=\"yes\">τ</italic><sub>t</sub> is year FE. <italic toggle=\"yes\">a</italic><sub>i</sub> is individual FE that account for all time-invariant factors that may affect the outcome variables. <italic toggle=\"yes\">ε</italic><sub>ict</sub> is a random error term. Standard errors are clustered at the city level to account for possible correlation in outcomes between older adults in the same city.</p>", "<p> The key assumption of the DID specification is that the potential trends in the outcome variables in both the treated and control groups should be parallel without the implementation of LTCI. We tested the assumption by using the 2011–2018 CHARLS panel and found no evidence of the differential pre-trends (Table S4). On the other hand, due to the large difference in sample size between the treatment group and the control group, the conclusions may be influenced by selection bias due to sample mismatch between the treatment and control groups.<sup>##UREF##6##29##,##REF##24476754##30##</sup> We combined the DID regression and the propensity score matching (PSM) method to achieve “double robustness.”<sup>##UREF##7##31##</sup> We first estimated a logit model to obtain the propensity score—that is, the probability of being in the treatment group given the set of baseline observable characteristics. With the estimated propensity score, we performed the DID analyses in the common support, so that the probability of LTCI coverage was similar between two groups. We used the nearest neighbor matching, after which all the observable characteristics were well balanced and propensity score distributions were more similar between the two groups, which further tested the validity and reliability of the results and proved that the sample equilibrium hypothesis was satisfied (Figure S1).</p>", "<p> In addition, there could exist the “spillover effect” of LTCI, which refers to the potential beneficial impact of the program on those who are not direct beneficiaries of the program but are covered by it. In our study, the “spillover effect” could be manifested as improvements in health outcomes among non-LTCI beneficiaries residing in regions with high coverage rates of LTCI (Chongqing, Guangdong, Heilongjiang, Hubei, Jiangsu, Jilin, Shandong, Shanghai, and Zhejiang). The distribution of treated and control groups in the spillover study is presented in Table S5. We also employed panel data analysis and the DID approach to compare the changes in health outcomes between areas with high and low LTCI coverage rates over time. It was found in Table S6 that individuals living in areas with high LTCI coverage rates did not manifest better self-rated health or cognitive function than those living in areas with low coverage rates, even after controlling for other variables such as age, sex, marital status, education level, etc, indicating that the spillover benefits of LTCI could be small.</p>", "<p> Further, the robustness test was carried out by selecting a different control group. This was done to ensure that the results were not affected by the selection of the control group and were reliable. The robustness test included two control groups - one comprising older adults living in pilot cities who were not covered by the LTCI program during the study period, and the other comprising older adults living in non-pilot cities who were not covered by the LTCI program during the study period. The process involved selecting the two new control groups, and then performing the same statistical analysis as done for the original control group. Results obtained from the original control group (uncovered respondents during 2015-2018) were compared with those obtained from the two new control groups. Lastly, we examined heterogeneity of health effects across different populations, ie, older adults with/without physical disability and older adults with/without intellectual disability, so as to provide information on how to target resources and interventions more effectively to improve health outcomes for the most vulnerable populations.</p>" ]	[ "<title>Results</title>", "<p>\n##TAB##0##Table 1## presents descriptive statistics for the treated and control groups in wave 2015 and 2018. T-test was applied for continuous variables and analysis of variance (ANOVA) for category variables, indicating the significance level of pairwise comparisons prior to and after the LTCI pilot. The treatment group was statistically similar to the control group in kinds of chronic diseases (<italic toggle=\"yes\">P</italic> = .12) and age (<italic toggle=\"yes\">P</italic> = .24). The treatment group were more likely to be female (<italic toggle=\"yes\">P</italic> < .001), single (<italic toggle=\"yes\">P</italic> = .001), educated (<italic toggle=\"yes\">P</italic> < .001), from rural areas (<italic toggle=\"yes\">P</italic> < .001), smoking (<italic toggle=\"yes\">P</italic> = .004), drinking (<italic toggle=\"yes\">P</italic> = .019), and had fewer living children (<italic toggle=\"yes\">P</italic> < .001). They had better self-rated health, worse physical function, better cognitive function, and less depression (<italic toggle=\"yes\">P</italic> < .001).</p>", "<p>\n##TAB##1##Table 2## reports the estimated effects of LTCI on health outcomes, including self-rated health status, physical function, kinds of chronic diseases, cognitive function, and depression. Column 1 in ##TAB##1##Table 2## demonstrates results from the DID estimate that LTCI coverage might improve health outcomes, but marginally non-significant. In column 2, using the PSM matched sample, the DID estimates for self-reported health (β = 0.15, <italic toggle=\"yes\">P</italic> < .05) and cognitive function (β = 0.59, <italic toggle=\"yes\">P</italic> < .01) were significantly positive. For physical function (β = 1.77, <italic toggle=\"yes\">P</italic> > .05), kinds of chronic diseases (β = -0.14, <italic toggle=\"yes\">P</italic> > .05), and depression (β = -0.41, <italic toggle=\"yes\">P</italic> > .05), there were no significant improvements.</p>", "<p> As a robustness check, we kept only the uncovered older adults living in pilot cities (N = 1450) or the uncovered sample living in non-pilot cities (N = 7276) as the control group. This was done to ensure that the results were not affected by the selection of the control group and were reliable. In ##TAB##2##Table 3##, we found that the results did not change much. In columns 2, LTCI significantly improved self-rated health status (β = 0.31, <italic toggle=\"yes\">P</italic> < .05), reduced kinds of chronic diseases (β = -0.42, <italic toggle=\"yes\">P</italic> < .001), improved cognitive function (β = 0.98, <italic toggle=\"yes\">P</italic> < .001), and alleviated depression (β = -1.49, <italic toggle=\"yes\">P</italic> < .001) compared to uncovered older adults living in pilot cities. In columns 4, LTCI significantly improved self-rated health status (β = 0.14, <italic toggle=\"yes\">P</italic> < .05) and cognitive function (β = 0.60, <italic toggle=\"yes\">P</italic> < .01) compared to uncovered older adults living in non-pilot cities.</p>", "<p> Older adults covered by LTCI became eligible for service benefits when they had moderate or severe physical disability. We provided indirect evidence by further investigating whether the effects of LTCI varied across older adults with or without physical disability in ##TAB##3##Table 4##. In our sample, 25.85% had moderate or severe physical disability in pretreatment year 2015. LTCI significantly improved their self-rated health status (β = 0.13, <italic toggle=\"yes\">P</italic> < .01) and cognitive function (β = 0.76, <italic toggle=\"yes\">P</italic> < .001). Table S7 added an interaction term between LTCI coverage and physical disability in pretreatment year 2015 using the same dataset. It was used to examine whether there existed heterogeneous effects of LTCI by physical function. The effects of LTCI on cognitive function (β = 2.75, <italic toggle=\"yes\">P</italic> < .01) varied significantly between older adults with or without moderate or severe physical disability.</p>", "<p> Intellectual disability is one of the inclusion criteria explicitly specified in the LTCI eligibility criteria in some cities (eg, Qingdao of Shandong province and Guangzhou of Guangdong province). In addition, intellectual disability can also be regarded as a kind of disability. We therefore investigated whether the effects of LTCI varied across older adults with or without intellectual disability (cut-off point at 6) in ##TAB##4##Table 5##. In our sample, 28.58% had intellectual disability in pretreatment year 2015. For older adults with intellectual disability, LTCI significantly improved self-rated health status (β = 0.20, <italic toggle=\"yes\">P</italic> < .01). For older adults without intellectual disability, LTCI had no effects on health outcomes. Table S8 added an interaction term between LTCI coverage and intellectual disability in pretreatment year 2015. The effects of LTCI on self-rated health (β = -0.24, <italic toggle=\"yes\">P</italic> < .05) and physical function (β = 10.51, <italic toggle=\"yes\">P</italic> < .05) varied with intellectual status.</p>" ]	[ "<title>Discussion</title>", "<p> With the rapid aging of the population and the weakening of traditional family care, the demand for formal LTC services among China’s elderly population is escalating. To explore a systematic financing mechanism, the government officially launched LTCI pilots in 2016. However, despite the rapid expansion of LTCI in China, the effects of the insurance scheme on health outcomes remain controversial. This paper assessed the effectiveness of LTCI pilots on health outcomes, using nationally representative longitudinal data of CHARLS. We employed a rigorous causal inference approach to determine the effects of LTCI coverage. LTCI significantly improved self-rated health and cognitive function in older adults. The results were robust when keeping only those living in pilot cities or non-pilot cities as the control group. The effects of LTCI were especially manifested in older adults with physical or intellectual disability.</p>", "<p> The implementation of LTCI resulted in significant improvements in health outcomes for older adults. LTCI improved self-rated health and cognitive function, which were consistent with existing research findings that publicly funded LTC had a positive impact on self-reported health.<sup>##REF##35093795##7##,##REF##16426689##9##,##REF##36403228##24##</sup> LTCI care beneficiaries had fewer declines in cognitive function<sup>##REF##36403228##24##</sup> and disability.<sup>##REF##30246886##12##</sup> A home-based intervention program targeting underlying impairments in physical abilities could reduce the progression of functional decline among physically frail older adults.<sup>##REF##12362007##32##</sup> However, for physical function, kinds of chronic diseases, and depression, there were no significant improvements. A possible explanation for the mixed evidence could be that the improvements in self-rated health might have been easier to achieve. The LTCI program might not have been in place for a long enough time to produce significant improvements in physical function, chronic diseases, and depression.</p>", "<p> Furthermore, this study showed that older adults with physical or intellectual disability benefited more from LTCI in terms of health outcomes, indicating the rationality of the LTCI eligibility criteria for disabled older adults. LTCI could have significant impacts on health outcomes of older adults with disabilities. Physical and intellectual disabilities can limit an individual’s ability to perform daily activities and negatively impact physical and mental health.<sup>##UREF##8##33##</sup> The LTCI program provides much-needed support and care to these individuals, leading to improved self-rated health status and cognitive function. Therefore, policy-makers and healthcare providers should prioritize the needs of older adults with disabilities, ensure that they have access to the LTCI program, and provide appropriate support and care tailored to their specific needs.<sup>##REF##33160305##34##</sup> It can ensure that resources are used most effectively to improve health outcomes for older adults.</p>", "<p> The positive impacts of the LTCI program on health outcomes among older adults are clear, but the stringent eligibility criteria limit the number of beneficiaries, even in pioneer cities with a broader LTCI coverage.<sup>##REF##34338215##35##</sup> This suggests that there is a significant unmet demand for LTC services in China, and that the current policy may not meet the needs of the aging population. Additionally, the proportion of older adults receiving benefits from LTCI in China is significantly lower than that in developed countries. Less than 2% of Chinese older adults aged 60 years and over has received benefits from LTCI by the end of 2017,<sup>##REF##31385373##8##</sup> while in Japan and Germany, LTCI provides benefits to 13.5% and 10.5% of their population aged 65+, respectively.<sup>##REF##20048365##36##</sup> This disclosed a large gap between the needs of disabled people and access to LTC benefits in China’s LTCI policy experimentation. There is an urgent need to expand the scope and coverage of LTCI in China, to ensure that all eligible older adults have access to the support and care they need.</p>", "<p> The contribution of this paper to the literature is mainly reflected in the following aspects. Firstly, the study provided robust evidence for the positive impacts of the LTCI program on health outcomes among older adults in China, utilizing rigorous DID and PSM methods, to control for confounding factors and identify causal effects. Secondly, a range of important health outcomes were studied among older adults, including self-reported health status, physical function, chronic diseases, cognitive function, and mental health. Thirdly, we explored the health effects of LTCI in 15 pilot cities and two provinces, so as to derive a full picture. Lastly, this paper further examined heterogeneity of health effects across different populations, which provided valuable information for policy-makers and healthcare providers on how to target resources and interventions more effectively to improve health outcomes for the most vulnerable populations. It also justified the LTCI eligibility and called for expanded policies.</p>", "<title> Limitations of the Study</title>", "<p> This study had several potential limitations. Firstly, due to the lack of individual-level data on the actual use of LTCI in the CHARLS data, we could not derive an exact estimate of the effects of LTCI. Secondly, there was no information on individuals’ eligibility for LTCI benefits. The intent-to-treat effects estimated in this study could include both direct effects for LTCI beneficiaries and spillover effects for nonusers covered by the program, so that the effects of the program for the beneficiaries might be underestimated.<sup>##UREF##9##37##,##UREF##10##38##</sup> Thirdly, due to data limitation, we could not separate the effects of home, community, and institutional care benefits.</p>" ]	[ "<title>Conclusion</title>", "<p> Overall, based on a quasi-experiment design, this study provides empirical evidence for the effectiveness of LTCI in improving self-rated health status and cognitive function for Chinese older adults, especially those with physical or cognitive disabilities. These findings have important policy implications for expanding LTCI pilots in China and development of LTCI in other middle-income or developing countries, as it could promote the health and well-being of older adults who were most vulnerable. It also highlighted the importance of developing policies that addressed the LTC needs of older adults, so as to secure their health.</p>" ]	[ "<p>\n<bold>Background:</bold> China’s long-term care insurance (LTCI) has been launched since 2016 to ensure that older disabled people obtain affordable care services. However, rigorous evaluations of the health effects of China’s LTCI pilots have been limited. This paper aimed to examine the effects of LTCI on health among older adults aged 60 years and above.\n</p>", "<p><bold>Methods:</bold> Drawing from panel data of the China Health and Retirement Longitudinal Study (CHARLS), we used a propensity score matching (PSM) and difference-in-difference (DID) approach to identify the health effects of the LTCI program and reduce the selection bias. Further, heterogeneity of the effects was examined by physical and intellectual function to evaluate whether the effects differed among subgroups of older population.</p>", "<p><bold>Results:</bold> The implementation of LTCI significantly improved self-rated health (β = 0.15, <italic toggle=\"yes\">P</italic><.05) and cognitive function (β = 0.59, <italic toggle=\"yes\">P</italic><.01) for older adults. The results were robust when keeping only those living in pilot cities (β = 0.31, <italic toggle=\"yes\">P</italic><.05 for self-rated health status; β = 0.98, <italic toggle=\"yes\">P</italic><.001 for cognitive function) or non-pilot cities (β = 0.14, <italic toggle=\"yes\">P</italic><.05 for self-rated health status; β = 0.60, <italic toggle=\"yes\">P</italic><.01 for cognitive function) as the control group. The effects of LTCI were especially manifested in older adults with physical disability (β = 0.13, <italic toggle=\"yes\">P</italic><.01 for self-rated health; β = 0.76, <italic toggle=\"yes\">P</italic><.001 for cognitive function) or intellectual disability (β = 0.16, <italic toggle=\"yes\">P</italic><.01 for self-rated health).</p>", "<p><bold>Conclusion:</bold> From a policy perspective, these findings suggested that LTCI in China could benefit the health outcomes of older adults, especially those with physical or cognitive disabilities. Policy-makers can target resources more effectively to improve health outcomes for the most vulnerable populations.</p>", "<p>\n<bold>Citation:</bold> Ye X, Hu M, Lin H. Effects of the long-term care insurance on health among older adults: a panel data from China. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7664. doi:10.34172/ijhpm.2023.7664</p>" ]	[ "<title>Acknowledgements</title>", "<p> We would like to thank all the participants in the CHARLS.</p>", "<title>Ethical issues</title>", "<p> The ethics application for collecting data on human subjects was approved and updated annually by Peking University’s Institutional Review Board (No. IRB00001052-11015). All participants provided written informed consent.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Supplementary files\n</title>" ]	[]	[]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Summary Statistics (2015-2018 Panel)\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" colspan=\"1\">\n</td><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Wave 2015 (n = 9040)</bold>\n</td><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Wave 2018 (n = 9040)</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Treated (n = 314)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Control (n = 8726)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P</bold>\n</italic>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Treated (n = 314)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Control (n = 8726)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P</bold>\n</italic>\n</td></tr><tr><td colspan=\"7\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Outcome Variables</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Self-rated health status (0-2)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1.12 (0.04)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.98 (0.01)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\"><.001</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1.09 (0.04)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.87 (0.01)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\"><.001</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Physical function (0-100)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">57.10 (1.98)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">67.83 (0.33)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">62.60 (1.89)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">69.66 (0.31)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Kinds of chronic diseases (0-12)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.43 (0.11)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.27 (0.02)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.12</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.71 (0.05)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.76 (0.01)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.38</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Cognitive function (0-21)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12.13 (0.22)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9.03 (0.05)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11.30 (0.23)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8.19 (0.05)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Depression (0-30)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">5.78 (0.34)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">8.39 (0.07)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\"><.001</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">5.69 (0.34)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">7.79 (0.07)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\"><.001</td></tr><tr><td colspan=\"7\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Covariates</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Age</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">68.51 (0.40)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">68.06 (0.07)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.24</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">71.51 (0.40)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">71.06 (0.07)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.24</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Gender</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">127 (40.45%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4552 (52.17%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">127 (40.45%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4552 (52.17%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Female</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">187 (59.55%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4174 (47.83%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">187 (59.55%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4174 (47.83%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Marital status</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.001</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.001</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Single</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">40 (12.74%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1788 (20.49%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">53 (16.88%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2181 (24.99%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Married</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">274 (87.26%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6938 (79.51%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">261 (83.12%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6545 (75.01%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Education level</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Illiterate</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">25 (7.96%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3056 (35.02%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">25 (7.96%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3056 (35.02%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Literate</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">36 (11.47%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1809 (20.73%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">36 (11.47%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1809 (20.73%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Primary school</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">83 (26.43%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2090 (23.95%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">83 (26.43%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2090 (23.95%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Junior high school and above</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">170 (54.14%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1771 (20.30%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">170 (54.14%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1771 (20.30%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Residence</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.001</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Urban </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">64 (20.38%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2054 (23.54%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">65 (20.70%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2096 (24.02%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Rural</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">250 (79.62%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6672 (76.46%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">249 (79.30%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6630 (75.98%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Smoking</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.004</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.002</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Never </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">145 (46.18%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4764 (54.60%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">146 (46.50%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4832 (55.37%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes or ever</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">169 (53.82%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3962 (45.40%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">168 (53.50%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3894 (44.63%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Drinking</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.019</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.014</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Never </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">148 (47.13%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4714 (54.02%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">145 (46.18%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4643 (53.21%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes or ever</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">166 (52.87%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4012 (45.98%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">169 (53.82%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4083 (46.79%)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Number of living children</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2.43 (0.08)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">3.25 (0.02)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\"><.001</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2.36 (0.08)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">3.08 (0.02)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\"><.001</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Effects of Long-term Care Insurance on Health Outcomes\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" colspan=\"1\">\n<bold>Dependent Variables</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Coefficient on Treat × Post</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID With Matching</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Self-rated health status </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.09 (0.04)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.15* (0.04)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Physical function </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.38 (2.46)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.77 (3.61)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Kinds of chronic diseases </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.13 (0.09)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.14 (0.19)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Cognitive function </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.10 (0.27)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.59** (0.20)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Depression </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.31 (0.08)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.41 (0.37)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Year FE</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Individual FE</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Effects of Long-term Care Insurance on Health Outcomes (Control Groups Limited to Uncovered Older Adults Living in Pilot Cities or Those Living in Non-pilot Cities)\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Dependent Variables</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Control Groups Limited to Uncovered Older Adults Living in Pilot Cities (N = 1450)</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Control Groups Limited to Uncovered Older Adults Living in Non-pilot Cities (N = 7276)</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID With Matching</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID With Matching</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Self-rated health status</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.05 (0.04)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.31* (0.11)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.10* (0.04)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.14* (0.07)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Physical function</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.02 (2.51)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5.07 (4.37)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.26 (2.51)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.23 (3.67)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Kinds of chronic diseases</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.12 (0.10)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.42* (0.05)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.13 (0.09)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.15 (0.19)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Cognitive function</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.34 (0.26)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.98* (0.21)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.05 (0.27)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.60** (0.21)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Depression</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.20* (0.10)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-1.49* (0.44)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.10 (0.09)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.80 (0.57)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Year FE</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Individual FE</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T4\"><label>Table 4</label><caption><title>Effects of Long-term Care Insurance on Health Outcomes, by Physical Function\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Dependent Variables</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Moderate or Severe Physical Disability</bold>\n<break/>\n<bold>(N = 2204)</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Mild Physical Disability or Full Independence</bold>\n<break/>\n<bold>(N = 6323)</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID With Matching</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID With Matching</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Self-rated health status</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.07 (0.05)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.13 (0.04)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.46* (0.20)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.39 (0.21)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Physical function</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.10 (0.10)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.10 (0.10)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.50 (0.38)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-1.11 (1.27)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Kinds of chronic diseases</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.05 (0.27)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.76*** (0.19)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.12 (0.88)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.34 (1.83)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Cognitive function</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.13 (0.09)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.57 (0.43)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.16 (0.40)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-1.21 (2.45)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Depression</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.20* (0.10)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-1.49* (0.44)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.10 (0.09)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.80 (0.57)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Year FE</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Individual FE</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T5\"><label>Table 5</label><caption><title>Effects of Long-term Care Insurance on Health Outcomes, by Intellectual Function\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Dependent Variables</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Intellectual Disability</bold>\n<break/>\n<bold>(N = 2329)</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>No Intellectual Disability</bold>\n<break/>\n<bold>(N = 5820)</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID With Matching</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>DID With Matching</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Self-rated health status</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.16 (0.06)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.20** (0.07)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.06 (0.05)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0.09 (0.09)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Physical function</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.66 (2.72)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.79 (4.04)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.38 (3.52)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.65 (2.06)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Kinds of chronic diseases</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.10 (0.16)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.34 (0.26)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.16 (0.12)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.14 (0.19)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Cognitive function</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.24 (0.15)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-1.07 (0.74)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.34 (0.11)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.37 (0.61)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Depression</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.20* (0.10)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-1.49*** (0.44)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.10 (0.09)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.80 (0.57)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Year FE</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Y</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Individual FE</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Y</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>The implementation of long-term care insurance (LTCI) significantly improved self-rated health and cognitive function for older adults. </p></list-item><list-item><p>The effects of LTCI were especially manifested in older adults with physical disability or intellectual disability. </p></list-item><list-item><p>Our study has important implications for the development of LTCI in China and other middle-income or developing countries, which are facing rapid population aging and increasing demands for LTC. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> China’s rapidly aging population has created a growing demand for long-term care insurance (LTCI). The implementation of LTCI in China had positive effects on the health of older adults. Specifically, LTCI improved self-rated health and cognitive function in this group, and the effects were especially noticeable for older adults with physical or intellectual disabilities. The implications for the public were significant, as they suggested that investing in LTCI programs could promote the health and well-being of older adults who were most vulnerable. It also highlighted the importance of developing policies that addressed the long-term care (LTC) needs of older adults, so as to secure their health.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1 contains Text S1, Tables S1-S8, and Figure S1.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Note: Standard deviations are in parentheses; standard errors clustered at the city level are in brackets in the last column.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: DID, difference-in-difference; FE, fixed effects; Y, yes.</p><p> Note: Standard errors are clustered at the city level. The significance levels of 0.1%, 5%, and 1% are denoted by *, , and , respectively. All regressions control for year FE, individual FE, and individual covariates.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: DID, difference-in-difference; FE, fixed effects; Y, yes.</p><p> Note: Standard errors are clustered at the city level. The significance levels of 0.1%, 5%, and 1% are denoted by , , and , respectively. All regressions control for year FE, individual FE, and individual covariates.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: DID, difference-in-difference; FE, fixed effects; Y, yes.</p><p> Note: Standard errors are clustered at the city level. The significance levels of 0.1%, 5%, and 1% are denoted by , , and , respectively. All regressions control for year FE, individual FE, and individual covariates.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: DID, difference-in-difference; FE, fixed effects; Y, yes.</p><p> Note: Standard errors are clustered at the city level. The significance levels of 0.1%, 5%, and 1% are denoted by , , and *, respectively. All regressions control for year FE, individual FE, and individual covariates.</p></fn></table-wrap-foot>" ]	[]	[ "<media xlink:href=\"ijhpm-12-7664-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["2"], "mixed-citation": [" UNFPA. UNFPA and HelpAge International Ageing. "], "uri": ["https://www.unfpa.org/ageing"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Kim", "Lim"], "given-names": ["HB", "W"], "article-title": ["Long-term care insurance, informal care, and medical expenditures"], "source": ["J Public Econ"], "year": ["2015"], "volume": ["125"], "fpage": ["128"], "lpage": ["142"], "pub-id": ["10.1016/j.jpubeco.2014.12.004"]}, {"label": ["16"], "mixed-citation": [" Takahashi M. Behavioral Effects of Insurance Coverage and Health Consequences: Evidence from Long-Term Care. "], "uri": ["https://www.jeameetings.org/2019s/Gabst/2233.pdf"]}, {"label": ["17"], "person-group": ["\n"], "surname": ["McKnight"], "given-names": ["R"], "article-title": ["Home care reimbursement, long-term care utilization, and health outcomes"], "source": ["J Public Econ"], "year": ["2006"], "volume": ["90"], "issue": ["1-2"], "fpage": ["293"], "lpage": ["323"], "pub-id": ["10.1016/j.jpubeco.2004.11.006"]}, {"label": ["18"], "person-group": ["\n"], "surname": ["Orsini"], "given-names": ["C"], "article-title": ["Changing the way the elderly live: evidence from the home health care market in the United States"], "source": ["J Public Econ"], "year": ["2010"], "volume": ["94"], "issue": ["1-2"], "fpage": ["142"], "lpage": ["152"], "pub-id": ["10.1016/j.jpubeco.2009.10.010"]}, {"label": ["19"], "mixed-citation": [" United Nations Department of Economic and Social Affairs (DESA). World Population Prospects 2019. DESA. 2019:141. "]}, {"label": ["29"], "mixed-citation": [" Wooldridge JM. Introductory Econometrics: A Modern Approach. Cengage Learning; 2015. "]}, {"label": ["31"], "person-group": ["\n"], "surname": ["Imbens", "Wooldridge"], "given-names": ["GW", "JM"], "article-title": ["Recent developments in the econometrics of program evaluation"], "source": ["J Econ Lit"], "year": ["2009"], "volume": ["47"], "issue": ["1"], "fpage": ["5"], "lpage": ["86"], "pub-id": ["10.1257/jel.47.1.5"]}, {"label": ["33"], "person-group": ["\n"], "surname": ["Shandra"], "given-names": ["CL"], "article-title": ["Disability as inequality: social disparities, health disparities, and participation in daily activities"], "source": ["Soc Forces"], "year": ["2018"], "volume": ["97"], "issue": ["1"], "fpage": ["157"], "lpage": ["192"], "pub-id": ["10.1093/sf/soy031"]}, {"label": ["37"], "person-group": ["\n"], "surname": ["Angelucci", "de Giorgi"], "given-names": ["M", "G"], "article-title": ["Indirect effects of an aid program: how do cash transfers affect ineligibles\u2019 consumption?"], "source": ["Am Econ Rev"], "year": ["2009"], "volume": ["99"], "issue": ["1"], "fpage": ["486"], "lpage": ["508"], "pub-id": ["10.1257/aer.99.1.486"]}, {"label": ["38"], "person-group": ["\n"], "surname": ["Huang", "Zhang"], "given-names": ["W", "C"], "article-title": ["The power of social pensions: evidence from China\u2019s new rural pension scheme"], "source": ["Am Econ J Appl Econ"], "year": ["2021"], "volume": ["13"], "issue": ["2"], "fpage": ["179"], "lpage": ["205"], "pub-id": ["10.1257/app.20170789"]}]	{ "acronym": [], "definition": [] }	38	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 22; 12:7664	oa_package/c2/0b/PMC10590242.tar.gz
PMC10590243	0	[ "<title>Background</title>", "<p> The COVID-19 pandemic underlined the importance of effective regional collaboration to control infectious diseases. In December 2021, we published a scoping review in this journal examining research on how to operationalise regional bodies to effectively address potential infectious disease threats.<sup>##REF##35042324##1##</sup> Key enablers included clear understanding of the regional context, sufficient budgeting, addressing cultural/language issues, staffing capacity, and governmental priorities. Initial engagement among institutional bodies involved in design, implementation, monitoring, or evaluation of such collaborations is essential, as are a transparent governance structure with clear responsibilities and secure long-term funding.</p>" ]	[]	[]	[]	[]	[ "<p>\n<bold>Citation:</bold> Durrance-Bagale A, Hsu LY, Howard N. Bridging borders for health: the vital role of regional cooperation in infectious disease control and mitigation of health emergencies; a response to the recent commentaries. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8200. doi:10.34172/ijhpm.2023.8200</p>" ]	[ "<title>Progress</title>", "<p> In 2022, Standley and Sorrell<sup>##REF##37579350##2##</sup> and Teerawattananon et al<sup>##REF##35942957##3##</sup> published two constructive commentaries on our work. Standley and Sorrell identified our lack of emphasis on ‘regional networks established by an external entity or donor’ (eg, US-CDC Disease Detection centres), noting dependency on external funding as a barrier to successful regional engagement. We agree, considering how these externally funded networks often function alongside national governance structures and priorities, and often — unintentionally or intentionally — exclude them. Thus, the influences of external funding on regional governance and technical bodies are an important area for further research. Teerawattananon and colleagues<sup>##REF##35942957##3##</sup> discussed issues around establishing an Association of Southeast Asian Nations (ASEAN) regional disease control body and initiation of the ASEAN Center for Public Health Emergencies and Emerging Diseases (ACPHEED) to prepare for the next pandemic. They outlined recommendations for fostering regional cooperation that reflect our findings, including identifying innovative financing mechanisms, applying a One Health approach, and involving private sector stakeholders. Teerawattananon and colleagues<sup>##REF##35942957##3##</sup> agreed with Standley and Sorrell<sup>##REF##37579350##2##</sup> that external funders, including private-sector funders, may play a key role in any future initiative.</p>", "<p> Building on our review findings and to help inform ACPHEED operationalisation, we interviewed 23 senior-level experts in regional organisations or networks globally, on their experiences with operationalising such bodies.<sup>##REF##36962233##4##</sup> Interviewee opinions tallied with review findings, and those of Standley and Sorrell<sup>##REF##37579350##2##</sup> and Teerawattananon et al,<sup>##REF##35942957##3##</sup> highlighting governance and diplomacy, financing, capacity-building, stakeholder engagement, and multilateral agreements as key to encouraging effective operationalisation. Interviewees further emphasised the importance of a One Health approach,<sup>##REF##23221123##5##</sup> the need to clarify how effective regional collaborations are — including through routine monitoring and evaluation, and diverse financing options — including potential private-sector involvement.</p>", "<title>Where Next…</title>", "<p> ACPHEED establishment was agreed at the 15th ASEAN Health Ministers Meeting, in May 2022, with a November 2022 launch, and Japan committing US$ 50 million of financial support.<sup>##UREF##0##6##,##UREF##1##7##</sup> In April 2023, Japan reaffirmed its commitment of US$50 million to develop ACPHEED, citing this as a step toward addressing global public health risks and strengthening cooperation within ASEAN.<sup>##UREF##2##8##</sup> These steps are encouraging. Lessons from the COVID-19 pandemic on the importance of sharing data, working with both proximal and distal countries, and effective resource pooling, must be incorporated for networks like ACPHEED to be effective. A notable aspect of ACPHEED progress is the decision to devolve functionally into a tripartite structure with secretariat in Bangkok and detection, response, and risk management based in Vietnam, Indonesia, and Thailand. Further research on operationalising regional disease control cooperation and ongoing learning from ACPHEED’s development and governance will help ensure we are better prepared for the next pandemic.</p>", "<title>Acknowledgements</title>", "<p> We thank the original review team<sup>##REF##35042324##1##</sup> and authors of the two commentaries<sup>##REF##37579350##2##,##REF##35942957##3##</sup> for their relevant contributions to this discussion.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["6"], "mixed-citation": [" Nikkei Asia. ASEAN Opens Secretariat for Medical Emergencies in Thailand. 2022. "], "uri": ["https://asia.nikkei.com/Politics/ASEAN-opens-secretariat-for-medical-emergencies-in-Thailand"]}, {"label": ["7"], "mixed-citation": [" Japan-ASEAN Integration Fund. ASEAN Centre for Public Health Emergencies and Emerging Diseases (ACPHEED). 2020. "], "uri": ["https://jaif.asean.org/whats-new/asean-center-for-public-health-emergencies-and-emerging-diseases-acpheed/"]}, {"label": ["8"], "mixed-citation": [" Vietnam Plus. Japan Pledges 50 Million USD Investment for ASEAN Public Health Centre. 2023. "], "uri": ["https://en.vietnamplus.vn/japan-pledges-50-million-usd-investment-for-asean-public-health-centre/251748.vnp"]}]	{ "acronym": [], "definition": [] }	8	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 6; 12:8200	oa_package/49/32/PMC10590243.tar.gz
PMC10590244	0	[ "<title>Background</title>", "<p> High intake of foods containing elevated levels of saturated fat, free sugars and salt is associated with increased prevalence of non-communicable diseases such as obesity, cardiovascular disease and type-2 diabetes which is costly to society and individuals.<sup>##UREF##0##1##</sup> The greatest burden of disease falls upon families experiencing socioeconomic disadvantage and the COVID-19 pandemic has exacerbated existing inequalities, doubling the deprivation gap in childhood obesity.<sup>##UREF##1##2##</sup> Such inequalities result from intergenerational patterning of environmental, social, economic and behavioural determinants of dietary quality.<sup>##UREF##2##3##,##REF##32249325##4##</sup> Government regulation is one of the most efficient, cost-effective, and far-reaching ways to change the food infrastructure which may positively contribute towards the health of individual consumers.<sup>##REF##25703111##5##</sup></p>", "<p> From October 1, 2022, the UK Government implemented legislation restricting the prominent placement (ie, store entrances, aisle ends, and checkouts) of high fat salt and sugar (HFSS) products in retail outlets and their online equivalents.<sup>##UREF##3##6##,##UREF##4##7##</sup> Plans to restrict multi-buy promotions on HFSS products have been delayed until October 2025 due to economic pressures on families and businesses as the cost of living increases.<sup>##UREF##5##8##</sup> To our knowledge, this comprehensive legislation is one of the first in the world to restrict where retailers can position less healthy food products and forms part of the UK government’s strategy to tackle childhood obesity.<sup>##UREF##6##9##</sup> Marketing strategies such as prominent product placement and price promotions are commonly used to promote less healthy food which in turn influences consumers’ choices and purchasing behaviours.<sup>##REF##31633289##10##,##UREF##7##11##</sup> There is increasing scientific evidence to demonstrate that healthier placement initiatives can shift food sales to be more nutritious, proving support for this government action.<sup>##REF##32483615##12##,##REF##29868912##13##</sup></p>", "<p> The healthfulness of retail settings can be determined using tools that assess the in-store environment by measuring the availability, price, promotions, placement, variety, quality, and/or nutrition information on a selection of healthy (eg, fruit, vegetables, high fibre cereals and breads, etc) and less healthy products (eg, crisps, confectionery, sugary drinks, white bread, processed meats etc).<sup>##UREF##8##14##</sup> These less healthy stores thereby compound existing inequalities in food choice because more socioeconomically vulnerable consumers have fewer psychosocial, financial and educational resources to protect them against unhealthy contextual cues.<sup>##UREF##9##15##, ####REF##27046234##16##, ##REF##27067035##17####27067035##17##</sup> Our previous qualitative work with women who shopped in less healthy discount stores,<sup>##REF##24200470##18##</sup> revealed that their intended shopping choices were frequently undermined by the prominent placement and promotion of unhealthy foods.<sup>##UREF##8##14##,##REF##34090410##19##</sup> The incoming placement and promotions legislation therefore has potential to reduce dietary inequalities.</p>", "<p> This is the first national legislation to restrict the promotion and placement of a number of different product categories and it is unknown how consumers will react, and what intended and unintended consequences it may have on their shopping practices. Understanding consumers’ perspectives will provide raw insights into adaptations they may make to their shopping behaviours or reveal whether further strategies to ensure public support are needed; these insights could inform effective implementation and uncover the potential public health impact the policy could have. Thus, rather than being driven by theory, this study adopted an inductive approach to understand consumers’ beliefs about the legislation’s potential impact. Furthermore, understanding the views of consumers themselves about who is responsible for healthy eating (ie, individuals, government, businesses) could also provide insight into factors influencing the acceptability and effectiveness of this incoming legislation. Using a sample of women who shopped at less healthy supermarkets, this qualitative study aimed to answer the following research questions: (<italic toggle=\"yes\">a</italic>) what impact do consumers think the food placement and promotion legislation is likely to have on food shopping behaviours? (<italic toggle=\"yes\">b</italic>) who do consumers believe is responsible for healthy eating?</p>" ]	[ "<title>Methods</title>", "<title> Setting and Ethics</title>", "<p> This study forms part of the process evaluation activities of the WRAPPED (Women’s Responses to Adjusted Product Placement and its Effects on Diet) study which is a natural experiment conducted in collaboration with a UK discount supermarket chain. WRAPPED utilises a prospective matched controlled cluster design to examine the impact of improved product placement of healthy foods in stores on the purchasing and dietary patterns of women and their young children.<sup>##UREF##10##20##</sup> The intervention involved increasing the availability of fresh fruit and vegetables, and placing them towards the front of stores. A control store was matched to each intervention store with improved layout on the basis of: (<italic toggle=\"yes\">i</italic>) sales profile, (<italic toggle=\"yes\">ii</italic>) customer profile, and (<italic toggle=\"yes\">iii</italic>) neighbourhood deprivation (index of multiple deprivation, IMD)<sup>##UREF##11##21##</sup> and was distanced at least 20 miles from an intervention store to reduce contamination of data. Discount supermarkets were chosen as the setting for this study because they typically have less healthy in-store environments than mid-range and premium supermarkets, having poorer availability, pricing and placement of healthy foods, and favouring promotion of unhealthy foods.<sup>##UREF##8##14##</sup> This study abides by the Declaration of Helsinki, Research Governance Framework for Health and Social Care and Data Protection regulations. Reporting of this study follows Consolidated criteria for Reporting Qualitative research (COREQ) recommendations.<sup>##REF##17872937##22##</sup></p>", "<title> Participants</title>", "<p> A purposive sample of 40 participants from both intervention and control stores of the WRAPPED study were invited to take part in this qualitative study. Aligned with the study protocol, participants of the WRAPPED study were aged between 18-45 years, held a loyalty card at the collaborating discount supermarket, and had shopped in a study store during the 12 week period prior to recruitment. The sampling frame aimed to include approximately equal representation from the WRAPPED intervention and control stores, north and south English regions, low and higher education levels, and households with and without young children. Information about demographic characteristics was collected, including participants age, ethnicity, marital status, neighbourhood deprivation (IMD), living with children, employment status and money spent on groceries each week. Educational attainment was used as a proxy for socioeconomic status asit is one of the strongest markers of dietary quality,<sup>##UREF##12##23##</sup> shapes other socio-demographic markers including employment status, job type and income<sup>##UREF##13##24##</sup> and higher educational attainment can help protect against exposure to unhealthy supermarket environments.<sup>##REF##27067035##17##</sup> Invitation letters were sent by post and an incentive (£10 voucher) was offered. Interested participants contacted the research team to schedule a telephone interview. Two women (not study participants) aged between 18 and 45 years, who shopped at the collaborating discount supermarket and held a store loyalty card were recruited to our WRAPPED Patient and Public Involvement (PPI) panel via targeted Facebook adverts. They provided valuable insight to the design, methods and interpretation of findings throughout the WRAPPED study.<sup>##UREF##10##20##</sup></p>", "<title> Interviews</title>", "<p> The semi-structured interview guide (see ##SUPPL##0##Supplementary file 1##) was devised to ask questions about (<italic toggle=\"yes\">i</italic>) shopping habits during COVID-19, (<italic toggle=\"yes\">ii</italic>) participants’ experiences of how retail promotions and placement strategies influence their food choices and perceptions of the food (placement and promotion) legislation, and (<italic toggle=\"yes\">iii</italic>) beliefs about government, retailer, and individual responsibility for healthy eating. Participants responses to the questions regarding experiences of retail promotions and placement strategies were asked to orientate participants to the topic area of interest in this study. These data were not specifically analysed in this study because we have previously published data describing such lived experience.<sup>##REF##34090410##19##</sup> Therefore, the analyses in this paper focused on questions related to perceptions to the incoming government regulation and responsibility for healthy eating. The full interview schedule was pilot tested with our WRAPPED PPI representatives after which minor edits were made to the wording of questions. Using a semi-structured interview guide allowed topics of interest to be explored systematically and comprehensively, while still enabling participants to direct the discussion and raise specific issues relevant to them.<sup>##REF##32148704##25##</sup> Interviews were conducted by phone and audio-recorded following participant’s consent. All interviews were conducted by PD, a registered public health nutritionist with over 10 years’ experience in health research. Some participants may have spoken to PD during WRAPPED outcome data collection but for most participants this was their first interaction with her.</p>", "<title> Thematic Analysis </title>", "<p> After removing all personal details, audio-recordings were transcribed verbatim. The data were analysed using inductive thematic analysis and guided by the research questions exploring likely impact of legislation on food shopping behaviours and responsibility for healthy eating.<sup>##UREF##14##26##</sup> SM, a psychologist with over 15 years’ experience conducting qualitative analysis, identified the initial themes. SM had little prior knowledge of consumer shopping styles and food policy. Each transcript was read for familiarisation and a summary of main points made by each participant was used to create initial codes. Using Microsoft Excel, key points were collated into broad, overarching themes relating to: shopping style, acceptability of legislation, impact of legislation, and suggestions for change. The Excel spreadsheet became refined over time to include quotes that related to emerging sub themes. The spreadsheet had a row of data for each participant which also included columns indicating education attainment, control or intervention group and weekly shopping budget (categorised as very high, high, average, low, very low based on comparisons to the national average). This approach allowed for comparison of themes to be made against these participant characteristics. Overarching themes were then reviewed and analysed in detail to understand nuances in meaning and were discussed at length by PD, SM, and CV before the final themes were agreed. SM and PD each reanalysed 10% of the transcripts and discussed any disagreements – these required only small changes to theme descriptions for clarity. The final themes and interpretation of these themes, including relationships between them, were discussed with our PPI representatives.</p>" ]	[ "<title>Results</title>", "<p> A total of 34 women expressed interest and consented to participate. They were interviewed in May 2020 and there were no dropouts; interviews lasted between 17 and 48 minutes (mean = 32 minutes). Slightly more participants (62%) were from the WRAPPED control stores<sup>##UREF##10##20##</sup> and were in paid employment (57%) and half had no educational qualifications beyond those attained at age 16 years (##TAB##0##Table##). Medians and interquartile ranges are provided for age and pounds spent per week on food. Percentages are provided for all other variables. Differences in medians for non-normally distributed continuous variables (age, educational qualifications, IMD decile and money spent on food per week) were assessed using Mann-Whitney rank sum tests. Differences in percentages for categorical variables (ethnicity, marital status, employment status, and living with children) were assessed using chi-squared tests. Median (interquartile range, IQR) participant age was similar in the control group (35.7 [31.7, 39.1] years) and intervention group (35.9 [32.4, 39.7] years), <italic toggle=\"yes\">P</italic> =.45. In the control group 76% of women were of white ethnicity, compared to 85% of women in the intervention group (<italic toggle=\"yes\">P</italic> =.56).</p>", "<p> Five core themes were identified in relation to the research questions: three related to the first question and two related to the second. No differences in views by demographic characteristics were identified in the thematic analysis. Each of these themes are discussed in detail below, accompanied by illustrative participant quotes. Details of whether participants were from the control (Cont) or intervention (Int) stores and low (LE) or higher (HE) education level are indicated.</p>", "<title> Research Question 1: What Impact Do Consumers Think the Food Placement and Promotion Legislation Is Likely to Have on Food Shopping Behaviours ?</title>", "<title> Theme 1: The legislation is acceptable, but people can still (and should be able to) buy HFSS items if they want them. </title>", "<p> Most participants responded positively to the legislation, believing it would help improve population health and address obesity by encouraging people to make healthier food choices. Participants believed that fewer promotions on HFSS items would make them less appealing, reduce pressure from children and other family members, and discourage customers from buying more HFSS items than they had planned to.</p>", "<p> “<italic toggle=\"yes\">I think the intent is good so that it discourages people from buying, especially the location bit like sometimes they buy it because they can see it […] if there’s no promotion at all then I guess we will be forced to reduce our spending on unhealthy food which may be a good thing</italic>” (P6280, Int, HE).</p>", "<p> “<italic toggle=\"yes\">I think it is good. I think they should restrict it […] if they are trying to get everyone to be healthier then they shouldn’t be putting things on the shelves, or you know at the end of tills or at the front to encourage people to eat that bad thing</italic>” (P6297, Cont, LE).</p>", "<p> Some participants felt less positive about the legislation, believing the government should not be interfering, or expressed concerns about the effectiveness of the legislation given that consumers were still able to buy HFSS products in-aisle or from other retailers.</p>", "<p> “<italic toggle=\"yes\">I’m kind of split because in a way government should butt out, what people pick is their own choice. But in another way with obesity epidemics and obesity in children and stuff like that I would probably say yeah great, so it’s a split one that one</italic>” (P6298, Cont, HE).</p>", "<p> “<italic toggle=\"yes\">I think its nanny state, I think it’s ridiculous. I just think if people want to buy the high fat, the high sugar foods people will buy them anyway so leave them to it</italic>” (P6275, Cont, LE).</p>", "<title> Theme 2: The legislation is likely to have more impact on shoppers who do not plan their shopping.</title>", "<p> Participants discussed their shopping styles and practices, which highlighted a likely differential impact of the legislation according to various shopping behaviours. Some participants described approaching their food shopping in a very conscious, planned manner which involved checking ingredients at home, meal planning and following a shopping list. Participants who planned before food shopping described making fewer impulse purchases or overbuying. Planning food shopping was often associated with participants sticking to a diet plan (eg, Slimming World), health being important to them or to accommodate a tight budget. However, some planned shoppers on universal credit reported buying unhealthy meal deals and predominantly freezer food which is suggestive of having a poor dietary pattern.</p>", "<p> “<italic toggle=\"yes\">I come up with kind of ideas for meals for the week and make a list of all the ingredients I would need […] I actually just look for the product so it’s a specific thing that I’m looking for so I will just look for that item no matter, you know regardless of where it’s placed. I think that’s the difference I’ve found from you know browse shopping to actual like target shopping if that makes sense</italic>” (P6266, Int, HE).</p>", "<p> “<italic toggle=\"yes\">I have to buy and survive for the month so normally I know what I’m going in for, I get it and I go</italic>” (P6282, Int, LE).</p>", "<p> Women who planned their food shopping reported that the legislation will have limited impact on their food choices. These consumers will still buy some HFSS products as treats, in moderation but the restrictions on the marketing of these foods is likely to have little impact on them.</p>", "<p> “<italic toggle=\"yes\">I don’t think it [legislation] will affect my shopping habits like I do buy them, but it is not something we sit and eat all the time, it is given to the kids as a treat, so I mean unless you cannot buy them at all I don’t think it is really going to affect me</italic>” (P6302, Cont, LE).</p>", "<p> Families who plan their shopping to a very tight budget do use price promotions, but these are consciously planned by comparing deals across supermarkets and visiting multiple retailers to buy deals or occasionally buy more-expensive branded products. Those with larger families and who rely on promotional strategies, felt they were likely to be impacted negatively by the legislation.</p>", "<p> “<italic toggle=\"yes\">I always look for good brands, a good brand but on rollback. I feel then that I’ve got a quality product. My aim is to get as much as I can for spending less. To make the money go further as a family</italic>” (P6054, Int, HE).</p>", "<p> “<italic toggle=\"yes\">If it’s [HFSS products are] too expensive obviously with having so many of them [5 children] then I don’t buy it. So yeah, it’s going to [affect] parents that rely on those mulitbuys and promotions and stuff like that</italic>” (P6298, Cont, HE).</p>", "<p> In contrast, participants who did not plan their shopping reported being more likely to be tempted by items in prominent locations and choose foods simply because they were on promotion. Women who did not plan their food shopping are likely to be positively impacted by legislation.</p>", "<p> “<italic toggle=\"yes\">Yeah, I’m a sucker for that, I do buy promotion stuff like two for one and stuff. When you go straight through the door and you see it then you think oh that’s a good deal and then just pick it up and put it in the trolley and then when you get to the till you see the stuff there, then you just pick that up as well” </italic>(P6314, Cont, LE).</p>", "<title> Theme 3: Affordability of healthy food is just as, or more, important than the legislation.</title>", "<p> Some participants expressed concern about the affordability of products for those who are accustomed to regularly buying items on promotion or that the money previously saved by consumers would now add to retailers’ profits.</p>", "<p> “<italic toggle=\"yes\">There’s a lot of people that look out for promotions, because a lot of people can’t afford them in the first place. So that’s their way of making something last them longer or buying probably twice at one time because they might not be able afford it the following week</italic>” (P6030, Int, HE).</p>", "<p> “<italic toggle=\"yes\">So instead of the savings being you know sent back down to the customer it’s going to just be money in the pocket of the Corporations isn’t it</italic>” (P6266, Int, HE).</p>", "<p> Participants also felt the legislation would have greater impact on population health if it was implemented in conjunction with increased promotion and reduced cost of healthier options, particularly fruit and vegetables. Many women commented that healthy foods were considerably more expensive than unhealthier options which restricted their ability to follow a healthy diet and made it easier to choose HFSS products.</p>", "<p> “<italic toggle=\"yes\">No point in them [Government] discouraging the non-healthy food when the healthy food prices are going really really high</italic>” (P6301, Cont, LE).</p>", "<p> “<italic toggle=\"yes\">I do strongly believe the government should actually keep the price of higher sugar and fat foods higher and the healthier food should be lower in price. Because at the moment it’s the opposite and that’s why a lot of people are finding it easier to just eat the bad food and that’s how we have a lot of obesity cases because it is cheaper to be bigger than slimmer</italic>” (P6303, Cont, HE).</p>", "<p> Participants also commented that cheaper HFSS products last longer and can be used for snacks throughout the week compared to more expensive healthier products which may comprise only a single, family snack. Women stated that the price of healthier food needed to be reduced and suggested that supermarkets offer more price promotions and permanent price reductions on fruits, vegetables, and healthier snacks to encourage long-lasting dietary change and allow parents to regularly buy these options for their children.</p>", "<p> “<italic toggle=\"yes\">I do feel with the crisps and snacks you do get more for less so obviously it does stretch out […] A punnet of strawberries can be £3, and they last one day. Whereas a packet of crisps can last all week</italic>” (P6302, Cont, LE).</p>", "<p> “<italic toggle=\"yes\">I find it frustrating that the unhealthy food are the cheaper ones and that I could buy rubbish for nothing and that I have to invest in making healthier choices. For mothers who simply don’t have the money it’s a choice between that, or putting gas and electricity on, and that’s a horrible position to be in</italic>” (P6101, Cont, HE).</p>", "<title> Research Question 2: Who Do Consumers Believe Is Responsible for Healthy Eating? </title>", "<title> Theme 4: It’s up to the individual to eat healthily: the importance of consumer autonomy.</title>", "<p> Participants, regardless of education level or budget, consistently expressed the view that consumers are ultimately responsible for what they choose to buy and eat. Many stated that it is their own decision whether or not they make healthier or unhealthier choices.</p>", "<p> “<italic toggle=\"yes\">You chose what you want to buy. No one is forcing you to have it regardless of the marketing. As an adult you are fully aware of what you are choosing to put in the trolley and pay for</italic>” (P6302, Cont, LE).</p>", "<p> “<italic toggle=\"yes\">If you’re paid monthly and you’re coming to the end of that month and you’ve got nothing, that’s your problem, you should’ve budgeted better</italic>” (P6275, Cont, LE).</p>", "<p> “<italic toggle=\"yes\">I think the onus has to be on the person really, the individual themselves to make that decision [to buy healthier foods], the shops at the end of the day are a business they want to make a profit</italic>” (P6039, Cont, HE).</p>", "<p> The strong belief that participants had about the importance of consumer autonomy meant they felt there was a limit to how extreme government intervention could be.</p>", "<p> “<italic toggle=\"yes\">I don’t think the government can police, or be legislative about the choices that people make, but they can encourage a culture where we value health and wellbeing, where we are encouraged to take our own individual responsibility which includes keeping as healthy as possible for the NHS</italic>” (P6101, Cont, HE).</p>", "<p> “<italic toggle=\"yes\">The government and all shops can do all the help and offer it to everybody but if people don’t want to do it there’s nothing, they can do but I think they should just try and put the healthy foods out there</italic>” (P6282, Int, LE).</p>", "<title> Theme 5: Government and retailers can better support consumers to make healthy choices.</title>", "<p> Although participants held strong views about personal responsibility for food decisions, they also made suggestions for how supermarkets and government could support them to make healthier choices. The difference in price between healthy and less healthy foods was raised again. While some participants believed that individuals are responsible for ensuring they budget appropriately to be able to afford healthy food as discussed in theme 4, many other participants felt that supermarkets were responsible for ensuring healthy food was affordable or that governments could offer incentives/vouchers to guarantee healthy foods are accessible for all consumers.</p>", "<p> “<italic toggle=\"yes\">By making it (healthier food) a lot more cheaper and a lot more special offers, and if they’re families then they (government) could always offer them like vouchers or something to help promote them to eat healthy…” </italic>(P6303, Cont, HE).</p>", "<p> Participants were pleased with government’s actions on taxing sugary drinks and felt that reduced promotion of less healthy foods and increased promotion of healthy products in advertising, media and at bus stops was needed.</p>", "<p> “<italic toggle=\"yes\">I think it’s good that they brought in things like the sugar tax and that sort of thing. I think there should be tax on unhealthy things, I think there should be tax on alcohol, cigarettes, sugar, takeaways, and that sort of things because that would encourage people to maybe not buy them as much” </italic>(P6308, Cont, LE).</p>", "<p> “<italic toggle=\"yes\">Like they did with the sugar they put it up in price and I think they should put the unhealthier stuff up in price slightly. Then that would encourage people to then eat healthier. And have not so many adverts on the television, regarding unhealthy stuff” </italic>(P6306, Int, HE).</p>", "<p> Other suggestions for how supermarkets could better support healthier choices included moving fruit, vegetables, healthier snacks, and healthy meal ingredients to prominent locations in place of HFSS products, having price promotions on healthy meal options, and co-locating healthy options with standard/unhealthy products.</p>", "<p> “<italic toggle=\"yes\">I think by putting the healthier things nearer the front would help, because some people might only be nipping in for a couple of things” </italic>(P6054, Int, HE).</p>", "<p> “<italic toggle=\"yes\">I think they should try and put better promotions on the healthy foods” </italic>(P6285, Cont, HE).</p>", "<p> “<italic toggle=\"yes\">I think they could do more deals at the end of the aisles instead of it being chocolate and cakes” </italic>(P6101, Int, HE).</p>" ]	[ "<title>Discussion</title>", "<title> Principal Findings</title>", "<p> Participants in the current study were generally positive about the incoming legislation and the impact it could have on reducing impulse buying of HFSS and improving population health. However, they also provided insight into a number of potential unexpected consequences of the legislation which have important implications for its effectiveness, evaluation, and acceptability. In particular, participants described: (<italic toggle=\"yes\">i</italic>) that the unaffordability of healthier foods could undermine the legislation’s benefits and be detrimental for low-income families, (<italic toggle=\"yes\">ii</italic>) differential impact of regulation according to shopping styles/practices (ie, planned vs unplanned food choices), and (<italic toggle=\"yes\">iii</italic>) because consumers have autonomy in their food choices and HFSS items will still be available to buy, many may simply change their journey through the shopping environment and not alter their purchasing patterns. Participants suggested ways in which both retailers and the government could support consumers in making healthier purchases.</p>", "<title> Comparison With Previous Literature</title>", "<p> Women participating in this study generally expressed their support for the incoming legislation to limit the prominent placement and promotion of HFSS products in retail outlets, although some believed it threatened individuals’ freedom to make food choices. These findings are similar to research conducted with parents of young children following the introduction of UK Soft Drinks Industry Levy in 2018, a volume tax based on the sugar concentration of non-alcoholic drinks.<sup>##REF##31919006##27##</sup> A large international survey conducted across five counties revealed that public support for supermarket placement and availability interventions in the United Kingdom was moderate compared to the four other countries (Australia, the United States, Canada, and Mexico).<sup>##REF##31477071##28##,##UREF##15##29##</sup> Survey responses from the United Kingdom showed the greatest public support for subsidies to reduce the price of fresh fruit and vegetables and for initiatives increasing the availability/shelf space of healthier options.<sup>##REF##31477071##28##,##UREF##15##29##</sup> Furthermore, socioeconomically disadvantaged families were less likely to favour legislative nutrition policies than more affluent participants. This finding may be attributed to the perception that these interventions limit individual choice and favour the narrative of individual responsibility for making healthier food decisions. Our study findings suggest that socioeconomic status may not predict support for legislative nutrition policies alone but the difference in results may relate to the qualitative approach used in the current study.</p>", "<p> This study also suggests that adopting a planned shopping style could be protective against in-store marketing strategies that promote HFSS products. Previous research indicates that meal planning is associated with a healthier diet and lower levels of obesity.<sup>##UREF##16##30##,##REF##25959448##31##</sup> Dubowitz et al demonstrated that poorer families who consistently used a shopping list have better quality diets and were less likely to experience unhealthy bodyweight than shoppers who did not plan their purchases.<sup>##REF##25959448##31##</sup> These findings suggest that while interventions to enhance meal-planning behaviours may be a tool for consumers to navigate unhealthy shopping environments, this approach requires consumers to be highly motivated.<sup>##UREF##17##32##</sup> For the participants of the current study, using a shopping list was motivated by being health conscious, wanting to reduce food waste and/or needing to adhere to a very restricted grocery budget.</p>", "<title> Policy and Research Implications </title>", "<p> Evaluation of the incoming legislation should be designed to assess possible unanticipated consequences due to differential shopping styles and affordability of healthier foods, some of which have been highlighted in this study. In particular, families most socioeconomically disadvantaged may be minimally affected by the legislation because of their strict adherence to shopping lists which are planned to enable their food budget to stretch as far as possible. However, the legislation may be highly effective among families who do not actively plan their shopping purchases. These differences in shopping practices could have implications for dietary inequalities, with those with the poorest quality diets receiving little benefit of the legislation without additional financial support. Most participants who reported low or very low grocery spend described planning their food shopping trips to achieve best value for their money. Although planning can be protective to navigate retail settings, it is not necessarily sufficient to support healthier consumption. The legislation is likely to be maximally effective if implemented alongside interventions that make fruit and vegetables more affordable and appealing, and ensure consumers have the time and resources required to plan, prepare, and cook healthier meals.<sup>##UREF##18##33##,##REF##25245799##34##</sup></p>", "<p> The higher price of healthy foods, compared to HFSS foods, was raised by many participants as a factor that could undermine effectiveness of the incoming legislation. Healthy food has been shown to cost more than unhealthy food per calorie and less money is spent on marketing healthy foods by businesses.<sup>##UREF##19##35##</sup> These factors make purchasing healthy foods restrictively expensive not an attractive option and not good value for lower income families. Recent research revealed that high fixed costs in the supply chain play a much greater role in the price of fruit and vegetables than the cost of other foods, meaning consumers buy approximately 15% fewer fresh fruit and vegetables than they would have if these retail market imperfections were removed.<sup>##REF##35353561##36##</sup> The economists conducting the study recommend the UK government introduce a 25% subsidy on fruit and vegetables to correct the market and improve population diet.<sup>##REF##35353561##36##</sup> Evidence shows that retailers can employ temporary price promotions and prominent placement of an expanded range of fruit and vegetables to improve population purchasing behaviours,<sup>##REF##35324919##37##,##REF##34491999##38##</sup> but further evidence of the effect of these strategies at a household and individual level and on inequalities is needed.<sup>##UREF##10##20##</sup></p>", "<p> Findings from this study and previous literature show that women who shopped at discount supermarkets attribute ultimate responsibility for healthy eating to themselves<sup>##REF##34090410##19##</sup> and do not recognise the powerful influence of food marketing practices and how they undermine personal choice. This sense of individual responsibility likely stems from the need to exercise autonomy over one’s life, including food choices. Autonomy is the capacity to make informed choices in relation to oneself and responsibility is the obligation to be answerable for one’s own actions.<sup>##UREF##20##39##</sup> Government policies and media narratives on obesity have previously adopted a neoliberalist approach to food policies which promotes a notion of free markets and individual responsibility for health instead of advocating government regulations on the food system.<sup>##REF##29546404##40##,##REF##34906093##41##</sup> In the recent UK Government Food Strategy,<sup>##UREF##21##42##</sup> there is recognition of a shared responsibility between industry, government and individuals but much of the focus remains on individual behaviour change, which is more difficult for individuals experiencing socioeconomic disadvantage. Public health advocates who are dedicated to addressing dietary inequalities argue that responsibility has to be proportionally attributed to consumers on the basis of their capacity to act.<sup>##UREF##22##43##</sup></p>", "<p> Consumers habitually shop in the same way and are also likely to have fewer time, financial or critical analysis resources to make informed decisions in the moment.<sup>##UREF##23##44##</sup> Furthermore, there is a need to raise awareness about the commercial determinants of diet among consumers.<sup>##REF##28619031##45##</sup> Increasing awareness in this way could boost public support for government policies and lead to changes in social norms for shopping behaviours. Civil society groups such as Sustain and Obesity Health Alliance are campaigning and calling for bold Government action<sup>##UREF##7##11##,##UREF##24##46##</sup> and academics can support these activities by conducting social experiments that explore values such as autonomy,<sup>##REF##30988478##47##</sup> and by improving how scientific evidence in this field is disseminated to the public.<sup>##UREF##25##48##</sup></p>", "<title> Strengths and Limitations</title>", "<p> To our knowledge this is the first study to explore consumers’ perspectives of the new promotion and placement legislation and to increase understanding of its potential impact before implementation. The findings can guide future evaluation of the legislation’s effectiveness and strategies to enhance public support for it. While equal numbers of participants from the intervention and control stores in the WRAPPED study were invited to take part in this qualitative study, greater numbers agreed from the control stores, however, no differences were seen in responses between participants from the intervention and control stores. Women of childbearing age were targeted in this study because they remain primarily responsible for household food-related responsibilities such as food shopping and cooking in many families.<sup>##UREF##26##49##</sup> It is, however, possible that men, women at other phases of the lifecourse have different perspectives on the potential impact of the incoming legislation and future research would benefit from engaging with a more diverse population sample. Nevertheless, the participants interviewed represent a valuable sample of women from both more and less disadvantaged backgrounds, northern and southern regions of England and with and without children. This study recruited women who shopped at the collaborating discount supermarket. Many women also reported shopping at other stores, however, those who shop exclusively from mid-range and premium supermarkets, or other store types, may have different perspectives to the participants of this study. Another limitation of this study is that the question guide focused on anticipated effects of the legislation on shopping in supermarkets whereas the incoming legislation affects all retail stores with more than 50 employees that sell HFSS products in prominent locations including franchises and symbol group convenience stores, and non-food retailers who sell HFSS products. The likely impact of the legislation in retail settings other than supermarkets should be assessed in future research. The timing of these interviews conducted was during the first wave of the COVID-19 pandemic; however, the results show this had little impact on participants’ perceptions of the likely promotions and placement restrictions. Participants were given the opportunity to reflect upon and discuss the impact of the COVID-19 lockdown on their shopping behaviours prior to moving to questions about retail marketing strategies and the incoming legislation. Participants shared both positive and negative views about the incoming legislation and their views were validated with representatives from the WRAPPED PPI panel.</p>" ]	[ "<title>Conclusion</title>", "<p> This study explored consumers’ perceptions of the likely impact of the incoming food placement and promotion legislation on their food shopping behaviours. While consumers were generally positive that the incoming legislation could reduce impulse buying of HFSS, they raised concerns that the high price of healthier foods could undermine the legislation’s benefits. Coupling the legislation with interventions to promote and reduce the costs of healthier products would go further to ensure its success. Furthermore, with the current cost of living crisis and the fact that those with the lowest food budgets tend to plan their shopping in detail, evaluations of the intended and unintended consequences of the legislation on health inequalities should explore the impact across a range of sociodemographic groups. Finally, initiatives to raise awareness about the influence marketing strategies have on consumer food choices, that play into consumer concerns for cost and autonomy, would be helpful to further increase consumer acceptance of, and support for, the legislation.</p>" ]	[ "<p>\n<bold>Background:</bold> As part of the childhood obesity strategy, the UK Government has introduced regulations to restrict the ways high fat salt and sugar (HFSS) products can be promoted in retail settings from October 2022. This study explored (<italic toggle=\"yes\">i</italic>) consumers’ views on the likely impact of the UK legislation restricting the placement and promotion of HFSS products on their shopping behaviours and (<italic toggle=\"yes\">ii</italic>) consumers’ beliefs about who is responsible for healthy eating.\n</p>", "<p><bold>Methods:</bold> Using a cross-sectional study design, qualitative semi-structured telephone interviews were conducted with a purposive sample of women who shopped at a discount supermarket. Thematic analysis was employed to identify key themes.\n</p>", "<p><bold>Results:</bold> Participants’ (n = 34) had a median age of 35 years and over half were in paid employment. Five themes were identified: (1) The legislation is acceptable, but people can still (and should be able to) buy HFSS items; (2) The legislation is likely to have more impact on shoppers who do not plan their shopping; (3) Affordability of healthy food is just as, or more, important than the legislation; (4) It’s up to the individual to eat healthily; and (5) Government and retailers can better support consumers to make healthy choices.\n</p>", "<p><bold>Conclusion:</bold> Most participants were optimistic about the incoming regulations and believed that it would support consumers to make healthier food choices. Many raised concerns, however, that the high price of healthy foods and continued availability of unhealthy foods within the stores could undermine the legislation’s benefits. Coupling the legislation with interventions to promote and reduce the costs of healthier products would go some way to ensure its success. Raising awareness about marketing strategies that play into consumer concerns for cost and autonomy could further increase acceptance of the policy.</p>", "<p>\n<bold>Citation:</bold> Dhuria P, Muir S, Lawrence W, et al. Women consumers’ views on legislation to restrict prominent placement and multibuy promotions of high fat, sugar, and salt products in England: a qualitative perspective. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7597. doi:10.34172/ijhpm.2023.7597</p>" ]	[ "<title>Acknowledgements</title>", "<p> We are grateful to the women who participated in this study and thank the dedicated team of research administrative staff especially Calum Shand, Julie Coleman, and Sue Curtis for their administrative support and contributions.</p>", "<title>Ethical issues</title>", "<p> This study was approved by the University of Southampton Faculty of Medicine ethics committee (Ethics ID: 20986.A6), and abides by the Declaration of Helsinki, Research Governance Framework for Health and Social Care and Data Protection regulations.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This research and the authors of this paper are supported by the following funding sources: National Institute for Health Research (NIHR) Public Health Research Programme (grant funding, 17/44/46), NIHR Southampton Biomedical Research Centre and the UK Medical Research Council (UKMRC). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, the UK Department of Health and Social Care or UKMRC.</p>", "<title>Supplementary files\n</title>" ]	[]	[]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table</label><caption><title>Participant Demographic Characteristics\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Characteristic</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Total</bold>\n<break/>\n<bold>(n = 34)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Control</bold>\n<break/>\n<bold>(n = 21)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Intervention </bold>\n<break/>\n<bold>(n = 13)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P</bold>\n</italic>\n<bold> Value</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Age (y), median (IQR)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">35.7 (31.7, 39.4)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">35.7 (31.7, 39.1)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">35.9 (32.4, 39.7)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.45</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">White ethnicity, % (n)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">79% (27)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">76% (16)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">85% (11)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.56</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Married, % (n)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">61% (19)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">67% (12)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">54% (7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.44</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Low education (no qualifications beyond age 16), % (n)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">50% (17)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">62% (13)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">31% (4)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.49</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Most deprived half of area deprivation (IMD), % (n)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">29% (10)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">29% (6)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">31% (4)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.58</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Paid employment, % (n)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">57% (19)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">55% (11)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">62% (8)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.71</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pounds (£) spent on food per week, median (IQR)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">70 (45, 100)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">70 (50, 100)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80 (40, 90)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.76</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Percentage (number) with children in the household</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">82% (27)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">83% (10)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">82% (27)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">.87</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>The unaffordability of healthier foods could undermine the high fat salt and sugar (HFSS) placement and promotion legislation’s benefits and be detrimental for low-income families. </p></list-item><list-item><p>Consumers believe in autonomy of their food choices, and many may continue to purchase the less healthy foods that are available. </p></list-item><list-item><p>Coupling the legislation with interventions to promote and reduce the costs of healthier products would go some way to ensure its success. </p></list-item><list-item><p>Families with the lowest food budgets tend to plan their shopping in detail, therefore evaluations of the legislation should assess impact across a range of sociodemographic groups and on health inequalities. </p></list-item><list-item><p>Implementing initiatives to raise consumer awareness about how marketing strategies restrict consumer choice and lead to increased spend on HFSS could help to increase consumer support for the policy. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> This study explored consumer’s perceptions towards the incoming food placement and promotion legislation and how it is likely to impact their food shopping behaviours. Most considered the legislation would reduce impulse buying of less healthy foods but acknowledged that the higher price of healthier foods could limit the benefits. Consumers who plan their shopping find it easier to buy fewer unhealthy foods and many may benefit from learning more about how marketing practices encourage unhealthy food choices.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Semi-structured Interview Guide – Consumers.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: IQR, interquartile range; IMD, index of multiple deprivation.</p><p> Mann-Whitney rank sum tests and chi-square tests.</p></fn></table-wrap-foot>" ]	[]	[ "<media xlink:href=\"ijhpm-12-7597-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" Henry Dimbleby. The National Food Strategy: An Independant Review for Government, Part 1. "], "uri": ["https://www.nationalfoodstrategy.org/part-one/"]}, {"label": ["2"], "mixed-citation": [" NHS Digital. National Child Measurement Programme, England 2020/21 School Year. "], "uri": ["https://digital.nhs.uk/data-and-information/publications/statistical/national-child-measurement-programme/2020-21-school-year"]}, {"label": ["3"], "mixed-citation": [" World Health Organization. Chapter 2, WHO European Regional Obesity Report. Regional Office for Europe; 2022. "]}, {"label": ["6"], "mixed-citation": [" Department of Health and Social Care. Tackling Obesity: Empowering Adults and Children to Live Healthier Lives. Department of Health and Social Care; 2020. "]}, {"label": ["7"], "mixed-citation": [" Department of Health and Social Care. The Nutrient Profiling Model. Department of Health and Social Care; 2011. "]}, {"label": ["8"], "mixed-citation": [" Gov.UK. PM backs public\u2019s right to choose with delay to BOGOF restrictions.\u2005"], "uri": ["https://www.gov.uk/government/news/pm-backs-publics-right-to-choose-with-delay-to-bogof-restrictions"]}, {"label": ["9"], "mixed-citation": [" Department of Health and Social Care. Childhood Obesity: A Plan for Action, Chapter 2. Department of Health and Social Care; 2018. "]}, {"label": ["11"], "mixed-citation": [" Obesity Health Alliance. Out of Place: The Extent of Unhealthy Foods in Prime Locations in Supermarkets. 2018. "], "uri": ["http://obesityhealthalliance.org.uk/wpcontent/uploads/2018/11/Out-of-Place-Obesity-Health-Alliance-2.pdf"]}, {"label": ["14"], "person-group": ["\n"], "surname": ["Black", "Ntani", "Inskip"], "given-names": ["C", "G", "H"], "article-title": ["Measuring the healthfulness of food retail stores: variations by store type and neighbourhood deprivation"], "source": ["Int J BehavNutr Phys Act"], "year": ["2014"], "volume": ["11"], "fpage": ["69"], "pub-id": ["10.1186/1479-5868-11-69"]}, {"label": ["15"], "person-group": ["\n"], "surname": ["Vogel", "Abbott", "Ntani"], "given-names": ["C", "G", "G"], "article-title": ["Examination of how food environment and psychological factors interact in their relationship with dietary behaviours: test of a cross-sectional model"], "source": ["Int J BehavNutr Phys Act"], "year": ["2019"], "volume": ["16"], "issue": ["1"], "fpage": ["12"], "pub-id": ["10.1186/s12966-019-0772-y"]}, {"label": ["20"], "person-group": ["\n"], "surname": ["Vogel", "Crozier", "Dhuria"], "given-names": ["C", "S", "P"], "article-title": ["Protocol of a natural experiment to evaluate a supermarket intervention to improve food purchasing and dietary behaviours of women (WRAPPED study) in England: a prospective matched controlled cluster design"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["2"], "fpage": ["e036758"], "pub-id": ["10.1136/bmjopen-2020-036758"]}, {"label": ["21"], "mixed-citation": [" Ministry of Housing, Communities & Local Government (MHCLG). English Indices of Deprivation 2019. London: MHCLG; 2019. "]}, {"label": ["23"], "person-group": ["\n"], "surname": ["Azizi Fard", "De Francisci Morales", "Mejova", "Schifanella"], "given-names": ["N", "G", "Y", "R"], "article-title": ["On the interplay between educational attainment and nutrition: a spatially-aware perspective"], "source": ["EPJ Data Sci"], "year": ["2021"], "volume": ["10"], "issue": ["1"], "fpage": ["18"], "pub-id": ["10.1140/epjds/s13688-021-00273-y"]}, {"label": ["24"], "person-group": ["\n"], "surname": ["Ross", "Wu"], "given-names": ["CE", "CL"], "article-title": ["The links between education and health"], "source": ["Am Sociol Rev"], "year": ["1995"], "volume": ["60"], "issue": ["5"], "fpage": ["719"], "lpage": ["745"], "pub-id": ["10.2307/2096319"]}, {"label": ["26"], "person-group": ["\n"], "surname": ["Braun", "Clarke"], "given-names": ["V", "V"], "article-title": ["Reflecting on reflexive thematic analysis"], "source": ["Qual Res Sport Exerc Health"], "year": ["2019"], "volume": ["11"], "issue": ["4"], "fpage": ["589"], "lpage": ["597"], "pub-id": ["10.1080/2159676x.2019.1628806"]}, {"label": ["29"], "person-group": ["\n"], "surname": ["G\u00f3mez-Donoso", "Sacks", "Vanderlee"], "given-names": ["C", "G", "L"], "article-title": ["Public support for healthy supermarket initiatives focused on product placement: a multi-country cross-sectional analysis of the 2018 International Food Policy Study"], "source": ["Int J BehavNutr Phys Act"], "year": ["2021"], "volume": ["18"], "issue": ["1"], "fpage": ["78"], "pub-id": ["10.1186/s12966-021-01149-0"]}, {"label": ["30"], "person-group": ["\n"], "surname": ["Ducrot", "M\u00e9jean", "Aroumougame"], "given-names": ["P", "C", "V"], "article-title": ["Meal planning is associated with food variety, diet quality and body weight status in a large sample of French adults"], "source": ["Int J BehavNutr Phys Act"], "year": ["2017"], "volume": ["14"], "issue": ["1"], "fpage": ["12"], "pub-id": ["10.1186/s12966-017-0461-7"]}, {"label": ["32"], "mixed-citation": [" Monroe J. You Don\u2019t Batch Cook When You\u2019re Suicidal. Cooking on a Bootstrap blog. "], "uri": ["https://cookingonabootstrap.com/2020/07/30/the-price-of-potatoes-and-the-value-of-compassion/#:~:text=Whenever%20food%20poverty%2C%20obesity%2C%20or,which%20way%20into%20the%20light"]}, {"label": ["33"], "mixed-citation": [" Harris J, de Steenhuijsen Piters B, McMullin S, Bajwa B, de Jager I, Brouwer ID. Fruits and vegetables for healthy diets: priorities for food system research and action. In: von Braun J, Afsana K, Fresco LO, Hassan MHA, eds. Science and Innovations for Food Systems Transformation. Cham: Springer International Publishing; 2023:87-104. "], "pub-id": ["10.1007/978-3-031-15703-5_6"]}, {"label": ["35"], "mixed-citation": [" Henry Dimbleby. The National Food Strategy: An Independant Review, The Plan. "], "uri": ["https://www.nationalfoodstrategy.org/"]}, {"label": ["39"], "mixed-citation": [" World Emergency COVID19 Pandemic Ethics (WeCope) Committee. Statement on Autonomy and Responsibility within a public health emergency. WeCope; 2020. "]}, {"label": ["42"], "mixed-citation": [" Department for Environment, Food & Rural Affairs. Government Food Strategy. Department for Environment, Food & Rural Affairs; 2022. "]}, {"label": ["43"], "person-group": ["\n"], "surname": ["Savona", "Thompson", "Smith", "Cummins"], "given-names": ["N", "C", "D", "S"], "article-title": ["Proportional responsibility versus individual responsibility for healthy eating: a complex systems analysis"], "source": ["Lancet"], "year": ["2017"], "volume": ["390 Suppl 3"], "fpage": ["S80"], "pub-id": ["10.1016/s0140-6736(17)33015-5"]}, {"label": ["44"], "person-group": ["\n"], "surname": ["Dieterle"], "given-names": ["JM"], "article-title": ["Agency and autonomy in food choice: can we really vote with our forks?"], "source": ["J Agric Environ Ethics"], "year": ["2022"], "volume": ["35"], "issue": ["1"], "fpage": ["5"], "pub-id": ["10.1007/s10806-022-09878-3"]}, {"label": ["46"], "mixed-citation": [" Sustain. "], "uri": ["https://www.sustainweb.org/what-we-do/"]}, {"label": ["48"], "mixed-citation": [" Bite Back 2030. The Video the Fast Food Industry Don\u2019t Want You to See. "], "uri": ["https://www.biteback2030.com/news/watch-video-fast-food-industry-dont-want-you-see"]}, {"label": ["49"], "mixed-citation": [" Food Standards Agency. The 2014 Food and You Survey. London: Food Standards Agency; 2014. "]}]	{ "acronym": [], "definition": [] }	49	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 10; 12:7597	oa_package/66/5f/PMC10590244.tar.gz
PMC10590249	0	[]	[]	[]	[]	[]	[ "<p>The paper by Guglielmin and colleagues<sup>1</sup> examines the implementation of Health in All Policies (HiAP) in a local government context in Kuopio Finland. The authors use a realist explanatory case study design to explore what has supported HiAP implementation with a focus on two specific hypotheses on what leads to success: common goals and committed leadership and staff. The paper is well argued using appropriate methodology and their findings support the importance of the success factors tested by their two hypotheses. However, the narrowed focus on just two hypotheses underrepresents the complexity of implementing HiAP at any level of government, including local government. Given its local government focus, the paper would have been strengthened by referencing the lessons gained from the Healthy Cities movement. Local government is a critical setting for action to address health and health equity and there is great potential to continue research that adds to the knowledge base on how to successful implement HiAP. Finally, it is important to acknowledge that Finland has a unique HiAP history. It is recognised as a global leader in the field, and the role of local government in Finland differs from many other countries. These factors may impact on the transferability of the case study findings.</p>", "<p>\n<bold>Citation:</bold> Williams C, Valentine N. Health in All Policies at the local level: what facilitates success?: Comment on \"A realist explanatory case study investigating how common goals, leadership, and committed staff facilitate Health in All Policies implementation in the municipality of Kuopio, Finland.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7975. doi:10.34172/ijhpm.2023.7975</p>" ]	[ "<p> Globally, there has been increasing movement within countries to apply approaches that increase healthy public policy, with the aim of delivering improved population health outcomes. Healthy public policy has long been recognised as an important lever for health systems, to use to influence the policy decisions made by governments, especially with agencies outside of heath. Public policy decisions of government have a significant impact on population health and wellbeing, as these decisions shape the distribution of the causes of the causes of disease, the underlying determinants of health and health equity.<sup>##UREF##0##2##</sup> Health sector actors need to engage with the policy decision-making process of government if they are to inform, influence and ultimately shape the policy decisions of other government agencies.<sup>##UREF##1##3##</sup> Working across government ministries, which tend to operate in vertical silos, is challenging. Health in All Policies (HiAP) is an approach that aims to support the health system to systematically engage in the policy making process of government.</p>", "<p> HiAP aims to support traditional areas of government programs and services such as education, urban planning and environmental health and safety. Importantly, HiAP aims to work beyond these areas to apply a health lens to public policy design on the issues that affect living, learning and work settings, such as the structure of the labour market, and how society deals with distributive mechanisms affecting access to basic resources needed for health and health equity. These policy areas have only been considered as “health” issues by a minority. The increasing evidence on the interconnections between human activity, population health, inequalities and the health of the planet (alongside the rise of well-being economic thinking<sup>##UREF##2##4##</sup>), is changing these perceptions, where the concept of healthy public policies is becoming more mainstream.</p>", "<p> There are advantages of working on HiAP at the local level.<sup>##REF##28334905##5##</sup> For example, in comparison to national and sub national governments, authorities working within local government operate in closer proximity to the community and are therefore better positioned to engage with their needs and respond to challenges and opportunities more actively.</p>", "<p> Governments systems tend to be constructed, in hierarchical vertical silos which is a key challenge for achieving healthy public policy outcomes and this is true regardless of the level of government national, sub-national or local. HiAP approaches lay out a framework of strategies, actions and processes designed to break through the siloed structures, both vertically and horizontally, and provide a bridge to the policy making process.</p>", "<p> The research to understand how HiAP approaches operate and what constitutes success is building. Much of the research has focussed at the state or national level, as Guglielmin and colleagues point out. Baum and colleagues undertook a 5-year evaluation of the South Australian HiAP approach and found a range critical factors that supported its implementation.<sup>##REF##30658616##6##</sup> In 2018, Shankardass and colleagues developed a framework for evaluating the implementation of HiAP that aims to take account to the complex political environment in which HiAP approaches operate called <italic toggle=\"yes\">HARMONICS</italic>. Guglielmin with Shankardass and colleagues have adapted this framework in the Kuopio Case Study.<sup>##REF##29544496##7##</sup></p>", "<p> A key observation put forward by the paper’s authors is that local government is an under-researched area in the HiAP field.<sup>##REF##28334905##5##</sup> While agreeing with this general point, it is also important to observe that documentation and research of HiAP at all levels, including the local level, is a growing area.<sup>##REF##28334905##5##</sup> There are several reports documenting cases studies and research on HiAP operating at the national and subnational levels of government. For example, the Global Status Report produced in 2019 by the Global Network for Health in All Policies documented 41 examples of HiAP practice at national, sub national and the local level, with 6 examples originating from the local level.<sup>##UREF##3##8##</sup> In the United States, the National Association of County and City Health Officials developed a report in 2017 on 14 local governments including from cities.<sup>##UREF##4##9##</sup></p>", "<p> In the academic literature there have been studies in Scandinavia and the Netherlands, examining HiAP of the local level, and these provide useful insights several of which are confirmed by the study by Guglielmin and colleagues.<sup>##REF##35247936##1##</sup></p>", "<p> Literature on HiAP is also increasing in the context of the World Health Organization (WHO) Healthy Cities movement, which has a long-standing history of working through the local level of government to improve health, wellbeing and equity. It is slightly surprising that the authors did not refer to these examples.</p>", "<p> In moving beyond descriptive studies to explanatory ones, to understand the mechanisms at play, mixed method evaluations are clearly needed, and the methodological efforts of Guglielmin et al<sup>##REF##35247936##1##</sup> are exemplary in this respect. The use of realist case study methods appears to be an appropriate way to research HiAP. HiAP initiatives operate in a highly political environment and are therefore difficult to research using traditional research methods.<sup>##REF##29037182##10##</sup> Case study methods offer the opportunity to unpack some of the activities in a detailed and sensitive manner. However, the research methods could have been strengthened by expanding the number of hypotheses and success factors under investigation. The HiAP approach supports actors and actor-groupings, who do not behave in predictable linear patterns, to work across organizational hierarchies, cultures, and disciplines to generate improved solutions to complex problems. As such it is itself complex intervention. Analytical frameworks using complexity concepts like structural and relational components affected by dynamic feedback loops can also enhance the framing of hypotheses.<sup>##REF##35219286##11##</sup></p>", "<p> The narrowing of the hypothesis to just two key hypotheses namely, (1) The existing of common goals between agencies and (2) that leadership and staff are committed to HiAP approach, limited the breadth of the case study. The authors decision to focus on just two key factors, despite evidence from the literature identifying multiple factors involved in successful HiAP implementation, is unclear. While the two hypothesises were informed from a scoping review of HiAP at the local government, the authors own argument that local government is under researched suggests that there will be limited evidence available. However, if they had expanded the scoping review to include all HiAP initiatives operating at the national, sub national level as well as the local level and from the healthy cities field, they will have identified a wider range of success factors that are considered instrumental in HiAP implementation. The reduction of success factors to just two key areas, narrows the results and limits the value of the case study paper.</p>", "<p> Through these two hypotheses, the authors in fact identify three important success factors – “strong supporting evidence for the hypotheses that having common goals between sectors, and that local leadership and committed staff, facilitate intersectoral work for health.” These three factors are also mentioned in the new WHO HiAP model, along with other important factors. While these success factors align with other research on the implementation of HiAP, they do not cover all the conditions required for successful HiAP implementation. For example, the accountability and governance processes and structures that are needed to enable cross sector collaboration, the finances and budget and skills required to work collaboratively. The authors point out the importance of the context. Part of that context is the importance of the culture within organisations and governments that make collaborating possible.<sup>##UREF##5##12##</sup></p>", "<p> These additional HiAP success factors are documented in the new HiAP 4 Pillars Model being put forward in a publication of the WHO for testing and refinement by practices in countries.</p>", "<p> In summary, the new HiAP model:</p>", "<p>outlines the organizational structures and mechanisms required to build collaboration; </p>", "<p>acknowledges the social determinants of health framing and the structural drivers of health inequity to frame the scope of policies and inclusion of the equity goal; </p>", "<p>applies to any public policy and/or health issue that requires multisectoral collaboration; </p>", "<p>is adaptable and relevant to different countries and political contexts; </p>", "<p>promotes the sustainability of a HiAP approach and its focus on public value; and </p>", "<p>connects HiAP to achievement of the Sustainable Development Goals, sustainability, and social development with equity. </p>", "<p> The New HiAP Model has at the centre, the “four pillars” and these focus on the functions and capacities needed to apply a collaborative HiAP approach.<sup>##UREF##6##13##</sup> Many of these functions are relevant to sustaining multisectoral collaboration regardless of the issue of focus or the level of government and they include supporting common goals, committed leadership and staff, proven success features in the Kuopio study.</p>", "<p> HiAP operates within the political and policy decision-making environment of governments and in these circumstances context matters. It was important that the authors acknowledged the special context of Finland, especially its political and social history of egalitarianism and social democracy. In addition, the authors identify the socio-economic circumstances of Kuopio as a high social economis status municipal area, with a history of collaboration and intersectoral action. Finland is also recognised as a global leader in the field of HiAP and the commitment from the Finnish government to health, wellbeing and equity is longstanding and nonpartisan. This unique history provides important background that may make implementing HiAP approaches smoother in the Finnish context. The autonomy and responsibility given to local governments in the Finnish context may be less transferable to many other countries, and so it would have been helpful if it was also emphasised.</p>", "<p> Finally, it would have been interesting if the case study methods could have been extended to a second and /or third Finnish local government area, perhaps including one that has a large low social economis status population. If the findings were consistent across these different local government areas, the generalisability of the findings would be strengthened, which may increase the potential for the findings to be transferable globally. Furthermore, the inclusion of equity-related values that enable explicit comparison between Kuopio and another municipality, would be interesting. In other Scandinavian countries, the difficulty of evidence on health and determinants inequalities at the local level has been raised as a barrier to action.<sup>##REF##28077033##14##</sup></p>", "<p> The paper “A realist Explanatory Case Study Investigating How Common Goals, Leadership and committed Staff, Facilitate Health in All Policies in the Municipality of Kuopio Finland” is a useful addition to the evidence base on how to successfully implement healthy public policy approaches such as HiAP within a local government context. Increasing HiAP action at the local government level offers strategic opportunities to influence the health and wellbeing of local communities across the globe, through informing, influencing and shaping the public policy decisions of local government decision-makers.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "mixed-citation": [" Wilkinson RG, Marmot M. Social Determinants of Health: The Solid Facts. 2nd ed. Geneva: WHO Regional Office for Europe; 2003. "]}, {"label": ["3"], "mixed-citation": [" World Health Organization, Government of South Australia. Adelaide Statement II (2017) on Health in All Policies. Adelaide: World Health Organization, Government of South Australia; 2019. "]}, {"label": ["4"], "person-group": ["\n"], "surname": ["McGregor", "Pouw"], "given-names": ["JA", "N"], "article-title": ["Towards an economics of well-being"], "source": ["Cambridge J Econ"], "year": ["2017"], "volume": ["41"], "issue": ["4"], "fpage": ["1123"], "lpage": ["1142"], "pub-id": ["10.1093/cje/bew044"]}, {"label": ["8"], "mixed-citation": [" Global Network for Health in All Policies, Government of South Australia. Global Status Report on Health in All Policies. Adelaide: Global Network for Health in All Policies, Government of South Australia; 2019. "], "uri": ["https://actionsdg.ctb.ku.edu/wp-content/uploads/2019/05/HiAP-summary-v5-final-SPREADS.pdf"]}, {"label": ["9"], "mixed-citation": [" National Association of County and City Health Officials (NACCHO). Health in All Policies- Experiences from Local Health Departments. Washington, DC: NACCHO; 2017. "], "uri": ["https://www.naccho.org/uploads/downloadable-resources/NACCHO-HiAP-Report_Experiences-from-Local-Health-Departments-Feb-2017.pdf"]}, {"label": ["12"], "mixed-citation": [" St\u00e5hl T, Koivusalo M. Health in all policies: concept, purpose, and implementation. In: Haring R, Kickbusch I, Ganten D, Moeti M, eds. Handbook of Global Health. Cham: Springer; 2022. "], "pub-id": ["10.1007/978-3-030-05325-3_80-1"]}, {"label": ["13"], "mixed-citation": [" World Health Organization (WHO). Working Together for Equity and Healthier Populations: Sustainable Multisectoral Collaboration Based on Health in All Policies Approaches. Geneva: WHO; 2023. "]}]	{ "acronym": [], "definition": [] }	14	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 21; 12:7975	oa_package/1f/04/PMC10590249.tar.gz
PMC10590250	0	[]	[]	[]	[]	[]	[ "<p>A rigorous evaluation of the implementation of a diabetes quality measure implementation program across community healthcare clinics in Shanghai, China, where both quality measurement and primary care delivery are relatively recent but centrally supported, identified important concerns about the meaningfulness, feasibility, and accuracy of quality measures that are relevant to all quality measurement programs. These include the importance of stakeholder involvement in measure development and implementation, the need to select measures that accurately and reliably reflect care quality, the link between incentives for improved performance and data manipulation, the necessity for scientific credibility and practical feasibility of the measure, and the assurance that measure performance can be impacted by those being evaluated. In addition to elaborating on these aspects of quality measurement, we also discuss the need for quality measures that are balanced across established domains of quality, are not burdensome to participants, and are transparent, parsimonious, nimble, and oriented around continuous evaluation and improvement.</p>", "<p>\n<bold>Citation:</bold> Matulis JC 3rd, McCoy RG. Quality measurement as a path to high quality care: Comment on \"Quality and performance measurement in primary diabetes care: a qualitative study in urban China.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7884. doi:10.34172/ijhpm.2023.7884</p>" ]	[ "<p> The increasing incidence and prevalence of diabetes is a threat to advances in life expectancy and quality of life. In 2019, 463 million people were living with diabetes worldwide (9.3% of the world adult population), with the prevalence expected to rise to 700 million people (10.9% of the world adult population) by 2045.<sup>##REF##31518657##1##</sup> The morbidity, disability, and mortality associated with diabetes stem from its many complications: acute complications of severe hypoglycemia and hyperglycemia (ie, diabetic ketoacidosis, hyperglycemic hyperosmolar state) and chronic complications of cardiovascular disease, kidney disease, neurological complications, amputations, retinopathy/blindness, and among others. The risk of these complications can be mitigated through optimal glycemic control. Accordingly, health systems, professional societies, and regulatory bodies worldwide have focused extensively on systems and processes which support timely and effective control of hyperglycemia on both individual and population levels. Quality measurement is essential and foundational to all such efforts.</p>", "<p> That one might endeavor to measure the care that is provided, as well as the outcomes that flow from that care is intuitive. For over a century, the concept of measuring different aspects of care, sharing those measurements with patients, and allowing patients to select “high quality” physicians, has been considered a fundamental component of building a better healthcare system. Pioneers such as Ernest Codman began measuring healthcare outcomes in the 1910s,<sup>##REF##12078360##2##</sup> while the concept of assessing and measuring the discrete structures, processes, and outcomes of healthcare through the lens of the Donabedian model was described in the 1960s.<sup>##UREF##0##3##,##REF##3045356##4##</sup> In today’s healthcare environment, quality measurement is pervasive, both in the United States and around the world.</p>", "<p> Despite the widespread acceptance of quality measurement, important questions remain on what actually comprises high quality care, including how individual and societal preferences may influence the perception of quality, and how structural and social determinants of health, among many other factors, need to be considered when measuring “high quality care.”<sup>##REF##3045356##4##</sup> As such, contemporary quality measurement can miss what is important to many patients, clinicians, and healthcare systems, and fail to deliver actionable information to stakeholders. Even when clarity can be achieved in developing measures that reflect shared societal values, measurement can be disproportionately weighted towards measures of clinical effectiveness and neglect other important dimensions of quality including timeliness, efficiency, patient centeredness, and equity of the care provided.<sup>##UREF##1##5##</sup> In an attempt to remedy these shortcomings, measure developers have created more measures, more complex measures, measures which may not be grounded in strong evidence, and measures that may not actually be under the purview of the healthcare system or the physician to improve.<sup>##REF##25470693##6##</sup></p>", "<p> The largest number of people with diabetes — nearly a quarter of the world population with diabetes — live in China, though just under half are aware that they have this condition.<sup>##REF##31518657##1##</sup> Cognizant of the need for quality measurement to improve diabetes management and health outcomes, as well as its potential downsides, Rasooly and colleagues conducted a large scale evaluation of the implementation of diabetes quality measurement across community healthcare centers delivering primary care in Shanghai, China.<sup>##REF##35942954##7##</sup> Specifically, they conducted in-depth interviews with endocrinologists, primary care physicians, community healthcare center managers, patients, and policy makers across two tertiary hospitals (which deliver specialty care and where patients historically received the majority of their diabetes care) and four community healthcare centers. They focused specifically on a core set of three diabetes quality measures set at the national level and used by the Shanghai Health Commission since 2009: (1) the health management rate, reflecting the percent of residents in the community healthcare center’s catchment area with diabetes who are treated by the community healthcare center; (2) the standardized management rate, representing the proportion of patients with diabetes treated by the community healthcare center who are seen there at least quarterly; and (3) the glycemic control rate, reflecting the percent of patients with diabetes treated by the community healthcare center who have fasting blood glucose <7 mmol/L. These measures are reported to the municipal health commission and used for large (potentially exceeding 50% of their total compensation) performance-based bonuses to physicians, nurses, and public health practitioners and promotion opportunities for community healthcare center and district leaders.</p>", "<p> Rasooly and colleagues share important learnings from their efforts to understand the front-line team members’ experience with quality measurement, which can be informative to stakeholders across different settings, populations, and regulatory environments. First, because these measures were developed and implemented without front-line clinician input — as most quality measures are — there were concerns about their appropriateness, feasibility, and usefulness. Some measure developers seek out stakeholder feedback and engagement, for example incorporating technical expert panels and having a public comment period, but even then, more transparency is needed to showcase the specific impact stakeholders had on the final quality metric. Pre-implementation field testing of quality measures, with publicly available evaluation results, can help ensure feasibility and utility. Second, while quality measures informed and prioritized practice initiatives to improve performance, these efforts seemed more focused on improving numeric <italic toggle=\"yes\">measurement of quality</italic>, rather than the actual <italic toggle=\"yes\">quality of care</italic> and downstream health outcomes as perceived by patients, physicians, and other stakeholders. Stakeholder engagement not only during the measure development process but throughout its life course can help ensure that the measure is meeting its intended objectives.</p>", "<p> Third, to sufficiently incentivize behavioral change, quality measures were designed to have a substantial impact on both physician reimbursement and community healthcare center managers’ career advancement. These incentives — while effective at motivating practice priorities and initiatives around these measures — also raised concerns about coerciveness, data manipulation, and “gaming” the system. Indeed, it was this concern for data manipulation vis-à-vis inclusion of healthy individuals as having diabetes that led to the decision to discontinue the health management rate measure. This is to be commended, as quality measures are rarely examined for unintended consequences or undesired implementation and are even more rarely de-implemented for these reasons. Additionally, quality control mechanisms with verification of reported data for the remaining measures were introduced, with punitive consequences for false reporting. While participants in the study felt that this did not entirely eliminate false reporting, it did make it more difficult, though also introduced additional administrative burden to measurement and reporting. Again, seeking stakeholder feedback after measure implementation proved invaluable.</p>", "<p> Fourth, the quality measure must be aligned with contemporary clinical care processes and scientific evidence. For example, while quality measurement called for attaining fasting blood glucose <7 mmol/L, the preferred means of monitoring glycemic control in patients with existing diabetes is hemoglobin A<sub>1c</sub> (HbA<sub>1c</sub>) and not fasting blood glucose.<sup>##REF##33298417##8##</sup> Yet, HbA<sub>1c</sub> testing was neither covered by insurance nor included in the measure, hindering implementation of the measure. For many people living with diabetes – particularly those treated with intensive insulin therapy – alternative markers of glycemic control such as time in range may be even more appropriate. Allowing flexibility to be responsive to contemporary scientific evidence and best practices would make quality measures to be evidence-based and patient-centered but may not be feasible for standardized measures used for public reporting and/or reimbursement (as opposed to internal quality improvement). Conversely, by making glucose-lowering medications available for longer periods and at lower cost at community healthcare centers than hospitals, measure attainment was made more feasible. Fifth, attaining the quality measure must be within the control of the individuals and entities held accountable for them. For example, while primary care physicians and community healthcare centers were accountable for diabetes quality measure attainment, many patients continued to bypass them in favor of hospital-based specialists. Broadening the eligible pool of responsible entities to include all clinicians who assume primary responsibility for the patient’s care — irrespective of their affiliation — would help support diabetes management on population scale. Sixth, the quality measures were viewed as disconnected from how patients experience their own health and what matters to them; engaging patients and their care partners as stakeholders in the quality measure development process can improve patient engagement with the healthcare system and their self-management. Finally, there were concerns about a rigid or militarized organizational culture that precluded innovation and optimization of care delivery at all levels, which may not be readily modifiable but underscores the importance of local culture and customs on health and healthcare delivery.</p>", "<p> In their study, Rasooly and colleagues also shared several broadly generalizable findings useful to policy makers and measurement developers across different settings. First and foremost, they found bi-directional communication between measure developers and program participants to be critically important, so that challenges to the validity and implementation of the measure can be iteratively identified, communicated, and addressed. Withdrawal of a measure, as in the case of the health management rate, speaks to the open dialogue necessary for success between measure developers and those ultimately accountable to those measures. They also highlight the value of parsimony in measurement development, demonstrating that selecting a small number of meaningful measures that can be iteratively improved allows for greater clarity and engagement with program participants. The authors also identified that both patient and physician experiences are important to attaining durable stakeholder engagement. Finally, insights into the impact of public reporting of rankings on performance and motivation were shared.</p>", "<p> There are important limitations to this work. Many patients in Shanghai continued to receive diabetes care through hospital systems instead of community health centers and these hospital-based practices may have had a more limited opportunity to introduce innovative solutions to improve performance. The challenge of understanding the locus of control for measures parallels the challenges faced in other settings where primary care practices are liable for quality of care that may be delivered by others. While some new policies and interventions for improving performance of these measures were referenced, little detail was provided on what was done, why, and how successful these interventions were. There are also significant concerns about the generalizability of these findings to other settings. Most of the clinics appeared to be in urban settings, and we do not know how these findings may translate to rural settings or to clinics with fewer available resources. Social determinants of health, which have a profound effect on diabetes management,<sup>##REF##33139407##9##</sup> were largely absent from this analysis. While the authors did carefully consider the patient’s experience of care within the community healthcare clinic setting, the gap between what patients and physicians consider high quality care and the patient facing discussion on how measurement systems could be further improved were not explored. Aligning measures between patient and physician perceptions of high quality care is a significant challenge, and an area where further research is needed. Strategies which have been implemented include integrating patient perspectives in the measurement development process,<sup>##REF##31044517##10##</sup> balancing clinically oriented measures with patient reported outcomes.<sup>##REF##28679102##11##</sup></p>", "<p> These findings should prompt measurement developers and stakeholders to reimagine the development and implementation of quality measurement to ensure that both the measures and the measurement process are responsive to the needs of all stakeholders in the diabetes care journey (##TAB##0##Table##).</p>", "<p> In addition, all relevant stakeholders (payors, patients, clinicians, other healthcare team members, health system leaders, and quality experts) need to be identified and their input on an optimal measurement approach needs to be carefully considered. This level of engagement and contribution must go beyond the Technical Expert Panels and public comment periods used by the US Centers for Medicare and Medicaid Services for quality measure development, and should seek to understand the healthcare needs, practice priorities, and implementation challenges faced by people responsible for and affected by measure attainment. Second, to ensure that quality measures truly measure quality, they must capture domains of quality beyond effectiveness and include measurements of the efficiency, safety, timeliness, patient-centeredness, and equity of the care provided.<sup>##REF##35759700##13##</sup> The value compass,<sup>##REF##8743061##14##</sup> summarized in Figure, is a tool that quality measure program developers can use to help guide their balance of measures, and to assure one domain isn’t under or over-represented. The domains, including the clinical effectiveness of the care provided (in Rasooly et al captured via glycemic control measure discussed above), the experience of care (captured, but not quantified), patient functional outcomes (not captured) and the costs and utilization of care (incompletely captured via utilization measures). Measure developers and evaluators can use the value compass in considering both quality measurement program design and evaluation, carefully considering the implications of measures related to cultural expectations around the experience of care, and addressing factors relevant to costs of care in healthcare systems outside of the United States where the value compass was developed. Third, while we are calling for a set of balanced measures, the number of measures must be limited to a narrow set of actionable measures with a strong evidence base for measuring and supporting quality.<sup>##REF##35759700##13##</sup> Indeed, a robust and balanced measure set can be derived from as few as four measures.<sup>##REF##8743061##14##</sup> Fourth, quality measures should be periodically reexamined to ensure that they are still meeting their objectives of improving quality without unintended consequences or manipulation. While countermeasures and data integrity initiatives can reduce the risks of undesired consequences, introduction of such efforts need to be weighed against the concerns for measurement burden. The discontinuation of the Shanghai Health Commission’s health management rate measure is a good example of responsive measure redesign, while policing efforts to prevent data manipulation and fraud can easily outweigh their benefits.</p>", "<p> We have previously examined the themes describing what healthcare stakeholders perceive to be an ideal quality measure.<sup>##UREF##2##15##</sup> Engaging a multi-disciplinary panel of clinicians, pharmacists, nurses, researchers, and representatives of both public and private health plans, we identified three themes and core value systems that underpin an ideal quality measure of diabetes management: promoting individualized, evidence-based and equitable care; balancing autonomy and prescriptiveness in clinical decision-making; and ensuring an accurate, reliable and practical quality measurement. These themes resonate with the findings of Rasooly and colleagues.</p>", "<p> Quality measurement, tracking, and reporting has been fundamental to nearly all efforts to improve diabetes care quality. Despite a proliferation of quality measures, evidence that measurement programs truly improve the quality of diabetes care and, more importantly, patient health, quality of life, and costs of care is scarce. The work of understanding, engaging with, and responding to the needs of different stakeholders in evaluating the quality of care is perhaps the most important challenge of 21st century healthcare delivery. It is therefore important to critically evaluate quality measure development, implement, and maintenance — as Rasooly and colleagues have done — to ensure that measures truly improve care delivery and health outcomes.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> In the last 36 months, Rozalina G. McCoy has received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute on Aging (NIA) of the NIH, the Patient Centered Outcomes Research Institute (PCORI), and the National Center for Advancing Translational Sciences (NCATS). She also serves as a consultant to Emmi® (Wolters Kluwer) on developing patient education materials related to diabetes.</p>", "<title>Funding</title>", "<p> This effort was funded by the NIDDK of the National Institute of Health (NIH) grant number K23DK114497 (McCoy).</p>", "<title>Disclaimer</title>", "<p> Study contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH.</p>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nThe Clinical Value Compass.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table</label><caption><title>Common Concerns and Mitigation Strategies in Quality Measurement\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quality Measure Development Question</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Concern</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Mitigation Strategy</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Example</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Shanghai Health Commission Program: Description and Validity</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">What are we measuring?</td><td style=\"text-align:left;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Is the evidence linking the quality measure to the desired outcome robust?<break/>Does measuring the proposed indicator allow for detection of clinically meaningful changes in health outcomes or other aspects of care that are meaningful to stakeholders?</td><td style=\"text-align:left;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">GRADE<sup>##REF##15205295##12##</sup> or GRADE-like recommendations are transparently applied to measure selection process. </td><td style=\"text-align:left;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">There is a robust evidence base in support of lowering HbA<sub>1c</sub> levels to reduce risks of chronic diabetes complications, though the exact threshold of HbA<sub>1c </sub>should be informed by the patient’s clinical complexity and a countermeasure for hypoglycemia should be considered.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Composite measure of healthcare utilization and glycemic control.<break/>Utilization measures (appt attendance) have not been linked to improved outcomes. Fasting glucose measurement is inferior to HbA<sub>1c</sub> in assessing diabetic control. </td></tr><tr><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Why is this specific indicator being measured?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Is the quality measure intended to support internal quality improvement efforts, being used to empower patients in selecting their healthcare provider and/or organization, or to encourage healthcare organizations to focus on this indicator? </td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Involvement of Patient-Family Advisory councils and multi-group stakeholder consortiums can collectively assert the primary rationale for initiating the measurement program. This rationale should guide all subsequent modifications to the program.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">A multi-stakeholder consortium, consisting of payors, physicians, patients, and community members, uses a consensus building process to agree on a prioritized set of diabetes measures that are realistic to improve, understandable to patients and other stakeholders, and represent a community health priority. </td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">The purpose of the program is to encourage physicians to focus on this indicator.<break/>As done in this work, input from a consortium of diverse stakeholders can improve the relevance and value of the measurement program.</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">What are the requirements for participating in the measurement program?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Does collecting and reporting the quality measure require investment apart from routine practice? What is the burden on patients, physicians, and healthcare systems?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Resources for collecting, storing, and reporting data should be made available to all participants if significant additional investment is required to report that measure.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Accepted measurements should be feasible for health systems to collect, analyze, and report without requiring substantial investment in electronic or personnel resources.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Practices would need to register, enter, and update the records of patients participating in this program.<break/>The burden and feasibility of data collection was not directly assessed. </td></tr><tr><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Who should be responsible for improving performance on the measure?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Is the individual provider responsible for improving this measure or should this measure be the responsibility of the organization, the community, or the health plan?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Measures should be assigned to entities with operational control over their attainment. There should be clarity and transparency about who is charged with improving performance on that measure.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Primary care physicians should not be the sole responsible entity for quality measure attainment if they are not solely responsible for delivering diabetes care and attaining measure outcomes. </td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Primary Care Physicians and community-based clinics.<break/>Specialist and other care were not included, and often, patients attributed to a physician were not receiving care through them. </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">What are the financial consequences of meeting or not meeting the metric?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">A single metric may have disproportionate impact on the physician’s or practice’s revenue and even on the financial viability of that practice, resulting in undue pressure to meet the measure at all costs. Conversely, a measure can have limited impact on income or operations of the practice, limiting its impact on performance.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Financial incentives need to be large enough to be meaningful, yet not so large that poor performance could impact viability. </td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">A health system participating in the measurement program can select available measures with different levels of risk and reward. Risk and reward trade-offs need to be meaningful but not coercive.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Substantial financial incentives and penalties for the practice and the individual physician were tied to this measure.<break/>Based on reports of false reporting and “gaming the system,” the degree of financial incentive through this program needs to be re-considered.</td></tr><tr><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">What are the burdens and opportunity costs of the measurement, tracking, and reporting of the quality measure?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Is there a measurement and reporting burden to the provider and system? Is there a substantial opportunity cost with prioritizing this measure over other measures?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">The number of quality measures must be limited to allow for a seamless/automated measurement system; the measures must reflect the priorities of the selected stakeholders.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Health systems, in collaboration with relevant stakeholders, can select from a narrow number of vetted measures which they find feasible, meaningful, and impactful to their communities.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Quality measurement programs have been reported as parsimonious, and this is the main measure primary care physicians are responsible for. <break/>The specific degree of burden or opportunity cost is not directly reported in this work. </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Could this measure worsen health disparities?</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Prioritizing certain measures could result in penalization of practices caring for disadvantaged populations and promote selective inclusion and exclusion of patients.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Stratified reporting of the measurement based on social determinants of health and health disparities should be considered.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Diabetes outcomes are stratified by socioeconomic status, access to transportation, availability of social services and other social determinants of health. Efforts to address social determinants of health and improvements in measure attainment within subgroups of populations are also considered.</td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Yes, as diabetes control and healthcare utilization are strongly predicated on Social Determinant of health.<break/>This was not directly reported in this work. </td></tr><tr><td style=\"text-align:left;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">What are the unintended or undesired consequences of pursuing the attainment of the quality measure?</td><td style=\"text-align:left;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Focus on a particular quality measure could result in overtreatment, non-individualized treatment goals and targets, purposeful selection of patients, manipulation of documentation and/or data, and detrimental impact on patient trust and the clinician-patient relationship.</td><td style=\"text-align:left;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Balancing measures should be implemented across different domains; counterbalance measures are needed.</td><td style=\"text-align:left;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">HbA<sub>1c</sub> target measures are coupled with hypoglycemia reporting.<break/>Measures are individualized based on patient’s health status and life expectancy.<break/>Measures of efficiency, timeliness of care, patient experience and safety are incorporated within the measurement program.</td><td style=\"text-align:left;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Unknown. <break/>Considerations of measures of patient cost, rates of hypoglycemia, and healthcare access could be considered in future analyses. </td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p> Abbreviation: HbA<sub>1c</sub>, hemoglobin A<sub>1c</sub>.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7884-g001\" position=\"float\"/>" ]	[]	[{"label": ["3"], "person-group": ["\n"], "surname": ["Donabedian"], "given-names": ["A"], "article-title": ["Evaluating the quality of medical care"], "source": ["Milbank Mem Fund Q"], "year": ["1966"], "volume": ["44"], "issue": ["3"], "fpage": ["166"], "lpage": ["206"]}, {"label": ["5"], "mixed-citation": [" Institute of Medicine (IOM). Committee on Quality of Health Care in America: Crossing the Quality Chasm: A New Health System for the 21st Century. IOM; 2001. "]}, {"label": ["15"], "person-group": ["\n"], "surname": ["LaVecchia", "Montori", "Shah", "McCoy"], "given-names": ["CM", "VM", "ND", "RG"], "article-title": ["Values informing the development of an indicator of appropriate diabetes therapy: qualitative study"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["12"], "fpage": ["e044395"], "pub-id": ["10.1136/bmjopen-2020-044395"]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 25; 12:7884	oa_package/f1/0c/PMC10590250.tar.gz
PMC10590252	0	[ "<title>Background</title>", "<p> Policy-makers increasingly seek to improve the third-party purchaser function in their aim to increase quality and reduce costs.<sup>##REF##18416918##1##</sup> Given the nature of consolidated healthcare markets, patient choice may not be sufficient to obtain allocative efficiency through provider competition, and third party purchasing may improve market outcomes.<sup>##UREF##0##2##,##REF##7863354##3##</sup> We define active purchasing (c.q. strategic purchasing, contracting, commissioning, and procurement) as interventions by third party payers to improve market outcomes. One aspect of active purchasing involves selective reallocation of resources from poor performers to best performers (supply-side steering) and channelling patients from poor to best performers (demand-side steering), eg, by patient education, consultation or prior authorization.<sup>##REF##7741842##4##, ####REF##2100984##5##, ##REF##25261074##6##, ##UREF##1##7##, ##REF##29502893##8####29502893##8##</sup> Through these channels, active purchasing implies reallocation of funds towards efficient providers.<sup>##REF##27784907##9##</sup> We therefore expect that active purchasing induces differences in the evolution of providers’ expenditures (ie, budgets/income/revenue/market share) over time: some providers grow substantially in total expenditures, while others’ stagnate or decline. We construct a novel indicator defined as the percentage of the total market expenditure that is reallocated between providers annually. While this is a crude measure of active purchasing, it reflects a main goal of improving static and dynamic efficiency. This measure allows analysis of the effect of different institutional arrangements with respect to the third-party purchasing function.</p>", "<p> Literature lacks consensus on the optimal payer system to enhance provider efficiency.<sup>##UREF##2##10##, ####REF##19633224##11##, ##REF##22152224##12##, ##UREF##3##13##, ##UREF##4##14####4##14##</sup> Managed competition aims to improve efficiency in the healthcare market by insurers competing over premiums, incentivizing active purchasing on the provider market. The theory of managed competition, as formulated by Alain Enthoven in 1988, assumes that third-party payers steer healthcare markets to more efficient outcomes by rewarding well-performing providers and disciplining underperforming providers.<sup>##REF##8477935##15##,##UREF##5##16##</sup> We use the Netherlands as case study leading in implementation of managed competition in the hospital sector.<sup>##REF##23399042##17##</sup> Parallel, non-competitive payer systems were retained in other healthcare markets, allowing within-country comparisons of systems with different institutional characteristics (##TAB##0##Table 1##).</p>", "<title> Hospital Care</title>", "<p> The hospital sector comprises 8 University Medical Centers (UMCs), about 100 general hospitals and about 300 independent treatment centers (ITCs). Some hospitals have multiple locations, and some ITCs are chain-affiliated. All hospitals are private entities, and predominantly non-profit foundations as a legislative ban on profits applies, although some ITCs are commercially oriented.<sup>##REF##26278627##18##</sup> A system of managed competition was implemented in the hospital sector in 2006, which included, among others, competition between insurers, room for free-pricing and selective contracting and the liberalization of the certificate-of-need regulations.<sup>##REF##26278627##18##, ####REF##18474971##19##, ##UREF##6##20####6##20##</sup> Currently 10 insurance companies compete in the market, with four insurance companies (the ‘big four’) possessing about 90% of the market. Insurers aim to set low premiums to be competitive. As the theory of managed competition postulates, active purchasing allow insurers to save costs and reduce premiums. The percentage of consumers that switch between insurers varies around 7% each year.<sup>##UREF##7##21##,##UREF##8##22##</sup> Financial risk of insurers has substantially increased in the research period as a consequence of the government’s policy to restrict ex-post equalization.<sup>##UREF##6##20##</sup> As the market is designed as a competitive market, we expect that payer incentives for active purchasing are high, leading to substantial reallocations of expenditures towards efficient providers.<sup>##REF##18474971##19##</sup></p>", "<title> Long-term Care</title>", "<p> The long-term care (LTC) sector, including elderly care, disability care, long-term mental care, and, up to 2015, home care, is divided into 32 regions, where a non-profit regional care office acts as single payer.<sup>##UREF##9##23##</sup> All +-750 providers are private entities, sometimes chain-affiliated or having multiple locations. As in hospital care, a legislative ban on profits applies, although some commercially oriented providers remain. Contrary to hospital care, incentives for active purchasing are (largely) absent in LTC. Each regional care office receives a block grant from the government for contracting providers. Since offices cannot overspend or build reserves, they do not bear any financial risk (with the exception of administrative costs), although underspending may result in block grand reallocation. This ‘threat’ incentivises each regional office to spend its full budget.<sup>##UREF##10##24##</sup> Our hypothesis is that a single payer system without financial risk displays low active purchasing, and as a result, few budget reallocations.</p>", "<title> Social Care Services</title>", "<p> The introduction of the Social Support Act in 2007 delegated social care procurement from the LTC system to municipalities.<sup>##UREF##11##25##</sup> In 2015, supportive home care was transferred from LTC to municipalities. As both the introduction in 2007 and the addendum in 2015 went along with a significant budgetary cut, municipalities are expected to have strong incentives for active purchasing.<sup>##UREF##12##26##</sup> WMO (Wet maatschappeljke ondersteuning) services are procured by individual municipalities or small groups of collaborating municipalities through competitive tenders. About a third of WMO is provided by large specialised companies (eg, cleaning companies), about a third by independent contractors, and about a third by LTC-providers as secondary source of income. Only the latter is formally non-profit, other providers may have profit motives. In purchasing, municipalities are financially at risk. If municipalities spend more than the annual state grant, budgetary cuts are required, as municipalities have limited ability to raise additional resources.<sup>##REF##26872702##27##</sup> Concurrently, public spending may be increased on other municipal expenditures in case of underspending on social support. Our hypothesis is that the Social Support Act contains strong incentives for municipalities to engage in active purchasing and reallocating budgets towards efficient providers.<sup>##UREF##11##25##</sup></p>", "<title> Personal Budgets</title>", "<p> Lastly, patients may self-procure social services and LTC through personal budgets. Patients that meet requirements for receiving home care and in-kind LTC have the option to apply for a personal budget of about 70%-80% of in-kind tariffs to self-procure care. The personal budget system is characterized by the absence of a third-party payer (insurer, care office, and municipality). Due to the nature of the opt-out system, personal budget holders are likely to critically assess the quality of providers. Furthermore, personal budget holders have a financial motive to be selective because the budget they receive is less than in-kind LTC-tariffs. Therefore, we expect that budget holders will engage in active purchasing by selecting efficient providers.</p>", "<title> Measuring Purchaser Activity</title>", "<p> We compare purchasing activity in different payer systems in the Netherlands through its effect on changes in provider expenditures. We research six provider markets with different institutional arrangements: Hospital care (competitive multi-payer system), long-term elderly care and long-term disability care (both non-competitive single payer system), mental care (mixed), social care services (municipal purchasing), and personal budgets (self-purchasing). Due to complexities of distinguishing short-term mental care (Zvw, Zorgverzekeringswet) and long-term mental care (Algemene wet bijzondere ziektekosten/Wet Langdurige Zorg, AWBZ/WLZ) in the data, mental care is included as a mixed purchasing system. As the theory of managed competition hinges on active purchasing as a means of achieving efficiency, we hypothesize that managed competition increases reallocation of funds between hospitals. As many factors besides active purchasing may affect changes in hospitals’ income, we test which institutional and provider characteristics are related to the rate of reallocation in the hospital market. Interestingly, two major competitive reforms occurred during our study period, allowing comparison of institutional changes within a single market. In 2007 the hospital sector was gradually reformed to a competitive multi-payer system. In 2015, LTC was reformed, including reallocation of home care from a regional single payer system partly to municipal payers (ancillary care) and partly to the managed care system (home nursing care). We hypothesize that these competitive reforms stimulated active purchasing, increasing provider budget reallocations.</p>" ]	[ "<title>Methods</title>", "<title> Data Collection</title>", "<p> To measure changes in providers’ expenditures over time, annual statements were collected for all Dutch health providers from 2007 to 2019, using the online dataset DigiMV.<sup>##UREF##13##28##</sup> Annual statements contain provider expenditures specified to payer system and type of care. Legislation mandates all providers of hospital care, mental care, home care and LTC to publicly disclose annual statements, although some exceptions apply (eg, very small companies and independent medical specialist associations). As annual statements contain information on the current year as well as the previous year, data on 2006 was retrieved from the 2007 annual statements. Data were corrected for input errors and missing data by crosschecking with financial reports from the provider website. By internet searching providers with missing years in the dataset, bankruptcies, mergers and takeovers were identified. Data from merged providers were aggregated retrospectively starting from 2006 to clean up administrative reallocation effects of mergers. Within a parent company, no expenditures per location, chain member or subcontractor are provided, allowing analysis at the level of parent company only.</p>", "<p> The final dataset contains 3066 providers. Of those, 685 providers, representing 92% of overall expenditures in the dataset, have data for at least 13 consecutive years. Predominantly small providers are more likely to emerge during the study period, experience bankruptcy, or have missing data for multiple years (eg, due to the voluntary nature of depositing annual statements). Combining the hospital and LTC sector, 1396 providers entered the market in the research period, responsible for 4.3% of total expenditures. In the same period, 206 providers exited the market, (1.8% of expenditures). 743 providers first entered and then exited the market during the study period (0.5% of total expenditures). The number of small providers that are exempt from annual statement provision is unknown.</p>", "<p> To express the coverage of the dataset in terms of total expenditures (data completeness), total sector spending is derived from official government financial statements (2006-2022). The most recent expenditure data for a given year is used. Mean completeness is 93% for hospital care, 91% for mental care and 95% for elderly and disability care. Completeness of the data for social care (73%) and personal budgets (14%) is significantly less, because the mandate to publish annual statements does not apply for companies that exclusively provide social care and personal budget care. In all sectors, distribution of funds is highly unequal with the 20 biggest providers (C20) capturing 43%, 22%, 47%, 65%, 21%, and 7% of the 2016 market for hospital care, elderly care, disability care, mental care, municipal care and personal budgets, respectively.</p>", "<title> Constructing the Market Activity Index</title>", "<p> We define the market activity index (MAI) as the part of total sector expenses that is reallocated between providers between years. In each year, market share (<italic toggle=\"yes\">MS</italic>) for provider <italic toggle=\"yes\">i</italic> is calculated by dividing provider expenditure <italic toggle=\"yes\">E</italic> in sector <italic toggle=\"yes\">k</italic> by total expenditures <italic toggle=\"yes\">S</italic> in sector <italic toggle=\"yes\">k</italic>:</p>", "<p> Where sector <italic toggle=\"yes\">k</italic> is hospital care, elderly care, disability care, mental care, municipal care and personal budgets, and <italic toggle=\"yes\">t</italic> is ‎ between 2006-2019, with t(0) = 2006. As denominator we use total expenditures according to government statements, which is less sensitive to changes in dataset composition. As robustness check, we use the sum of expenditures in the dataset as denominator. To calculate the MAI, we sum the absolute change in market share for each provider <italic toggle=\"yes\">i</italic> in sector <italic toggle=\"yes\">k</italic>, ranging from 1 to <italic toggle=\"yes\">I</italic>:‎</p>", "<p> We divide the sum by two, as a gain in market share for one provider by definition means an equivalent loss in market share for other providers<sup>[<xref rid=\"fn1\" ref-type=\"fn\">1</xref>]</sup>. Because very small providers are missing from the dataset, the sum of market shares of providers in the dataset does not add up to unity. Therefore, we extrapolate the MAI to total sector expenditures by assuming that reallocations in unobserved market shares of small providers are equal to observed share reallocation fractions:</p>", "<p> To discern between annual fluctuations (eg, increases in one year and reductions in the next) and structural reallocations (eg, a trend of changes in the same direction for n years in a row), we calculate structural reallocations as market share changes between a period of n years:</p>", "<p> Mean structural reallocations are by definition equal or lower than mean annual market share reallocations. For example, the total market share change between 2011 and 2015 is by definition equal or less than the sum of each absolute annual change over the same period. Although MAI is an imperfect indicator of active purchasing, it has a number of advantages over existing indicators (##BOX##1##Box 1##).</p>", "<title> Trend Analysis and Explanatory Regression Analysis</title>", "<p> To assess the effect of managed competition on MAI, we compare the hospital MAI over time and to other sectors. We hypothesize that the incentives for active purchasing are reflected in the height of the MAI, placing the hospital sector on par with municipal care and personal budgets. As robustness checks, we exclude the effect of entry and exit on the MAI. Next, we analyse the effect of competitive reform on MAI. In 2015, home care was reallocated from the LTC-sector to the managed competition health insurance sector (home nursing care) and municipalities (home ancillary care). While these reallocations cannot be distinguished in the data directly, we can indirectly gauge the effects by focusing on a subset of providers that specialize in home care (over 90% of clients receive home care). We analyzed MAI before and after the reform, to research whether an institutional setting aimed to promote active purchasing results in higher MAI within the home care sector.</p>", "<p> Next, we performed additional regression analyses on an individual provider level to further investigate active purchasing and its relation to market characteristics. We use two outcome measures at the provider level that relate directly to the MAI: (1) Relative changes in hospital market share over time, reflecting causal impact on market share growth (or decline); and (2) Absolute changes in hospital market share over time, reflecting impact on the size of market share reallocations (either positive or negative). We use the extent of selective contracting as proxy for active purchasing, use quality measures as a proxy for efficiency, and we correct for provider size, type of hospital, and fixed assets as a measure of flexibility.</p>", "<p> Selective contracting is an important tool for active purchasing under managed competition to increase efficiency.<sup>##REF##8477935##15##,##REF##31932076##29##</sup> Data on the extent of selective contracting between 2015 and 2019 is obtained from Mediquest, a company that constructs online tools for consumers to facilitate insurance plan choice. For each insurer plan, data is collected on whether each hospital is contracted, but also within each contracted hospital is registered whether certain procedures are contracted. It may be the case that a hospital is contracted in an insurer plan, but specific treatments are excluded. In total 1655 procedures are eligible for selective contracting (for example, elective breast cancer care). However, not all hospitals offer all procedures. On average, hospitals and ITCs provide 475, respectively 37 eligible procedures. We construct a contracting index defined as the fraction of offered procedures contracted by an insurance plan. The contracting index is zero when a hospital is not contracted, one if all procedures are contracted, and between zero and one if certain procedures are excluded. Next, an average contracting index (<italic toggle=\"yes\">ACI</italic>), ‎weighed by the market share of each insurer, is calculated for each provider, ranging from zero (not contracted for any offered procedure in any insurer plan) to one (contracted for all offered procedures in all insurer plans)<sup>[<xref rid=\"fn2\" ref-type=\"fn\">2</xref>]</sup>. For 161 providers, data on all years is available, covering 88% of total hospital expenditures. All hospitals and ITCs experience selective contracting to a certain extent, with mean contracting indices of 0.86 and 0.56 for hospitals and ITCs, respectively. We hypothesize that when an insurer excludes a provider from his network, the total expenditures (ie, market share) of that provider are reduced. Vice versa, if an insurer adds a provider to the plan network, provider income (ie, market share) is expected to increase. As robustness check, we differentiate our analysis between hospitals, UMCs, and ITC.</p>", "<p> Provider size may affect the potential of payers to reallocate funds. Furthermore, provider concentration increased during our study period, particularly in the hospital sector. On the one hand, provider market power and limited alternatives may reduce the potential to reallocate budgets between providers. On the other hand, large providers may have more flexibility to accommodate large reallocations in absolute terms, ie, a reallocation of one million euro is easier to accommodate for large providers than for small providers. Literature on provider concentration finds mixed results.<sup>##UREF##14##30##, ####REF##18038246##31##, ##UREF##15##32##, ##UREF##16##33####16##33##</sup> Depending on which effect dominates, provider concentration could result in differences in the baseline level of MAI between sectors. Therefore, we research the relation between reallocations and provider size in the previous year, both in absolute terms and in relative terms. Quadratic effects are estimated for provider size to allow nonlinear effect. As robustness checks, we repeat the analysis for the other sectors.</p>", "<p> The potential for reallocation of funds may also relate to care characteristics, eg, patient length-of-stay. Inpatient care, having longer lengths of stay, may have intrinsically higher MAI. Therefore, we differentiate between traditional hospitals (mostly in-patient care) and ITCs (mostly outpatient care). As a robustness check, we repeat the analysis for LTC, distinguishing between nursing home care (in-patient residential care) and home care (out-patient non-residential care). Related, sectors with high fixed costs may have lower baseline MAI, because high fixed costs limits the capacity of providers to cope with large negative income shocks. Fixed costs (<italic toggle=\"yes\">FC</italic>) are defined as costs related to real estate: interest payments, rents and capital depreciation as percentage of total expenditures. As a robustness check, we estimate type and fixed costs separately to avoid potential multicollinearity.</p>", "<p> The optimal MAI may be a trade-off between budget continuity and allocative efficiency. If funds are redirected towards high-quality providers, efficiency may still be achieved. To test this, we employ a method similar to Chandra et al, relating market share changes to quality performance measures in US regional markets.<sup>##REF##27784907##9##</sup> While our data lacks regional market indicators, this is less problematic in a small country as the Netherlands, which could be regarded as a single market. As quality measures, we calculate mean z-scores of publicly available structure, process and outcome indicators from 2010-2018. For details on Dutch hospital quality indicators, see Wackers et al.<sup>##REF##37579390##34##</sup> As robustness check, — following Chandra et al — we estimate a pooled regression relating absolute size to quality measures to correct for the possibility that large providers have higher quality overall. Due to limited data availability of hospital standardized mortality ratio (HSMR) data (available for general hospitals and UMCs only from 2010-2013 and 2016-2019), we include HSMR in a robustness check.</p>", "<title> Regression Analysis</title>", "<p> We estimate two sets of multivariate pooled linear regressions:</p>", "<p>\n<italic toggle=\"yes\">Δm</italic><sub>i,t</sub> is the change in market share of provider <italic toggle=\"yes\">i</italic>between year <italic toggle=\"yes\">t</italic> and year <italic toggle=\"yes\">t-1</italic>, while \|<italic toggle=\"yes\">Δm</italic><sub>i,t</sub>\| is the absolute change in market share of provider <italic toggle=\"yes\">i</italic> between year <italic toggle=\"yes\">t</italic> and year <italic toggle=\"yes\">t-1</italic>. The first regression can be interpreted as testing causal relations between confounders and the <italic toggle=\"yes\">direction</italic> of market share changes, while the second regression tests how confounders affect the <italic toggle=\"yes\">absolute size</italic> of market share changes, irrespective of the direction.</p>", "<p> As confounders, <italic toggle=\"yes\">ΔACI</italic><sub>i,t</sub> is the change in ACI between year t and year t-1 for provider <italic toggle=\"yes\">i</italic>, <italic toggle=\"yes\">S</italic><sub>i,t-1</sub> is the size of provider <italic toggle=\"yes\">i</italic> in year <italic toggle=\"yes\">t-1</italic>, <italic toggle=\"yes\">FC</italic> are fixed costs as percentage of provider expenditures, <italic toggle=\"yes\">ICT</italic> is one if a provider is an ITC and zero if the provider is a regular hospital or UMC, <italic toggle=\"yes\"><bold>Q</bold></italic><sub>i,t-1</sub> is a set of quality measures (HSMR, structure, process, outcome), and <italic toggle=\"yes\">t</italic> are year dummies. The error term <italic toggle=\"yes\">u</italic><sub>it</sub> is corrected for panel clusters. The sample is limited by contracting index data (from 2015) and HSMR (hospitals only from 2010). To address missing (at random) values for variables <italic toggle=\"yes\">ACI</italic>, <italic toggle=\"yes\">FC</italic>, and <italic toggle=\"yes\">Q</italic>, ‎we perform multiple imputation using a multivariate normal model and a Markov chain Monte Carlo procedure, with ten iterations and size and (relative) change in market share as predictors. As additional robustness checks, regressions excluding ACI and HSMR are run. Regressions are estimated using Stata 17.</p>" ]	[ "<title>Results</title>", "<title> Descriptive Statistics</title>", "<p> Descriptive statistics of total sector expenditures and spending growth are given in ##SUPPL##0##Supplementary file 1## (Tables S1 and S2). Growth in total spending is irregular in all sectors. For example, the hospital budget increased by 11% in 2013, while nominal growth was only 3% in 2011.<sup>##UREF##17##35##</sup> Similarly, LTC grew by 11% in 2012 and by 0% in 2013.<sup>##UREF##17##35##</sup> Municipal spending doubles in 2015 due to the reform reallocating home care partly from LTC to municipalities. Hospitals have higher mean expenditures than other sectors, but variation in provider budgets is large in all sectors. In the hospital sector, 49% of providers are ITCs, while for elderly care and disability care providers, 69%, respectively 45% of patients are receiving home care (out-patient setting). Capital expenditures on average comprises 10% of total expenditures.</p>", "<p> Table S3 displays provider level statistics for the hospital market. The sample covers 90% of the hospital market. Average market share is 0.26%, and the maximum provider market share is 2.4%. The mean change in market share between two years is 0.01%, with a maximum change of 0.74%. The ACI is 0.77, which means that the average provider of hospital care is contracted for 77% of all available types of treatments over all insurance companies. The mean change in contracting index between two years is 2.2%. The mean fixed costs in the sample are 7%, which is lower than in other sectors.</p>", "<title> Trend Analysis: Market Activity Per Sector</title>", "<p> Hospital MAI was between 2% and 3% in non-reform years, similar to LTC (##FIG##0##Figure 1##). Contrary, MAI in social services and personal budgets was between 9%-13%. Generally, MAI is lower than changes in total sector expenses, suggesting that fluctuations in the macro budget are predominantly passed on to providers with little concern for reallocations. Given all policies taken to improve the purchasing function in hospital care, specifically reductions in ex-post compensations, market reallocations in the hospital sector were expected to increase over time. However, ##FIG##0##Figure 1## shows a downward trend in MAI in all sectors. In the hospital sector, MAI on average is lower after 2015 (1.8%) than before 2015 (2.7%).</p>", "<p> Peaks in MAI in 2015 predominantly reflect administrative changes induced by reforms. In the hospital sector, payment system reform incorporated independent medical specialist payments into hospital expenses of most general hospitals in 2015, causing administrative changes in market share distributions. In the other sectors, reallocation of funds from LTC to municipalities and health insurers led to large reductions in LTC market share and large increases in municipal market share for those most affected by the change.<sup>##UREF##18##36##</sup> To – partly – correct for administrative effects, we aggregate LTC-provider expenditures over all sectors (Figure S1 in ##SUPPL##0##Supplementary file 1##). After reform, real MAI increases of 1%-2% are found, potentially induced by the reform. Comparable total and public MAI indicates limited substitution between public and private provider income.</p>", "<p> The 2015 reform does allow assessment of MAI of home care providers under different payer systems (Figure S2). After 2015, MAI for home care purchased by health insurers slightly increased in the year after reform before returning to pre-reform levels (Figure S3). Contrary, increases are much higher for home care procured by municipalities. In both sectors, MAI is initially higher in the years after reform but declines over time.</p>", "<p>\n##FIG##1##Figure 2## disaggregates annual and structural reallocations. Most of the MAI is structural, ie, a two-year trend in increases or declines in expenditures, suggesting year-to-year fluctuations only explain a small part of sector reallocations. When correcting for year-to-year fluctuations, structural MAI in the hospital sector declines to 1.8% versus 1.9% in elderly care and 1.6% in disability care, suggesting structural reallocations are similar under competitive multi-payers and non-competitive single payers. Overall, the trends suggest that a system of managed competition does not necessarily result in higher reallocations of funds.</p>", "<p> As robustness check, we recalculated MAI excluding providers that entered or exited the marked during our study period. Entry and exit are responsible for about 0.2 percentage point change in the budget annually in both the hospital sector and LTC sector (Figure S4). Furthermore, we find similar results when recalculating MAI using non-missing providers only (Figure S5).</p>", "<p> Overall, MAI in hospital care appears relatively low given the institutional emphasis on active purchasing. However, certain characteristics of the hospital market may lead to inherently lower reallocations, irrespective of active purchasing. In the following section, we assess the effect of market and provider characteristics on the MAI to check the robustness of our findings.</p>", "<title> Regression Analysis Results</title>", "<p>\n##TAB##1##Table 2## displays the results of the main regressions. No significant relation was found between changes in selective contracting and changes in provider income, both in relative terms and in absolute terms. This finding is robust to the imputation procedure (Table S4). Robustness checks (Table S5) find a positive correlation between direction of market share growth and contracting index for ITCs, but not for hospitals or UMCs. No effects on absolute size of reallocations were found, suggesting contracting may predominantly affect small ITCs. Size does increase reallocations in absolute terms, with larger provider experiencing larger absolute changes in market share. Provider size is negatively correlated to market share growth, indicating that small providers grow at the cost of large providers, but with diminishing returns to size. To validate these findings, we repeat the analysis for all years and for all sectors (Tables S5-S8). In all sectors, larger providers experience larger absolute changes in budget growth. The effect of size on relative market share changes is ambiguous; in the full sample the signs flip in the hospital market, and in other sectors no clear relation emerges. While the effect of provider size on the <italic toggle=\"yes\">direction</italic> of reallocations is ambiguous, the <italic toggle=\"yes\">size </italic>of reallocations increases with provider size in all health markets. This indicates that concentrated markets may demonstrate larger absolute changes in budgetary allocations and therefore larger MAI. The main regression displays a significant effect of fixed costs on absolute size of reallocations, suggesting that high fixed costs are associated with smaller reallocations of funds. Sensitivity analyses (Table S5) finds similar results for elderly care and personal budgets, but not for other sectors, suggesting the results are not robust over specifications and sectors.</p>", "<p> After correcting for size (and fixed costs), no significant differences in reallocations are found between ITC and hospitals. While outpatient care displays higher reallocations (Figure S6), this can be fully explained by differences in size. Robustness checks (Tables S7 and S8) find that for elderly care and disability care, outpatient care is associated with lower budgetary growth. Outpatient elderly care displays larger reallocations than inpatient elderly care. Quality measures do not have any significant effect on market share changes. This is validated in the robustness checks (Table S9). Interestingly, process, outcome and HSMR are negatively associated with size, but do not affect changes in market share. Larger providers do have higher structural quality, but higher structural quality is associated with lower market share growth in the following year. This effect is not robust to restriction to the subset of hospitals with contracting data, however.</p>" ]	[ "<title>Discussion</title>", "<p> Active purchasing is advocated to improve healthcare efficiency. While active purchasing may take different forms, one major tool to improve efficiency is reallocation of funds from underperforming providers to well-performing providers. We designed and applied the MAI to measure reallocations of funds between providers in Dutch health markets under different institutional settings. The municipal local procurement system and procurement through personal budgets displayed high MAI, consistent with previous findings.<sup>##UREF##18##36##</sup> Contrary to our hypothesis, competitive managed competition in the hospital care sector did not display higher MAI than the non-competitive single payer LTC sector. This suggests that managed competition in the health insurance market did not increase reallocations of funds. Although the extent of reallocations is only one indicator of active purchasing, the results suggest that managed competition in the Netherlands does not perform as predicted by theory.</p>", "<p> Additional analyses confirm this conclusion. First, no correlation was found between the extent of selective contracting and budget reallocations, suggesting that selective contracting is not used to reallocate market shares. Second, no correlation was found between budget reallocations and quality measures, suggesting that any reallocations are not the result of quality gradients, as would be expected when active purchasing works as intended. Third, low MAI cannot be explained by market characteristics. We found that while provider size has ambiguous effects on the direction of market share changes, the size of reallocations is unambiguously larger for large providers. This is unsurprising: large providers may be able to accommodate larger changes in absolute euro amounts (eg, a one million euro change in provider income is more easy to accommodate for a provider with one billion euro in revenue than for a provider with 20 million euro in revenue). Since the size of reallocations are positively correlated to provider size, a more highly concentrated hospital market would allow higher base MAI than less concentrated sectors, such as elderly care. We also found some indications that high fixed costs reduce the size of reallocations. As fixed costs are lower in the hospital sector than in LTC, a higher baseline MAI could be expected in hospital care. The proportion of outpatient care has no effect on MAI, after correcting for size and fixed costs, suggesting lower percentages of outpatient care in the hospital sector has limited influence on baseline MAI. To conclude, we found no evidence for hospital market characteristics biasing MAI downwards; actually we would expect higher baseline MAI in the hospital sector, which confirm the finding that reallocation of funds between providers is relatively low in the hospital sector.</p>", "<p> These results quantitatively validate international qualitative experiences on strategic purchasing, both for the Dutch managed care system as for active purchasing in other countries.<sup>##REF##29502893##8##,##REF##23399042##17##,##REF##32749005##37##</sup> Second, our results confirm international comparisons finding few structural differences between payer systems.<sup>##UREF##2##10##, ####REF##19633224##11##, ##REF##22152224##12##, ##UREF##3##13##, ##UREF##4##14####4##14##</sup> Third, our results underline that competitive reform may not increase allocative efficiency. In the United Kingdom, for example, waves of competitive purchaser reforms had little effect on provider practice.<sup>##UREF##2##10##,##UREF##19##38##, ####REF##20478105##39##, ##REF##10388198##40##, ##UREF##20##41####20##41##</sup></p>", "<p> Our study finds preliminary evidence that allocative activity is correlated not with the number of payers or payer competitiveness, but with decentralized purchasing and purchaser’ monetary incentives. International studies on the effect of decentralized purchasing on budgetary reallocations (eg, in Scandinavian systems) could validate these preliminary results.</p>", "<p> Interestingly, we found no relation between reallocations and quality measures, although the validity of quality indicators that are publicly available for the Netherlands may be questionable.<sup>##REF##34191196##42##</sup> Furthermore, literature on the effects of quality differences on prices, volumes or market share, displays mixed results,<sup>##REF##27784907##9##,##REF##15755946##43##, ####REF##9674613##44##, ##REF##16595409##45##, ##REF##12773839##46####12773839##46##</sup> although for specific treatments a positive relationship between quality and market share -in terms of patient numbers- has been found.<sup>##REF##27784907##9##,##REF##18516254##47##, ####REF##24158316##48##, ##REF##22425770##49####22425770##49##</sup> One potential explanation for these conflicting findings is that growth in the number of new patients may not correlate with growth in hospital expenditures, for example when prices or treatment intensity decline correspondingly.<sup>##REF##30977557##50##</sup> Furthermore, it remains unclear whether active purchasing or patient choice drives these results.<sup>##REF##15755946##43##,##REF##30977557##50##</sup> Paradoxically, we found extensive differences in selective contracting between providers and over time, without any distinguishable effect on provider budgets. Potential explanations include selective contracting having limited impact on patient flows,<sup>##REF##28381338##51##</sup> with insurers required to (partially) reimburse noncontracted care,<sup>##REF##23399042##17##</sup> hospitals levering market power to compensate reductions in income,<sup>##REF##27923494##52##</sup> hospitals shifting costs between insurers as a response to selective contracting,<sup>##REF##21418314##53##</sup> or insurers using selective contracting to concentrate care symmetrically between providers without affecting total expenditures.<sup>##UREF##21##54##</sup> In theory, selective contracting could even steer patients towards high-quality providers without affecting total provider expenditures, for example if prices adjust downwards to compensate increases in the number of patients. Additional studies on the correlation between active purchasing (eg, selective contracting) and quality measures could further elucidate the role of active purchasing in stimulating market efficiency.</p>", "<title> Strengths and Limitations</title>", "<p> This research provides a new indicator to empirically investigate reallocations of funds between providers as a proxy for active purchasing. However, factors unrelated to purchasing may influence market share changes, such as shifts in financing arrangements and socio-demographic trends. Due to these limitations, MAI should be interpreted as one proxy for active purchasing, acknowledging that external factors may affect MAI. Furthermore, purchasing may constitute actions that do not result in reallocations of funds. For example, active purchasing may focus on across-the-board quality improvements or cost containment without affecting provider expenditures. Recent examples of multi-year fixed budget contracts aiming to improve quality indicate that insurers may use other strategies to improve efficiency.<sup>##UREF##22##55##, ####REF##30685212##56##, ##UREF##23##57####23##57##</sup> Insurers may also aim to direct active purchasing to concentrate specific types of care and reduce other types of care within a hospital, without affecting the total budget, as is suggested by the high extent of selectively contracting specific procedures in the Netherlands. In theory, concentration efforts could be reciprocal between providers, resulting in improved efficiency without budgetary changes.<sup>##UREF##21##54##</sup> This would cause the MAI to underestimate active purchasing. Ideally, detailed data on provider expenditures per location and per payer would allow us to test these alternative explanations, but collecting these detailed data is an area for future research.</p>", "<p> Data constructs may also affect MAI. Data errors unequivocally increase MAI. Contrary, if small providers, which are exempted from the dataset experience higher reallocations, MAI may be underestimated. Especially for municipal care and personal budget care, only data for relatively large, formal care providers is available. If independent contractors and specialised cleaning/household assistance companies, which are missing from the dataset, experience higher reallocations, MAI is biased downwards. Missing providers may also reduce external validity of our explanatory analyses. Potentially, quality and MAI could be correlated for very small providers outside the dataset. However, the results are valid for large providers covering 93% of total spending. Furthermore, internal validity of the results from the explanatory regression analysis seems unaffected by imputation of missing values.</p>", "<p> While the MAI may be used to compare health systems, the optimal or baseline level of reallocations remains undetermined. A certain amount of reallocations are necessary to accommodate demographic changes and improve efficiency, but very high budgetary volatility may risk provider continuity. Furthermore, reallocations do not necessarily imply improved efficiency, ie, being geared towards high quality providers.</p>", "<title> Policy Implications and Suggestions for Future Research</title>", "<p> Despite theory predicting that managed competition should increase reallocations of funds between providers, evidence finds relatively low reallocations in the Dutch hospital sector. While provider expenditures in the Dutch system are constrained by global budget agreements, users may still have a significant role: if users are inclined to visit the nearest hospital only, there may be little room to reallocate provider expenditures. That would render competitive payer reforms useless in terms of allocative efficiency. However, studies do demonstrate some willingness to travel for care or acceptance of restrictive policies.<sup>##REF##22425770##49##,##REF##17256180##58##,##REF##35644719##59##</sup> Furthermore, municipal care and personal budgets do show potential for high MAI. Especially in a small, rich, very densely populated country with high quality road infrastructure such as the Netherlands, potential for competitive payer reform to improve allocative efficiency exists. Possibly, implementation of managed competition in the Netherlands is imperfect, for example due to a lack of quality transparency.<sup>##REF##23399042##17##</sup> Improving valid quality indicators may enable insurers to select well-performing providers.</p>", "<p> Other potential explanations may be more structural: payers may lack legitimacy, bargaining power and purchasing tools to reallocate budgets.<sup>##REF##32749005##37##</sup> For example, establishing a good relationship with providers may be beneficial for improving outcomes, but may hinder active purchasing.<sup>##REF##10388198##40##,##UREF##24##60##,##UREF##25##61##</sup> Evidence from Germany stipulates frictions due to competition in a corporatist health system.<sup>##REF##27908564##62##</sup> Lastly, in the United Kingdom active purchasing was found to be incompatible with the mindset of commissioners.<sup>##UREF##26##63##</sup> A similar explanation could be applicable to the Netherlands: both insurers and LTC- providers may experience difficulties in deciding which provider patients should visit. On the other hand, evidence from the United States and the Netherlands suggests that purchasers are to a certain extent able and willing to steer patients.<sup>##REF##28381338##51##,##REF##11055452##64##,##REF##9639337##65##</sup> However, purchasers may be more inclined to retain the status-quo. Boonen and Schut hypothesize the credible commitment problem: if consumers do not trust purchasers to act prudently on their behalf, insurers fear loss of reputation and customers upon selective contracting of providers.<sup>##REF##25261074##6##,##REF##21122187##66##</sup></p>", "<p> Concentrated purchaser markets may exert market power over providers. While purchaser concentration increased during our study period, reallocations of funds between providers did not. Possibly, increases in purchaser concentration were counteracted by increases in provider concentration. Additional research on purchaser-provider bargaining is required to assess the effect of market concentration on allocative efficiency. Related, reallocations require sufficient potential of providers to increase capacity, or -in case of budgetary reductions- to reduce expenditures, eg, personnel or capital expenditures. The expenditure side might be relatively fixed, so large changes in the budget might risk provider continuity. As insurers are obliged to procure sufficient volumes of care, insufficient flexibility and excess capacity may form a barrier for reallocation of budgets in the hospital market. We find that provider concentration is associated with higher reallocations, consistent with some but not all literature.<sup>##UREF##14##30##, ####REF##18038246##31##, ##UREF##15##32##, ##UREF##16##33####16##33##</sup></p>", "<p> Managed competition has been advocated to constrain total costs, although this was not the main objective of the 2007 competitive reform.<sup>##UREF##6##20##,##REF##27066728##67##</sup> If insurers pursue cost containment under managed competition uniformly, this could be reflected in a low MAI. However, between 2007 and 2012 hospital expenditures grew rapidly.<sup>##UREF##6##20##</sup> In 2012, the government addressed fast growing hospital expenditures by negotiating agreements between hospital and insurer representatives to cap real overall hospital growth to 2.5% per year. These industry agreements were renewed in 2018, with real growth rates gradually declining towards 0% in 2022. These agreements did not formally prevent budget reallocations, as within the total hospital budget, purchasers were still expected to negotiate individual budgets, but the 2.5% limit may have informally functioned as an anchor in individual negotiations. While this could have reduced reallocations, no clear trend break was found after 2012.</p>", "<p> Governments contemplating competitive reforms and managed competition may find these measures insufficient to improve allocative efficiency. Besides improving market preconditions — eg, quality transparency, sufficient provider capacity, adequate antitrust policy —, monitoring and benchmarking purchaser activity could further incentivise improvements in efficiency-driven budget reallocations.<sup>##REF##22668608##68##</sup> The MAI could be used as one of the indicators for purchaser performance.</p>" ]	[ "<title>Conclusion</title>", "<p> Contrary to the theory of managed competition, low reallocations of funds between providers were found in the competitive Dutch hospital sector, questioning the premise that managed competition improves allocative efficiency by means of selectively contracting high-quality providers. Competitive reform and managed competition may not be sufficient to ensure static and dynamic efficiency in the healthcare market. Policy-makers may need to monitor progress, remove barriers and adjust incentives to obtain well-functioning healthcare markets. The MAI provides a useful indicator for policy-makers to monitor allocative activity in different purchaser systems.</p>" ]	[ "<p>\n<bold>Background:</bold> Purchasing systems aim to improve resource allocation in healthcare markets. The Netherlands is characterized by four different purchasing systems: managed competition in the hospital market, a non-competitive single payer system for long-term care (LTC), municipal procurement for home care and social services, and self-procurement via personal budgets. We hypothesize that managed competition and competitive payer reforms boost reallocations of provider market share by means of active purchasing, ie, redistributing funds from high-quality providers to low-quality providers.\n</p>", "<p><bold>Methods:</bold> We define a Market Activity Index (MAI) as the sum of funds reallocated between providers annually. Provider expenditures are extracted from provider financial statements between 2006 and 2019. We compare MAI in six healthcare sectors under four different purchasing systems, adjusting for reforms, and market entry/exit. Next, we perform in-depth analyses on the hospital market. Using multivariate linear regressions, we relate reallocations to selective contracting, provider quality, and market characteristics.\n</p>", "<p><bold>Results:</bold> No difference was found between reallocations in the hospital care market under managed competition and the non-competitive single payer LTC (MAI between 2% and 3%), while MAI was markedly higher under procurement by municipalities and personal budget holders (between 5% and 15%). While competitive reforms temporarily increased MAI, no structural effects were found. Relatively low hospital MAI could not be explained by market characteristics. Furthermore, the extent of selective contracting or hospital quality differences had no significant effects on reallocations of funds.\n</p>", "<p><bold>Conclusion:</bold> Dutch managed competition and competitive purchaser reforms had no discernible effect on reallocations of funds between providers. This casts doubt on the mechanisms advocated by managed competition and active purchasing to improve allocative efficiency.</p>", "<p>\n<bold>Citation:</bold> Stadhouders NW, Koolman X, Tanke MAC, Maarse H, Jeurissen PPT. Measuring active purchasing in healthcare: analysing reallocations of funds between providers to evaluate purchasing systems performance in the Netherlands. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7506. doi:10.34172/ijhpm.2023.7506</p>" ]	[ "<title>Acknowledgements</title>", "<p> The authors would like to acknowledge Raf van Gestel and participants of the LolaHESG conference 2016 for constructive comments on a previous version of this manuscript.</p>", "<title>Ethical issues</title>", "<p> No approval from an ethical committee was required, as the study was conducted on publicly available datasets according to Dutch regulations (WTZa, Wet Toetreding Zorgaanbieders). Dutch legislature exempt ethics approval for studies that use aggregate, pseudonomized data (WMO, Wet Medisch-wetenschappelijk onderzoek met mensen). Use of publicly available company data is permitted for scientific research under Dutch legislation (AGV, algemene verordening gegevensbescherming).</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Endnotes</title>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nMarket Activity Index Over Time for Dutch Healthcare Sectors, 2006/2007-2018/2019.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nMean Market Activity Index for Dutch Healthcare sectors in Non-reform Years, 2007/2008-2018/2019.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Overview of Sectors in Dutch Healthcare Between 2007 and 2019\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Health System</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Hospital Care</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>LTC </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Social Care Services</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Personal Budgets</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Law</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Health insurance Act (Zvw)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Up to 2015: Exceptional Medical Expenses Act (AWBZ). As of 2015: Long-term Care Act (WLZ)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Social Care Act (WMO<sup>a</sup>)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Included in AWBZ/WLZ and WMO/Zvw</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Purchaser type</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Competitive multi-payer system (health insurers)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Single payer system (regional care offices)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Single payer system (municipalities)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Self-purchasing</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Care sectors</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Hospital care, short-term mental care, primary care<sup>b</sup>, home nursing care (as of 2015)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Elderly care, disability care, long term mental care, home care (up to 2015)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Social support, youth care<sup>c</sup>, ancillary home care services (expanded in 2015)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Personal budgets for LTC and home care</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public expenses in 2019</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">€49 billion</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">€24 billion</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">€7 billion</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">€2 billion</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Financing system</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Premiums (set by insurer) and income-related contributions (set by government)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Payroll-related contributions (set by government)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Tax funded grant to municipalities (set by government)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Tariffs about 70% of LTC</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Incentives to purchase actively</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes, budgetary gains may result in competitive advantage through lower premiums</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No, budgetary gains of active purchasing flow back to the government </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes, budgetary gains can be used to fund other municipal projects</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes, budgetary gains accrue to the patient</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Financial risk of payer</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Increased over time through reduced ex-post equalization</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Absent (overspending is forbidden)</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">High (no ex-post equalization)</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">High (personal two-way risk)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Main Regression Results (Pooled Linear Regression With Clustered Standard Errors And Year Fixed-Effects)\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Relative Market Share Changes</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Absolute Market Share Changes</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Relative Market Share Changes, Including HSMR</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Absolute Market Share Changes, Including HSMR</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Delta ACI</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">‎-0.04 (0.04) ‎</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">‎-0.04 (0.06)‎</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">‎-0.03 (0.06) ‎</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">‎0.03 (0.05)‎</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">MS (t-1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-1.76* (0.84) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎4.00 (1.45)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.70 (1.02) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎2.84* (0.77)‎</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">MS<sup>2</sup>(t-1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎35.47* (15.97) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-50.99 (32.91)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-15.31 (26.18) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-34.90* (14.11)‎</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">FC (t-1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.02 (0.02) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.03* (0.01)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.05 (0.15) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.124 (0.12)‎</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">ITC dummy </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.02 (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.03 (0.03)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎#‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎#‎</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Structural Q (t-1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.002 (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.01 (0.01)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.03 (0.02) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.03 (0.02)‎</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Process Q (t-1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.005 (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.01 (0.01)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.01 (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.01 (0.01)‎</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Outcome Q (t-1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.002 (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.01 (0.01)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.02 (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.01 (0.02)‎</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">HSMR (t-1)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.03 (0.02) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.02 (0.01)‎</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Year = 2016</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\">Baseline</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Year = 2017</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.01 (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.01 (0.01)‎</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\">Baseline</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Year = 2018</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.03** (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.01 (0.01)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.02* (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.001 (0.005)‎</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Year = 2019</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.03 (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.01 (0.01)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.02* (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.004 (0.005)‎</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Constant</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.01* (0.01) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎-0.001 (0.01)‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.01 (0.02) ‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎0.03 (0.02)‎</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"># Observations</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎285‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎285‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎185‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎185‎</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">F-statistic</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎4.6‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎6.8‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎3.7‎</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">‎4.5‎</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">R<sup>2</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">‎0.08‎</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">‎0.16‎</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">‎0.11‎</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">‎0.18‎</td></tr></tbody></table></table-wrap>" ]	[ "<disp-formula id=\"DF1\">\n<label>(1)</label>\n<mml:math id=\"m1\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mi>M</mml:mi><mml:msubsup><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow><mml:mi>k</mml:mi></mml:msubsup><mml:mo>=</mml:mo><mml:msubsup><mml:mi>E</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow><mml:mi>k</mml:mi></mml:msubsup><mml:mo>/</mml:mo><mml:msubsup><mml:mi>S</mml:mi><mml:mi>t</mml:mi><mml:mi>k</mml:mi></mml:msubsup></mml:mrow></mml:math>\n</disp-formula>", "<disp-formula id=\"DF2\">\n<label>(2)</label>\n<mml:math id=\"m2\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mi>M</mml:mi><mml:mi>A</mml:mi><mml:msubsup><mml:mi>I</mml:mi><mml:mi>t</mml:mi><mml:mi>k</mml:mi></mml:msubsup><mml:mo>=</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mstyle displaystyle=\"true\"><mml:munderover><mml:mo>∑</mml:mo><mml:mn>1</mml:mn><mml:mi>I</mml:mi></mml:munderover><mml:mrow><mml:mfenced close=\"\|\" open=\"\|\"><mml:mrow><mml:mi>M</mml:mi><mml:msubsup><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow><mml:mi>k</mml:mi></mml:msubsup><mml:mo>−</mml:mo><mml:mi>M</mml:mi><mml:msubsup><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mi>k</mml:mi></mml:msubsup></mml:mrow></mml:mfenced></mml:mrow></mml:mstyle></mml:mrow></mml:math>\n</disp-formula>", "<disp-formula id=\"DF3\">\n<label>(3)</label>\n<mml:math id=\"m3\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:msubsup><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>M</mml:mi><mml:mi>A</mml:mi><mml:mi>I</mml:mi></mml:mrow><mml:mo stretchy=\"true\">^</mml:mo></mml:mover></mml:mrow><mml:mi>t</mml:mi><mml:mi>k</mml:mi></mml:msubsup><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mi>M</mml:mi><mml:mi>A</mml:mi><mml:msub><mml:mi>I</mml:mi><mml:mi>t</mml:mi></mml:msub></mml:mrow><mml:mrow><mml:mstyle displaystyle=\"true\"><mml:msubsup><mml:mo>∑</mml:mo><mml:mn>1</mml:mn><mml:mi>I</mml:mi></mml:msubsup><mml:mrow><mml:mi>M</mml:mi><mml:msubsup><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow><mml:mi>k</mml:mi></mml:msubsup></mml:mrow></mml:mstyle></mml:mrow></mml:mfrac></mml:mrow></mml:math>\n</disp-formula>", "<disp-formula id=\"DF4\">\n<label>(4)</label>\n<mml:math id=\"m4\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mi>M</mml:mi><mml:mi>A</mml:mi><mml:msubsup><mml:mi>I</mml:mi><mml:mi>t</mml:mi><mml:mi>k</mml:mi></mml:msubsup><mml:mo>=</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mn>2</mml:mn><mml:mi>n</mml:mi></mml:mrow></mml:mfrac><mml:mstyle displaystyle=\"true\"><mml:munderover><mml:mo>∑</mml:mo><mml:mn>1</mml:mn><mml:mi>I</mml:mi></mml:munderover><mml:mrow><mml:mfenced close=\"\|\" open=\"\|\"><mml:mrow><mml:mi>M</mml:mi><mml:msubsup><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow><mml:mi>k</mml:mi></mml:msubsup><mml:mo>−</mml:mo><mml:mi>M</mml:mi><mml:msubsup><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mi>n</mml:mi></mml:mrow><mml:mi>k</mml:mi></mml:msubsup></mml:mrow></mml:mfenced></mml:mrow></mml:mstyle></mml:mrow></mml:math>\n</disp-formula>", "<disp-formula id=\"DF5\">\n<label>(5)</label>\n<mml:math id=\"m5\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mi>Δ</mml:mi><mml:msub><mml:mi>m</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mi>Δ</mml:mi><mml:mi>A</mml:mi><mml:mi>C</mml:mi><mml:msub><mml:mi>I</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:msub><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>3</mml:mn></mml:msub><mml:msubsup><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mn>2</mml:mn></mml:msubsup><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>4</mml:mn></mml:msub><mml:mi>F</mml:mi><mml:msub><mml:mi>C</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>5</mml:mn></mml:msub><mml:mi>I</mml:mi><mml:mi>C</mml:mi><mml:msub><mml:mi>T</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:mi>β</mml:mi><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mi>β</mml:mi><mml:mi>t</mml:mi><mml:mo>+</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math>\n</disp-formula>", "<disp-formula id=\"DF6\">\n<label>(6)</label>\n<mml:math id=\"m6\" display=\"block\" overflow=\"scroll\"><mml:mrow><mml:mfenced close=\"\|\" open=\"\|\"><mml:mrow><mml:mi>Δ</mml:mi><mml:msub><mml:mi>m</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>0</mml:mn></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mfenced close=\"\|\" open=\"\|\"><mml:mrow><mml:mi>Δ</mml:mi><mml:mi>A</mml:mi><mml:mi>C</mml:mi><mml:msub><mml:mi>I</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:msub><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>3</mml:mn></mml:msub><mml:msubsup><mml:mi>S</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mn>2</mml:mn></mml:msubsup><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>4</mml:mn></mml:msub><mml:mi>F</mml:mi><mml:msub><mml:mi>C</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>5</mml:mn></mml:msub><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>β</mml:mi><mml:mn>6</mml:mn></mml:msub><mml:mi>I</mml:mi><mml:mi>C</mml:mi><mml:msub><mml:mi>T</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:mi>β</mml:mi><mml:mi>t</mml:mi><mml:mo>+</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math>\n</disp-formula>" ]	[ "<boxed-text id=\"BT2\" position=\"float\"><sec id=\"bx2\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Competitive payer system reforms, such as managed competition, do not necessarily lead to increased reallocations of funds. </p></list-item><list-item><p>Furthermore, existing market share reallocations between hospitals did not correlate to selective contracting or quality measures. </p></list-item><list-item><p>The market activity index (MAI) can be used to monitor budget reallocations as a proxy for efficiency gains. </p></list-item><list-item><p>Concurrently, alternative pathways to increase efficiency should be pursued, rather than relying solely on budgetary reallocations. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> As health costs rise, ensuring that money is spend well becomes increasingly important. However, the extent that purchasers, either health insurance companies or government agencies, allocate budgets towards high-quality providers is currently unknown. Theory predicts that competitive reform stimulates efficient allocation of funds. However, comparing different purchasing systems in the Netherlands reveals little evidence of elevated allocative activity. This suggests that competitive reforms may either have limited effect on healthcare efficiency, or currently unknown mechanisms are used to improve efficiency by competitive third-party payers. Our results can guide purchasers and policy-makers to improve efforts to steer funds towards the most efficient providers.</p></sec></boxed-text>", "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title><bold>Box 1.</bold> A Closer Examination of the Market Activity Index</title><p> The MAI is a measure of market stability: a low MAI signals that providers have relatively stable shares in the market over time. Contrary, high MAI signals volatility. The optimal MAI is uncertain: it is nonzero, as reallocations towards efficient providers is desired. Furthermore, markets need to respond to trends in consumer needs, demographics and innovation, which increases MAI when providers are impacted heterogeneously. However, volatile markets may have high costs of acquiring capital and lost investments due to bankruptcies. The optimal MAI is likely dependent on market characteristics, which means that each market has a unique optimum, which may change over time. For example, emerging markets tend to be highly volatile, while mature markets may me more stable. High volatility is expected in markets with low fixed investments and low cost of entry and exit.</p><p> External trends may further impact MAI. For example, temporary losses of provider income (eg, due to renovations) unambiguously increase MAI. Mergers and acquisitions have a major impact MAI, as acquired providers transfer their full market shares to the new parent company. Therefore, we correct for mergers retrospectively to account for these administrative changes. This does allow for real effects of mergers, eg, due to increased market power of the merged company or due to concentration of specialized care. These real effects may be considered as part of market activity potentially impacted by active purchasing and are included in the MAI. Bankruptcies, whether or not the result of active purchasing, unambiguously increase MAI. Lastly, policy changes may impact MAI. These may be administrative changes in funding, for example when certain services are transferred from one sector to another. If these services are distributed heterogeneously between providers, MAI is expected to increase due to denominator effects. Real policy changes, eg, investments in quality or cost containment, may increase MAI if effects are distributed heterogeneously over providers. While there have been minor policy changes during the study period that predominantly impact sectoral spending [1], they likely have a minor impact on the MAI. It is difficult to correct for these contributing factors, implying that the MAI overestimates reallocations resulting from active third party purchasing.</p><p> The relation between competitiveness and reallocation of funds is ambiguous. In equilibrium, perfectly competitive markets may exhibit low reallocations. However, small perturbations may induce large changes in allocations. Reallocations may be expected to decline in more concentrated markets if market power is exerted by providers to retain market shares. Traditional market indicators, such as the Hirschman-Herfindahl index and comparable concentration indices carry the implicit assumption that more competitive, ie, less concentrated markets perform better. However, allocative changes due to active purchasing generally have little effects on concentration indices, and may even leave them unaffected, for example when funds are reallocated between providers without affecting the overall distribution of funds. Conversely, mergers may impact concentration indices without affecting real budgetary allocations. The assumption that less concentrated markets function better may not hold in regulated markets, where concentration and reduced competitivity are reasons to install active third-party purchasers in the first place. This calls for additional indicators that measure actual market performance, of which reallocations of funds between providers is one factor. However, other indicators may be needed; third parties may engage in strategic purchasing that leave the MAI unaffected. Examples include uniform across-the-board quality improvements or cost containment, as well as activities that aim to improve provider efficiency within a fixed budget. So while MAI is one indicator of active third party purchasing, it may not fully capture all potential outcomes of active purchasing.</p><p>----------------------</p><p> Abbreviation: MAI, market activity index.</p><p>\n<sup>a</sup> For example, short term recovery for elderly (€0.7 billion) was transferred from LTC to hospital care in 2013.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1 contains Figures S1-S6 and Tables S1-S9.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: LTC, long-term care; Zvm, Zorgverzekeringswet; AWBZ, Algemene wet bijzondere ziektekosten; WLZ, Wet Langdurige Zorg; WMO, Wet maatschappeljke ondersteuning.</p><p>\n<sup>a</sup> WMO was expanded in 2015 (WMO-2015).</p><p>\n<sup>b</sup> Primary care includes family physician care, dental care, physiotherapy, pharmaceuticals and paramedical treatments. Primary care is not included in our dataset.</p><p>\n<sup>c</sup> Youth care includes specialty (mental) care for children and parents, and is excluded from the dataset.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: ACI, average contracting index; MS, market share; HSMR, hospital standardized mortality ratio; ITC, independent treatment center; FC, Fixed costs.</p><p> # Omit-ted due to collinearity (all observations of HSMR have ITC = 0). Standard errors are in parentheses.</p><p> * 5% significance; 1% significance; * 0.1% significance.</p></fn></table-wrap-foot>", "<fn-group><fn id=\"fn1\"><p> [1] For example, if a payer reallocates 5% of the market, he takes 5% from providers and gives 5% to other providers. The sum of absolute changes in the market is 10%, but the percentage of the market that has been redistributed is half that (5%).</p></fn><fn id=\"fn2\"><p> [2] For example, if insurer A contracts provider X for 300 of the 400 potential types of care, the contracting index is 0.75.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"ijhpm-12-7506-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7506-g002\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7506-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["2"], "mixed-citation": [" Arrow KJ. Uncertainty and the Welfare Economics of Medical Care (American Economic Review, 1963). Duke University Press; 2003. "]}, {"label": ["7"], "mixed-citation": [" Mays N, Hand K. A Review of Options for Health and Disability Support Purchasing in New Zealand. New Zealand Treasury; 2000. "]}, {"label": ["10"], "mixed-citation": [" Smith J, Mays N, Dixon J, et al. A Review of the Effectiveness of Primary Care-Led Commissioning and its Place in the NHS. London: The Health Foundation; 2004. "]}, {"label": ["13"], "mixed-citation": [" Figueras J, Robinson R, Jakubowski E. Purchasing to Improve Health Systems Performance. McGraw-Hill Education (UK); 2005. "]}, {"label": ["14"], "person-group": ["\n"], "surname": ["Jeong", "Niki"], "given-names": ["HS", "R"], "article-title": ["Divergence in the development of public health insurance in Japan and the Republic of Korea: a multiple-payer versus a single-payer system"], "source": ["Int Soc Secur Rev"], "year": ["2012"], "volume": ["65"], "issue": ["2"], "fpage": ["51"], "lpage": ["73"], "pub-id": ["10.1111/j.1468-246X.2012.01428.x"]}, {"label": ["16"], "person-group": ["\n"], "surname": ["Enthoven"], "given-names": ["AC"], "article-title": ["Managed competition: an agenda for action"], "source": ["Health Aff (Millwood)"], "year": ["1988"], "volume": ["7"], "issue": ["3"], "fpage": ["25"], "lpage": ["47"], "pub-id": ["10.1377/hlthaff.7.3.25"]}, {"label": ["20"], "mixed-citation": [" Jeurissen P, Maarse H. The Market Reform in Dutch Health Care: Results, Lessons and Prospects. Copenhagen, Denmark: European Observatory on Health Systems and Policies; 2021. "]}, {"label": ["21"], "mixed-citation": [" NZa. Marktscan Zorgverzekeringsmarkt 2017. Utrecht: NZa; 2017. "]}, {"label": ["22"], "mixed-citation": [" NZa. Marktscan Zorgverzekeringen 2021. Utrecht: NZa; 2021. "]}, {"label": ["23"], "mixed-citation": [" Schut E, Sorbe S, H\u00f8j J. Health Care Reform and Long-Term Care in the Netherlands. OECD Economics Department Working Papers, No. 1010. Paris: OECD Publishing; 2013. "], "pub-id": ["10.1787/5k4dlw04vx0n-en"]}, {"label": ["24"], "mixed-citation": [" Mot ES, Aouragh A. The Dutch System of Long-Term Care. ENEPRI; 2010. "]}, {"label": ["25"], "mixed-citation": [" Uenk N. Commissioning of Social Care Services: Municipal Commissioning Approaches for Social Care Services-Evidence from a Countrywide Live Experiment [dissertation]. Universiteit Utrecht; 2019. "]}, {"label": ["26"], "mixed-citation": [" Putters K, Grit K, Janssen M, Schmidt D, Meurs P. Governance of Local Care and Social Service. Erasmus School of Health Policy & Management (ESHPM); 2010. "]}, {"label": ["28"], "mixed-citation": [" CIBG. Jaarverantwoording in de zorg (DigiMV). In: CIBG, ed. Den Haag; 2007-2019. "]}, {"label": ["30"], "mixed-citation": [" Gaynor M, Vogt WB. Antitrust and competition in health care markets. In: Handbook of Health Economics. Vol 1. Elsevier. 2000:1405-1487. "], "pub-id": ["10.1016/s1574-0064(00)80040-2"]}, {"label": ["32"], "mixed-citation": [" Mosca I, Pomp M, Shestalova V. Market Share and Price in Dutch Home Care: Market Power or Quality? CPB Netherlands Bureau for Economic Policy Analysis; 2007. "]}, {"label": ["33"], "person-group": ["\n"], "surname": ["Gaynor", "Ho", "Town"], "given-names": ["M", "K", "RJ"], "article-title": ["The industrial organization of health-care markets"], "source": ["J Econ Lit"], "year": ["2015"], "volume": ["53"], "issue": ["2"], "fpage": ["235"], "lpage": ["284"], "pub-id": ["10.1257/jel.53.2.235"]}, {"label": ["35"], "mixed-citation": [" Rijksoverheid. Rijksbegroting 2014, XVI Volksgezondheid, Welzijn en Sport. "], "uri": ["https://www.rijksfinancien.nl/jaarverslag/2014/XVI2014"]}, {"label": ["36"], "mixed-citation": [" van Eijkel R, Kattenberg M. Competition and Pricing Behavior in Long Term Care Markets: Evidence from the Market for Assistance in Daily Housekeeping Activities. CPB Netherlands Bureau for Economic Policy Analysis; 2018. "]}, {"label": ["38"], "mixed-citation": [" Brereton L, Vasoodaven V. The Impact of the NHS Market. London: Civitas; 2010. "]}, {"label": ["41"], "person-group": ["\n"], "surname": ["Porter", "Mays", "Shaw", "Rosen", "Smith"], "given-names": ["A", "N", "SE", "R", "J"], "article-title": ["Commissioning healthcare for people with long term conditions: the persistence of relational contracting in England\u2019s NHS quasi-market"], "source": ["BMC Health Serv Res"], "year": ["2013"], "volume": ["13"], "issue": ["suppl 1"], "fpage": ["S2"], "pub-id": ["10.1186/1472-6963-13-s1-s2"]}, {"label": ["54"], "person-group": ["\n"], "surname": ["van der Schors", "Kemp", "Varkevisser"], "given-names": ["W", "R", "M"], "article-title": ["Collaboration and competition policy in a market-based hospital system: a case study from the Netherlands"], "source": ["J Compet Law Econ"], "year": ["2020"], "volume": ["16"], "issue": ["2"], "fpage": ["262"], "lpage": ["288"], "pub-id": ["10.1093/joclec/nhaa009"]}, {"label": ["55"], "mixed-citation": [" van Dulmen S, Stadhouders N, Westert G, Wackers E, Jeurissen P. Op weg naar hoge kwaliteit en lage kosten in de medisch specialistische zorg. Nijmegen: IQ healthcare; 2020. "]}, {"label": ["57"], "mixed-citation": [" CPB Policy Brief. Evaluation Programmes Beatrix Hospital and Bernhoven. CPB Netherlands Bureau for Economic Policy Analysis; 2020. "]}, {"label": ["60"], "person-group": ["\n"], "surname": ["Petsoulas", "Allen", "Checkland"], "given-names": ["C", "P", "K"], "article-title": ["Views of NHS commissioners on commissioning support provision Evidence from a qualitative study examining the early development of clinical commissioning groups in England"], "source": ["BMJ Open"], "year": ["2014"], "volume": ["4"], "issue": ["10"], "fpage": ["e005970"], "pub-id": ["10.1136/bmjopen-2014-005970"]}, {"label": ["61"], "person-group": ["\n"], "surname": ["Hughes", "Allen", "Doheny", "Petsoulas", "Vincent-Jones"], "given-names": ["D", "P", "S", "C", "P"], "article-title": ["Co-operation and conflict under hard and soft contracting regimes: case studies from England and Wales"], "source": ["BMC Health Serv Res"], "year": ["2013"], "volume": ["13"], "issue": ["Suppl 1"], "fpage": ["S7"], "pub-id": ["10.1186/1472-6963-13-s1-s7"]}, {"label": ["63"], "person-group": ["\n"], "surname": ["Checkland", "Harrison", "Snow", "McDermott", "Coleman"], "given-names": ["K", "S", "S", "I", "A"], "article-title": ["Commissioning in the English National Health Service: what\u2019s the problem?"], "source": ["J Soc Policy"], "year": ["2012"], "volume": ["41"], "issue": ["3"], "fpage": ["533"], "lpage": ["550"], "pub-id": ["10.1017/s0047279412000232"]}]	{ "acronym": [], "definition": [] }	68	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Sep 17; 12:7506	oa_package/f4/e9/PMC10590252.tar.gz
PMC10590253	0	[ "<title>Background</title>", "<p> Collaborations between pharmaceutical companies and healthcare professionals, healthcare institutions, such as regulatory bodies, hospitals or medical schools, and patient institutions are essential for understanding diseases and the development of novel drugs.<sup>##REF##32125404##1##,##REF##22371130##2##</sup> However, these collaborations often entail financial relationships leading to conflicts of interest (COIs). In addition to COIs affecting individual healthcare professionals, there are institutional COIs (ICOIs) arising at the level of recipient institutions or their subunits, such as hospital departments.<sup>##UREF##0##3##</sup> The National Academy of Medicine in the United States states that “institutional COIs arise when an institution’s own financial interests or those of its senior officials pose risks of undue influence on decisions involving the institution’s primary interests.”<sup>##UREF##0##3##</sup> ICOIs have received less attention than individual COIs as they are more difficult to identify and usually conform to legal norms because more stakeholders are involved compared to individual COIs. However, both individual COIs and ICOIs with pharmaceutical companies have repeatedly disturbed patient-centered care, leading to bias in research findings,<sup>##REF##31533704##4##</sup> influence on drug prescribing patterns<sup>##REF##27322350##5##, ####UREF##1##6##, ##REF##33226858##7####33226858##7##</sup> and recommendations of clinical guidelines.<sup>##REF##19407031##8##,##REF##17251529##9##</sup></p>", "<p> One of the most substantial and widespread examples of ICOIs is “scholarship donations” (<italic toggle=\"yes\">Shogaku-kifu</italic> in Japanese) unique to Japan. Scholarship donations are a traditional payment type that, to the best of our knowledge, does not exist outside of Japan.<sup>##REF##35047471##10##</sup> Although contracts between healthcare institutions and pharmaceutical companies typically undergo formal review at the administrative offices of recipient healthcare institutions, scholarship donations need not document specific purposes, usage, costs, or periods associated with payments. Namely, the term “scholarship donation” may be misleading, as it could imply a direct support for student tuition or training. While these donations may be presented with an educational purpose on the surface, they can also be used for non-educational purposes, such as hiring staff, holding social events, purchasing furniture, etc. Also, it differs from non-research payments for lecturing, consulting, and writing compensations. Unlike “unrestricted educational grants” or “unrestricted research grants,” “scholarship donations” do not necessarily imply a clear educational or research purpose, and their usage may be more flexible and open to potential COIs, underscoring the need to investigate this unique form of industry sponsorship in Japan. Due to these characteristics and flexibility in spending money obtained from pharmaceutical companies, scholarship donations have been vital in supporting the operation of many healthcare institutions in Japan.</p>", "<p> On the other hand, scholarship donations can easily have implicit promotional purposes by pharmaceutical companies, mostly highlighted in adverse cases such as the recent bribery case at the Mie University<sup>##REF##35047471##10##</sup> and the Diovan scandal.<sup>##REF##31099864##11##</sup> In the Diovan scandal, Novartis admitted paying about US$ 11 million scholarship donations for funding and honoraria to conduct five clinical trials. However, none of the trials disclosed that they were funded by scholarship donations,<sup>##REF##22232134##12##, ####REF##17363751##13##, ##REF##19723695##14##, ##REF##17467513##15##, ##REF##20927112##16##, ##REF##35351964##17####35351964##17##</sup> nor did they explain to patients the source of funding for the trials.<sup>##REF##35047471##10##</sup> After this scandal, several pharmaceutical companies, foreign pharmaceutical companies in particular such as Janssen Pharmaceutical K.K., Bristol-Myers Squibb Company, and Celgene Corporation, have quitted or reduced donating scholarship donations. As another example, Astellas Pharma has stopped making scholarship donations and instead has donated to the government agency to allocate their research funds to healthcare institutions and healthcare professionals since 2020. Also, the recent scandal of scholarship donation in exchange for the increased prescription at the Department of Anesthesiology, Mie University has led to discussions about closing the door on scholarship donations in all pharmaceutical companies in Japan, because the scholarship donation was judged as a bribe by the adjudgment in the first instance at a Japanese District Court. Meanwhile, many university hospitals in Japan face difficulties in continuing research due to a decrease in public research funds from the Japanese government.<sup>##REF##35047471##10##</sup> Under these circumstances, it might be the case that the scholarship donations have been playing a role in supporting healthcare institutions and professionals at universities to continue research in Japan.</p>", "<p> Inappropriately managed COIs between pharmaceutical companies and healthcare sectors have repeatedly triggered medical scandals in Japan.<sup>##REF##31099864##11##</sup> To manage COIs in line with other developed countries, the Japan Pharmaceutical Manufacturers Association (JPMA) set a transparency guideline in 2011, and based on this guideline, since 2013, full details of scholarship donations and their recipients have been required to be disclosed annually by companies on their websites. We previously reported that the disclosure and collection of payment data from pharmaceutical companies elucidated that a total of $203 380 412 scholarship donations were paid to healthcare institutions from the 71 member companies of the JPMA in 2016, which was as large as the amount of payments to healthcare professionals ($235 958 130) for lecturing, consulting, and writing in 2016.<sup>##REF##32439213##18##</sup> However, scholarship donations have not yet been analyzed systematically, in contrast to individual-level payments.<sup>##REF##31099864##11##,##REF##36353778##19##, ####REF##36705373##20##, ##REF##36729793##21##, ##UREF##2##22##, ##REF##34826620##23##, ##REF##33316403##24##, ##REF##33306236##25##, ##REF##35623883##26##, ##REF##35393417##27####35393417##27##</sup></p>", "<p> This study aimed to elucidate the extent and distribution of financial relationships between pharmaceutical companies and healthcare institutions in Japan, using publicly disclosed payment data of scholarship donations from all pharmaceutical companies belonging to the JPMA in 2017.</p>" ]	[ "<title>Methods</title>", "<title> Data Collection</title>", "<p> Payment data for the member of the JPMA were published on the website of each company at the time of data collection in 2019. Pharmaceutical companies that adhere to the transparency guideline disclose the amount of their scholarship donations as part of their academic research support expenses. The transparency guidelines are not mandatory, and there is no reporting requirement or penalty for violations when disclosing them, but most companies belonging to the JPMA report in detail. We collected payment data concerning scholarship donations from the 73 companies which belonged to the JPMA in 2017. Using the collected data, we generated a unified single database, as described previously.<sup>##REF##36353778##19##,##REF##36518089##28##</sup> Our database included the names of hospitals or university departments, the names of pharmaceutical companies, the monetary amounts of the payments, and the frequency of the payments. The unified database was stored by Microsoft Excel, version 16.0 (Microsoft Corp).</p>", "<title> Data Analysis </title>", "<p> After structuring the payment database, each payment was categorized, based on additional web searches, by the type of institution (university, research institution, specialty hospital, other hospitals such as community-based or privately-established, or unknown institution), institutional jurisdiction (national, private, or public such as prefectural or municipal), type of pharmaceutical companies (domestic or international), and department specialty.</p>", "<p> First, an individual investigator categorized the payments by the type of institution and institutional jurisdiction by searching the official websites of each institution and department. Second, the two investigators, AM and the investigator independently categorized the payments by specialty referring to the official website of each institution and department. Our original specialty category was based on the Japanese Medical Specialty Board. However, during the specialty classification, to capture the real picture of payments by specialty, the final specialty classification was discussed by AO, HS, and TT, and decided to specialize into 51 main categories including 28 clinical medicines, 12 basic medicines, 8 social medicine, and 3 other subjects related to the hospital sectors. Internal medicine and surgery were further divided into 14 internal medicine subcategories and 7 surgery subcategories.</p>", "<p> As for a department providing both surgical and medical procedures, we categorized it as “general.” For example, a department concerning oncology, which provides both surgical and medical therapy, was categorized as “General Oncology.” For departments containing more than one specialty, multiple classifications were adopted. For departments that we could not find information on official websites or official information, we contacted pharmaceutical companies or affiliated institutions by email for detailed information on the payments and the department. We filled in the department based on the response we received with detailed information from pharmaceutical companies and the institution for all departments. There were cases where we could not identify specialties for multiple payments.</p>", "<p> After the first specialty classification, the two data that AM and an individual investigator were each responsible for were integrated into one dataset. Then the integrated dataset was divided into three parts, and each part was scrutinized by three different reviewers (AM, an individual investigator, and one external research assistant) for the validity of the classification and discrepancies in the classification of departments with the same name. When discrepancies were found, we organized and cleaned the data to meet the final criteria of categorization. Finally, the three separate parts of the data were combined and used for analysis.</p>", "<p> Then we conducted descriptive analysis for the payment data by the type of institution, pharmaceutical companies, and department specialty. Pharmaceutical companies were classified as foreign companies and domestic companies based on the location of the company’s headquarters. A foreign company was defined as a pharmaceutical company whose headquarters was outside of Japan, and a domestic one was vice versa. We calculated the payments at the level of department, institution, pharmaceutical company, and specialty. In the analysis by specialties, when payment was classified in more than one specialty, the payment value was divided according to the number of specialties in which it was classified. Japanese yen was converted into US dollars using the 2017 average monthly exchange rate of ¥112.1 per $1. We conducted all statistical analyses using Microsoft Excel, version 16.0 (Microsoft Corp), and Stata version 15 (Stata Corporation).</p>" ]	[ "<title>Results</title>", "<p> We identified a total of 27 007 payments concerning scholarship donations worth $178 703 721 (¥20 032 687 112) from 67 pharmaceutical companies (67/73, 91.8%) to 4839 specific departments and laboratories at 251 different institutions in 2017.</p>", "<p>\n##TAB##0##Table 1## summarizes the characteristics of 251 institutions receiving scholarship donations and 67 pharmaceutical companies making scholarship donations. A breakdown of the institutions was as follows: 73 private universities (29.1%); 47 national universities (18.7%); 42 national hospitals (16.7%); 16 public universities (6.4%); 11 private research institutes (4.4%); 10 private hospitals (4.0%) and 52 other institutions (20.7%). All 82 medical schools in Japan received one or more scholarship donations (data not shown).</p>", "<p>\n##TAB##1##Table 2## shows the financial characteristics of scholarship donations. At the department level, each department or laboratory received scholarship donations worth of $36 930 on average (standard deviation [SD]: $58 073), and with the median of $16 503 (interquartile ranges [IQR]: $5 352‒$44 603). Similarly, the average and median scholarship donations were $711 967 (SD: $1 283 742) and $32 114 (IQR: $7136‒$1 219 224) per institution, respectively. Also, pharmaceutical companies made payments concerning scholarship donation worth of $2 666 827 (SD: $3 282 833) and $1 151 204 (IQR: $352 783‒$3 061 073) per company in average and median, respectively. 96.5% of payments are concentrated on university departments and laboratories.</p>", "<p> Data on scholarship donations were collected from 67 of the 73 pharmaceutical companies. This includes 52 domestic companies (96.3% of the 54 total domestic companies) and 15 foreign companies (78.9% of the 19 total foreign companies) (##TAB##2##Table 3## and ##SUPPL##0##Supplementary file 1##). Of the total payments, domestic companies contributed 77.1%, amounting to $137 797 302. In 2017, four foreign companies — Janssen Pharmaceutical K.K., Bristol-Myers Squibb Company, Celgene Corporation, and Shire Japan — did not make payments related to scholarship donations. Similarly, one domestic company, Seikagaku Corporation, did not make such payments. Kyowa Kirin Co., Ltd. made a scholarship donation payment and disclosed it, but we missed collecting the data during its disclosure period. When we later attempted to collect their 2017 payment data, the company started disclosing the 2018 data and declined our request to once again disclose the 2017 data. Chugai Pharmaceutical Co. Ltd. made the largest payment of $13 445 495 to 1325 departments and institutions, followed by Astellas with $11 684 211, Takeda with $10 316 057, Daiichi Sankyo with $9 750 277, and Eisai with $9 365 745. Among the top ten pharmaceutical companies with the largest scholarship donations, eight companies were domestic pharmaceutical companies, while two foreign pharmaceutical companies, MSD and Pfizer made the eighth and ninth largest payments concerning scholarship donations, respectively.</p>", "<p> As for specialty, 89.6% of scholarship donations concentrated on 28 clinical medicine specialties including internal medicine, surgery, orthopedic surgery, urology, dermatology, and ophthalmology (##SUPPL##1##Supplementary file 2##). Among them, internal medicine occupied 46.0% ($82 236 275) of the total scholarship donations from the pharmaceutical companies in 2017, followed by surgery ($18 430 776, 10.3%), orthopedic surgery ($9 055 291, 5.1%), urology ($8 544 900, 4.8%), and dermatology ($6 964 935, 3.9%). Among all 70 specialties including 14 internal medicine and 7 surgical sub-specialties, the amounts made to top-three specialties (endocrinology, cardiology, and gastroenterology) totaled $40 981 299, which was equivalent to 22.9% of the total scholarship donations in 2017. Of all scholarship donations, 6.2% were allocated to 12 basic medicine specialties, including pharmacology, oncology, biochemistry, and medical engineering. Meanwhile, 2.0% were distributed among eight social medicine specialties. (##FIG##0##Figure##).</p>" ]	[ "<title>Discussion</title>", "<p> This study found that a total of $178 703 721 of scholarship donations, which is a major source of non-research ICOIs among Japanese medical society, were paid to 4839 specific departments and laboratories at 251 different institutions by 67, primarily domestic, pharmaceutical companies. The distribution of scholarship donations concentrated on several particular clinical medicine specialties such as endocrinology, cardiology, and gastroenterology. We firstly elucidated Japan’s scholarship donations, although such financial relationships between the pharmaceutical companies and healthcare institutions are different from those of the United States<sup>##REF##32897778##29##,##REF##31848860##30##</sup> and the United Kingdom.<sup>##REF##31225896##31##, ####REF##34874975##32##, ##REF##29298763##33####29298763##33##</sup> Our previous study found that the scholarship donation accounted for 11.5% of all non-research payments and was equivalent to the payments to healthcare professionals in 2016.<sup>##REF##36353778##19##</sup> Our current study additionally clarified that a roughly equal amount of scholarship donations were made by pharmaceutical companies in 2016 ($179 937 555) compared to those in 2017 ($178 703 719). Our findings suggest that financial relationships between pharmaceutical companies and healthcare institutions in Japan may continue to persist, suggesting a deeply ingrained custom. It is true that a majority of the pharmaceutical companies are quitting this custom following the recent scandal in Mie University.<sup>##REF##35047471##10##</sup> However, further longitudinal studies are needed to understand the intentions and motivations of both players in maintaining these relationships.</p>", "<p> First, we found that most of the major pharmaceutical companies in Japan, especially domestic companies, made substantial amounts of scholarship donations to healthcare institutions in 2017. Foreign companies typically conform to Western standards, while Japanese companies often follow traditional home-grown rules. This difference would be particularly relevant in the case of scholarship donations. By distinguishing between foreign and domestic companies, we elucidated the role of these donations in shaping industry payments and the implications for physician-industry relationships in Japan. Despite its unique feature where the scholarship donation does not specify its usage, we can partly analogize it to non-research payments to healthcare institutions in other countries. As for non-research payments to healthcare institutions in the United Kingdom, Ozieranski et al reported that 4028 healthcare institutions received $72 110 157 from 100 pharmaceutical companies in 2015.<sup>##REF##31225896##31##</sup> The pharmaceutical companies paid $36 487 990 in donations and grants in the United Kingdom. Similarly, Anderson et al found that 1170 US teaching hospitals, equivalent to 91.3% of all teaching hospitals in the United States, received $831 938 468 non-research payments from 529 pharmaceutical companies and medical device manufacturer companies in 2018.<sup>##REF##31848860##30##</sup> Of all non-research payments made by the companies, 75.2% ($625 700 554) were made for royalty or licenses, and 12.2% ($101 642 765) were for educational purposes. Among the $831 938 468 non-research payments, $315 813 239 (38.0%) were related to biologics or drugs. Therefore, the amount of Japanese scholarship donations in 2017 was 4.90 times higher than the non-research payments from all UK pharmaceutical companies, and 1.76 times higher than the non-research payments from all pharmaceutical companies in the United States, even though the pharmaceutical market size of Japan was less than one-fifth that of the United States (US$ 87.3 billion in Japan vs US$ 508.7 billion in the United States). Given that the US Open Payments Database covers payments from all pharmaceutical and medical device companies and our payment database covered payments from only pharmaceutical companies belonging to the JPMA, the Japanese pharmaceutical companies made much more substantial payments to healthcare institutions as non-research payments than those in other developed countries.</p>", "<p> Second, this study found that $172 512 024 (96.5%) of scholarship donations were distributed to the universities, and all 82 Japanese universities with medical schools received payments from pharmaceutical companies. Considering the nature of medical schools where medical students learn role models for the future, less transparent non-research payments that do not clarify the direct purpose of the payments, such as the scholarship donation, might bias and influence medical education in the universities, clinical practice by university clinicians, and result in less evidence-based treatment leading to wasteful medical spending. In the case of opioid prescription, Anderson et al suggested that the US teaching hospitals should voluntarily prohibit accepting non-research payments from pharmaceutical companies marketing opioids. Indeed, historically, Japan’s scholarship donations have been utilized as hidden research funds and bribes, as in the case of the Diovan scandal<sup>##REF##31099864##11##</sup> and the Mie University.<sup>##REF##35047471##10##</sup></p>", "<p> We found that most major domestic pharmaceutical companies paid scholarship donations to healthcare professionals. In this sense, it is also important to recognize that the debate on quitting scholarship donations without considering this current circumstance might lead to further difficulties in conducting research at Japanese universities. We acknowledge that scholarship donations, as described in our study, are a unique custom in Japan and may not be directly applicable to Western countries. However, we believe that understanding this custom and its implications can still provide valuable insights for the international community, especially for non-Western developing countries where similar customs might exist. By sharing the Japanese experience, our study can contribute to a broader understanding of the varied relationships between the pharmaceutical industry and healthcare institutions across different cultural and regulatory contexts including the importance of transparency, industry self-regulation, transparency codes, and regulation of payments from industry to healthcare institutions. Future studies should assess whether scholarship donations help healthcare institutions to promote research without playing a role of a bribe from pharmaceutical companies to promote their own products.</p>", "<title> Limitations</title>", "<p> This study included several limitations. First, the institution type, nationality of pharmaceutical companies, and specialties of the departments were manually categorized, so human error in the categorizations may be included. Second, since there was no penalty when the pharmaceutical companies did not disclose the payments correctly, the original payment data might have some errors. However, we believe that these issues would have a negligible effect on the overall trends and patterns observed in our study. Finally, the data of non-member companies were not included, but our data sources covered a large majority of the payments made within the industry including most major and influential pharmaceutical companies in the market, which we believe minimizes the potential impact of non-member companies on our findings. Although we cannot provide an exact figure for the number of non-member companies, we estimate that they would account for less than 20% of the market. Given their relatively smaller market share, the influence of these non-member companies on the overall trends observed in our study is likely to be limited.</p>" ]	[ "<title>Conclusion</title>", "<p> This study unraveled that there were substantial scholarship donations from pharmaceutical companies to healthcare institutions in 2017, amounting to more than US$ 178 million in Japan. Most scholarship donations concentrated on universities with medical school, potentially influencing medical practice, accumulating evidence by conducting research, and medical education in favor of pharmaceutical companies. Further study should be conducted to indicate whether these scholarship donations help healthcare institutions and professionals to improve research and clinical practice.</p>" ]	[ "<p>\n<bold>Background:</bold> Financial relationships between healthcare institutions and pharmaceutical companies can lead to conflicts of interest (COIs), potentially compromising patients’ care. In Japan, scholarship donations, unique type of payments made to healthcare institutions and their subunits by pharmaceutical industries without restricting their use including non-educational or research purpose, may often have implicit promotional purposes. However, detailed information about these payments remains scarce.\n</p>", "<p><bold>Methods:</bold> This study employed a cross-sectional design to analyse the extent and distribution of all scholarship donations made by all 73 pharmaceutical companies belonging to the Japan Pharmaceutical Manufacturers Association (JPMA) to healthcare institutions in 2017. Data were obtained from publicly available sources from the companies, and the total number of payments, their distributions across various institutions and specialties were analysed. </p>", "<p><bold>Results:</bold> A total of 27 007 payment contracts amounting to $178 703 721 in scholarship donations were made to 4839 specific departments and laboratories at 251 different institutions by 67 pharmaceutical companies. National universities received 50.8% of total payments. All universities setting medical school in Japan received one or more payments. Domestic pharmaceutical companies contributed to $137 797 302 (77.1%) in total. Clinical medicine departments received 89.6% ($160 113 147) with 6.2% ($11 011 946) and 2.0% ($3 600 456) allocated to basic medicine and social medicine specialties, respectively.</p>", "<p><bold>Conclusion:</bold> This study provided a comprehensive overview of scholarship donations from pharmaceutical companies to healthcare institutions in Japan, revealing significant financial support primarily directed to national universities and clinical medicine departments. Japanese policy-makers should consider implementing regulations that promote transparency and mitigate potential COIs arising from scholarship donations, which may be useful in other countries with similar schemes.</p>", "<p>\n<bold>Citation:</bold> Murayama A, Kamamoto S, Saito H, et al. Characteristics and distribution of scholarship donations from pharmaceutical companies to Japanese healthcare institutions in 2017: a cross-sectional analysis. <italic toggle=\"yes\">Int J Health Policy Mana</italic>g. 2023;12:7621. doi:10.34172/ijhpm.2023.7621</p>" ]	[ "<title>Acknowledgements</title>", "<p> This study was funded in part by the Medical Governance Research Institute. This non-profit enterprise receives donations from pharmaceutical companies, including a dispensing pharmacy, namely Ain Pharmacies, Inc., other organizations, and private individuals. This study also received support from Tansa, an independent non-profit news organization dedicated to investigative journalism. The authors also thank Kayo Harada for her dedicated work in obtaining the data. However, none of the entities providing financial support for this study contributed to the design, execution, data analyses, or interpretation of study findings and the drafting of this manuscript.</p>", "<title>Ethical issues</title>", "<p> This study was approved by the Institutional Review Board of the Medical Governance Research Institute. Informed consent was waived from the donated institutions and departments since all the data used in this study were publicly available and did not involve any privacy concerns.</p>", "<title>Competing interests</title>", "<p> HS received personal fees from Taiho Pharmaceutical Co., Ltd. outside the scope of the submitted work. AO receives personal fees from Medical Network Systems, Kyowa Kirin Co., Ltd., and Taiho Pharmaceutical Co., Ltd. outside the scope of the submitted work. TT receives personal fees from Medical Network Systems and Bionics Co. Ltd. outside the scope of the submitted work. The remaining authors declare no conflicts of interest.</p>", "<title>Funding</title>", "<p> This study was funded in part by the Medical Governance Research Institute. This non-profit enterprise receives donations from pharmaceutical companies, including a dispensing pharmacy, namely Ain Pharmacies, Inc., other organizations, and private individuals. This study also received support from Tansa, an independent non-profit news organization dedicated to investigative journalism. However, none of the entities providing financial support for this study contributed to the design, execution, data analyses, or interpretation of study findings and the drafting of this manuscript.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nAmounts of the Scholarship Donations Across Major Specialties. While internal medicine and surgeries are presented as distinct subcategories, the 12 basic medicine categories and the 8 social medicine categories were grouped together, respectively. There were cases where we could not identify specialties for multiple payments.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Characteristics of the Healthcare Institutions and Pharmaceutical Companies Made the Scholarship Donations in 2017\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Variables </bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Institutions Receiving Donations From Japanese Domestic Companies (N = 228 Institutions)</bold><sup>a</sup>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Institutions Receiving Donations From Foreign Companies (N=228 Institutions)</bold><sup>b</sup>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Overall (N = 251 Institutions)</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Total, No. (%)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">228 (90.8)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">164 (65.3)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">251</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">University, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">131 (96.3)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">102 (75.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">136 (54.2)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">47 (100.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">42 (89.4)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">47 (18.7)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 16 (100.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11 (68.8)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">16 (6.4)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">68 (93.2)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">49 (67.1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">73 (29.1)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Research institute, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">24 (96.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14 (56.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">25 (10.0)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8 (100.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7 (87.5)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8 (3.2)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6 (100.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 (16.7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6 (2.4)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10 (90.9)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6 (54.5)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11 (4.4)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Special hospital, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">16 (88.9)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12 (66.7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">18 (7.2)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9 (100.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5 (55.6)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9 (3.6)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pubic </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5 (71.4)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6 (85.7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7 (2.8)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2 (100.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 (50.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2 (0.8)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Municipal and other hospitals, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">54 (90.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">27 (45.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">60 (23.9)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">39 (92.9)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">21 (50.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">42 (16.7)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7 (87.5)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4 (50.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8 (3.2)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9 (90.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2 (20.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10 (4.0)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Other institutions</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3 (25.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9 (75.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12 (4.8)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pharmaceutical companies collecting payment data, N</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">73 Companies</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Domestic </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">54 Companies</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\"> International </td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">19 Companies</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Financial Characteristics of the Scholarship Donation in Japan in 2017\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Variables</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Payment, $</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Number of Cases, n</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Total </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">178 703 721</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">27 007</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Average (SD) </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Department level</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">36 930 (58 073)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5.6 (6.4)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Institution level</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">711 967 (1 283 742)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">107.6 (158.8)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pharmaceutical company level<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2 666 827 (3 282 833)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">385.8 (476.2)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Median (IQR) </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Department level</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">16 503 (5 352‒44 603)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3 (1‒8)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Institution level</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">32 114 (7 136‒1 219 224)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5 (1‒231)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pharmaceutical company level</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 151 204 (352 783‒3 061 073)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">213 (39‒558)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Total payments by institution type</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">University </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">172 512 024 (96.5%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">25 974 (96.2%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">90 861 713 (50.8%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12 627 (46.8%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14 386 619 (8.1%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2 418 (9.0%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">67 263 692 (37.6%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10 929 (40.5%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Research institute </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2 169 856 (1.2%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">320 (1.2%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 085 459 (0.6%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">185 (0.7%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">34 790 (0.0%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11 (0.0%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 049 607 (0.6%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">124 (0.5%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Special hospital </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 681 980 (0.9%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">263 (1.0%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">710 972 (0.4%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">165 (0.6%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pubic </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">792 596 (0.4%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">40 (0.2%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">178 412 (0.1%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">58 (0.2%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Municipal and other hospitals </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 871 989 (1.1%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">438 (1.6%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 316 682 (0.7%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">283 (1.0%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">285 459 (0.2%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">84 (0.3%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">269 848 (0.2%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">71 (0.3%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Other institution</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">467 868 (0.3%)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">12 (0.0%)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Scholarship Donation Provided by the Top Five Paying Companies in Japan in 2017\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Top Five Paying Company</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Payment Amounts (%), $</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Number of Cases (%), n</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Chugai Pharmaceutical Co., Ltd.</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">13 445 495 (7.5)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1485 (5.5)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Astellas Pharma Inc.</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11 684 211 (6.5)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1455 (5.4)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Takeda Pharmaceutical Company Ltd.</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10 316 057 (5.8)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1591 (5.9)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Daiichi Sankyo Company Ltd.</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9 750 277 (5.5)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1603 (5.9)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Eisai Co., Ltd.</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">9 365 745 (5.2)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1590 (5.9)</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>There were substantial scholarship donations from pharmaceutical companies to healthcare institutions in 2017, amounting to more than US$ 178 million in Japan. </p></list-item><list-item><p>Substantial scholarship donations were mostly made to national universities specializing clinical medicine by domestic pharmaceutical companies in Japan. </p></list-item><list-item><p>Further study should be conducted to indicate whether these scholarship donations help healthcare institutions and professionals to improve research and clinical practice. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> Scholarship donation is Japan’s traditional type of payment made to healthcare institutions and their subunits by pharmaceutical industries without restricting their use, and may often have implicit promotional purpose. There were substantial scholarship donations from pharmaceutical companies to healthcare institutions in 2017, amounting to more than UD$ 178 million in Japan. Substantial scholarship donations were mostly made to national universities specializing clinical medicine by domestic pharmaceutical companies in Japan. The debate on quitting scholarship donations without considering this current circumstance might lead to further difficulties in conducting research at Japanese universities. Future studies should assess whether the scholarship donations help healthcare institutions to promote research without playing a role of a bribe from pharmaceutical companies to promote their own products.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Scholarship Donation by Pharmaceutical Companies in Japan in 2017.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 2. Scholarship Donation Distributions Across Specialties in 2017.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p>\n<sup>a</sup> Proportion represents a number of institutions receiving donations from Japanese domestic companies per entire institutions with the same characteristics receiving donations from at least one company.</p><p>\n<sup>b</sup>Proportion represents a number of institutions receiving donations from foreign companies per entire institutions with the same characteristics receiving donations from at least one company.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: SD, standard deviation; IQR, interquartile range.</p><p>\n<sup>a</sup>Calculations were made among the pharmaceutical companies for which data on scholarship donations was available.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7621-g001\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7621-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7621-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["3"], "mixed-citation": [" Institute of Medicine. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: National Academies Press; 2009. "]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Fickweiler", "Fickweiler", "Urbach"], "given-names": ["F", "W", "E"], "article-title": ["Interactions between physicians and the pharmaceutical industry generally and sales representatives specifically and their association with physicians\u2019 attitudes and prescribing habits: a systematic review"], "source": ["BMJ Open"], "year": ["2017"], "volume": ["7"], "issue": ["9"], "fpage": ["e016408"], "pub-id": ["10.1136/bmjopen-2017-016408"]}, {"label": ["22"], "mixed-citation": [" Murayama A, Saito H, Tanimoto T, Ozaki A. Financial conflicts of interest between pharmaceutical companies and executive board members of internal medicine subspecialty societies in Japan between 2016 and 2020. J Eval Clin Pract. 2023. "], "pub-id": ["10.1111/jep.13877"]}]	{ "acronym": [], "definition": [] }	33	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 21; 12:7621	oa_package/97/9f/PMC10590253.tar.gz
PMC10590254	0	[ "<title>Background</title>", "<p> Globally, the number of conflict-affected settings (CAS) is rising. In 2017, the number of people living in proximity of conflict (defined as within 60 km of at least 25 conflict-related deaths) was 220 million: double compared to the number a decade ago. The Word Bank estimates that by 2030, two-thirds of the global extreme poor will be living in fragile and conflict-affected situations.<sup>##UREF##0##1##</sup></p>", "<p> Conflict has devastating effects on health systems. It results in destruction of health infrastructure, loss of healthcare workers (HCWs), and weakening of health governance at all levels. At the same time, demand for health services increases.<sup>##UREF##1##2##,##UREF##2##3##</sup> This poses a serious threat to achieving universal health coverage.</p>", "<p> The health workforce is the engine of any health system, as all activities and programmes have to be adopted or adapted through them.<sup>##REF##29149313##4##</sup> Insecurity and direct attacks lead HCWs to leave or avoid working in CAS. Consequently, small numbers of health workers are left in CAS, working in difficult conditions with often very little support.<sup>##REF##32470071##5##,##UREF##3##6##</sup> The COVID-19 pandemic further aggravated this situation for many HCW.</p>", "<p> Responding to crises in human resources of health (HRH), including in CAS, requires a systems approach.<sup>##REF##22205886##7##</sup> Increasing the availability of HCWs is often difficult in low-income countries and particularly in CAS. Maintaining or enhancing HCWs’ competence, responsiveness, and productivity is often also constrained, for example because of disconnection from social and professional support systems, limited supplies and equipment, increased workload and stress.<sup>##REF##25274642##8##</sup></p>", "<p> Despite the increasing availability of tools and guidelines on HRH, only a few resources are available for how policy-makers can optimize the organization of the health workforce and support HCWs to deliver accessible and trustworthy health services in CAS.<sup>##REF##32470071##5##,##UREF##4##9##</sup> Health systems research (including on HRH) in CAS is scarce because of lack of (financial) support, complex and rapidly changing research environments in terms of security and access, limited research capacity, difficulties in obtaining ethical clearance, mistrust towards (outside) researchers, and a lack of research application.<sup>##UREF##5##10##,##REF##28592283##11##</sup> Despite this, there is literature available, often based on small-scale studies in particular settings. To date, no attempt has been made to review these studies to obtain an overview of their findings and extract learnings for governments and development partners operating in CAS.</p>" ]	[ "<title>Methods</title>", "<p> This scoping review aims to identify the human resources for health challenges that are specific to conflict affected settings. We thereby mean the challenges that HCWs face, constraints that governments and development partners face in managing the health workforce and its required supporting systems, and contextual factors influencing HRH. The discussion takes a broad health labour market (HLM) and health systems lens to address the complex and interconnected nature of these challenges. In anticipation of a scarcity of studies available and a variety in study designs and topics within the area of HRH we chose to conduct a scoping review. We have followed the steps outlined by Arksey and O’Malley,<sup>##UREF##6##12##</sup> and completed a PRISMA-SCr (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) checklist.</p>", "<p> We <italic toggle=\"yes\">identified relevant studies</italic> reporting about HRH topics from countries on the high-intensity or medium-intensity conflict lists of the World Bank (fragile and conflict-affected situations list, financial year 2021). This criterion meant we focus on settings (countries or parts of countries) that are currently in conflict or have very recently experienced conflict. To be included, studies had to explicitly report on dimensions of conflict (eg, studies from Nigeria from non-restive areas and without reference to dynamics of conflict were excluded). Relevant HRH topics were defined as HRH policies, programmes and interventions, or factors influencing the HLM and health workers in CAS. We included only primary research studies; (systematic) reviews were excluded. The review included English language peer reviewed scientific publications published between 2016 and August 2022. Grey literature was explicitly not included to ensure the review reflected the current state of reliable, academic, peer reviewed knowledge.</p>", "<p>\n<italic toggle=\"yes\">Studies were selected</italic> using a three-pronged search strategy. First, studies from the period 2016-2019 were selected from the systematic review of Bou-Karroum et al.<sup>##REF##32470071##5##</sup> This systematic review comprehensively mapped the evidence base on HCWs in conflict and post-conflict settings, yet did not itself thematically analyse the content of these papers. Out of a total of 304 studies, 20 studies were included for further assessment. Second, PubMed and Google Scholar searches were conducted for papers from the period of 2016 – August 2022. These searches combined terms (in titles and abstracts) on intervention characteristics with the relevant countries (##TAB##0##Table 1## and ##SUPPL##0##Supplementary file 1##). Assessment of study titles (and where unclear, abstracts) resulted in 85 studies being included for further assessment. Third, 7 studies were suggested, and 3 included, through expert consultation and reviewer suggestion. Bibliographies of included studies were checked during extraction to identify additional sources.</p>", "<p> One hundred eight studies were divided among three researchers for abstract reading. Studies that included a focus on all three of the publication characteristics (##TAB##0##Table 1##) were included. In case of doubt, the full study was read. A second reading was done by another researcher if the article was to be included. This led to 36 studies being included in this scoping review (##FIG##0##Figure 1##).</p>", "<p> Included studies were read, extracted and charted using an Excel data extraction form. We used the HLM framework as the basis for the thematic analysis of papers and presentation of results. The choice for this framework, as well as inclusion of two specific adaptations to this model to better reflect the situation in conflict affected settings are described in ##BOX##0##Box 1## and ##FIG##1##Figure 2##.</p>", "<p> Four researchers extracted relevant excerpts from the results sections of the included studies and sorted these according to key elements of the adapted HLM framework (##BOX##1##Box 2##). Quality assessment was not part of this scoping review.</p>", "<title> Collating, Summarising, and Reporting Results</title>", "<p> Once extracted, discussions between the researchers took place on the findings for each of these main result areas of the adapted framework (see ##BOX##1##Box 2##), which were summarized in narratives per results area. A first draft was discussed with key experts in HRH to further refine the focus of the results and strengthen the discussion.</p>" ]	[ "<title>Results</title>", "<title> Overview of Included Studies</title>", "<p> Details of the 36 included studies are shown in ##TAB##1##Table 2##. The most reported contexts were Syria (n = 11), followed by the Democratic Republic of Congo (DRC) (n = 6). Most studies were qualitative (n = 29). They focused on a variety of HCWs. The findings of these studies are summarised in ##TAB##2##Table 3##.</p>", "<title> Education Sector</title>", "<p> In CAS, production or supply of HCWs coming from education and training is often disrupted. Disruptions or inefficiencies in the education pathway have adverse effects on the number, quality and recognition of (future) HCWs in CAS.</p>", "<p> Conflict can bring disruptions to production of HCWs as teaching staff flee, educational institutes seize operations or even become direct focus of attacks. As a response to disruptions, new institutes (often private and/or non-aligned with the government) were founded in several contexts including Libya, Syria, and DRC. However, this expansion took place in a context of limited capacity and support systems and de-facto absence of regulation or centralised planning.<sup>##UREF##7##17##,##REF##33148279##21##,##REF##32665784##24##</sup> A few studies reported about the accreditation of (medical) education, which often lacked quality<sup>##UREF##7##17##,##UREF##9##23##,##REF##28314568##30##</sup> or was different in parts on the country controlled by non-state actors.<sup>##REF##30938434##15##,##REF##32665784##24##</sup> Development partners partly and temporarily filled gaps regarding training of HCWs, but these initiatives were also not harmonized in terms of focus, content and quality of training.<sup>##REF##32665784##24##</sup></p>", "<p> Like qualified health workers, students and their teachers face serious challenges in CAS. Barnett-Vanes et al reported that students in Iraq were concerned that conflict caused them to have a low level of clinical competence due to perceived low quality of education, mental exhaustion, and fears for personal safety. The same study indicated that the majority of medical students surveyed intended to leave the country after graduation.<sup>##UREF##9##23##</sup> In Syria, some medical students also had to transfer to other universities in Syria, because of the risk of arrest by the Government of Syria if they were thought to oppose the government or to have studied at ‘opposition institutions.’<sup>##REF##32665784##24##</sup></p>", "<p> Fouad et al reported that the content of existing curricula and training was inadequate for preparing HCWs to deliver quality of care in times of conflict.<sup>##UREF##11##27##</sup> The medical training in Syria did not include specialisation in trauma management, intensive care, or emergency medicine, which resulted in HCWs needing to acquire these knowledge and skills on the job.<sup>##UREF##11##27##,##REF##28314568##30##</sup> The quality of education was compromised by inadequate infrastructure, issues with recruitment and retention of qualified professors, and limited guidance and mentorship provided to interns.Al-Areibi reported that the operation of educational facilities in Libya was highly constrained by, amongst other factors, a lack of physical space, insufficient library resources and inadequate laboratory equipment.<sup>##UREF##7##17##</sup> Barnett-Vanes et al described that in Iraq staff recruitment and retention became a serious issue, resulting in missed classes, study delay and perceived lower quality.<sup>##UREF##9##23##</sup> Footer et al reported that in high intensity conflict settings like in Syria, interns and other HCWs in training often had to take on more responsibilities than could normally be expected, whilst at the same time receiving less guidance, supervision and mentorship. This had implications for standards of care and caused significant psychological pressure and increased physical workload.<sup>##UREF##12##29##</sup> Some adaptations to curricula and teaching methods were reported, such as the inclusion of focus on gender based violence in the midwifery curricula in the DRC<sup>##REF##34411878##39##</sup> and distance learning being provided by certain institutions in Syria.<sup>##REF##32665784##24##</sup></p>", "<title> Labour Market Dynamics</title>", "<title> Inflows and Outflows</title>", "<p> Studies describe specific several conflict related dynamics that impact the mobility of HCWs to enter and exit the labour market, and the ability of employing organisations to develop and implement policies that can shape and direct that mobility. Disconnects and imbalances between in- and out-flows of HCWs in the labour market lead to an inadequate and/or unstable pool of HCWs.</p>", "<p> The review found that most studies indicated limited recruitment and deployment of HCWs was caused by insufficient numbers of graduates or HCWs to meet demand. Other identified factors include the limited motivation of potential or current HCWs to work in areas with high insecurity and high workload. Lar et al described that heightened intercommunal tensions in Nigeria made communities more suspicious of community health workers (CHWs) from outside the main ethno-religious group, which narrowed the potential scope of people to be deployed.<sup>##REF##35871004##38##</sup> When it proved not possible to recruit specific cadres or types of HCWs, a common policy response was recruitment and deployment of CHWs. CHWs programmes can be effective when CHWs receive appropriate training, supervision and other support. However CHWs, like in many low- and middle-income countries (LMICs), were found to have poor job security and be under-remunerated.<sup>##REF##32960742##19##,##REF##34458226##48##</sup></p>", "<p> Conflict often led to the (forced) outflow of HCWs, both in terms of migration or internal displacement to more secure areas within or outside the country and leaving the profession or health sector employment all together.Fear for being targeted professionally as well as general decreasing security for health workers and their families is reported on in literature and is a key driver for both of these outflows.<sup>##REF##34933986##18##,##UREF##16##35##,##REF##32514295##49##</sup> Studies from Syria reported that many health workers either fled or voluntarily emigrated, and that whilst this attrition affected the whole of Syria, the situation was very different between government-controlled areas and nongovernment-controlled areas.<sup>##REF##28314568##30##</sup> Other reported factors causing attrition were economic meltdown caused by conflict<sup>##REF##28314568##30##</sup> and better opportunities abroad.<sup>##REF##29733267##44##,##REF##32514295##49##</sup> A key issue to understand the volume of outflows is inadequate data monitoring HCW outflow.<sup>##REF##33121500##22##</sup></p>", "<p> Reliance on external humanitarian HCWs was noted in some studies to fill gaps. Tensions between locals, regional workers and expatriates lead to HCWs leavingIn South Sudan, HCWs reported unfavourable government policies towards foreign workers and short-term employment contracts due to stringent donor funding requirements.<sup>##UREF##10##25##</sup></p>", "<title> Distribution</title>", "<p> The review indicated that maldistribution of HCWs was associated with attractiveness of working areas (urban versus rural, stable versus unstable/in conflict). In Afghanistan, reliance on CHWs in remote and more conflict prone areas meant they were effectively the main health workers accessible to certain communities.<sup>##REF##34458226##48##</sup> Some studies described differences in distribution in terms of the gender of HCWs. A study in DRC found that less than one third of nurses in rural health districts were female, while in the urban health district they made up 61% of the nurses.<sup>##REF##33121500##22##</sup> This can be problematic, particularly in settings where certain cadres are underrepresented by one of the genders or where communities have a preference to receive care by one gender.</p>", "<title> Employment and Remuneration</title>", "<p> The studies that reported about pay or incentives in CAS showed that HCWs often received little and irregular income, and that this was worse in rural and unstable areas than in urban and more stable areas.<sup>##REF##33148279##21##,##REF##33121500##22##</sup> Risk allowances were officially in place in some settings like the DRC, but often remained unpaid.<sup>##REF##33148279##21##,##REF##33121500##22##</sup> Health workers reported a need to supplement income through user fees in DRC<sup>##REF##33148279##21##</sup> or through over prescription of certain drugs in Myanmar.<sup>##UREF##17##36##</sup> A few studies reported on issues related to staff within the same institution being employed on different contracts, terms and conditions.<sup>##REF##33148279##21##,##REF##30728062##45##</sup> One study in Yemen described that HCWs actively shifted between contracts to find better pay – with one study specifically noting the distorting role of humanitarian organisations, who come in in offering higher pay. This leads to tensions between different workers on different types of contracts.<sup>##REF##32514295##49##</sup> One study focusing on experiences of frontline workers in Burkina Faso highlighted that it was generally considered an advantage to be employed in the public sector compared to the private sector, because it was perceived to be a more secure position and it included a pension system.<sup>##REF##33028153##47##</sup> In Syria, at the beginning of the conflict some doctors would remain officially employed and paid by the government, but volunteer in underground hospitals.<sup>##REF##34980205##34##</sup></p>", "<p> A study among local aid workers in South Sudan reported that they may be influenced to continue working in the humanitarian and development sectors, if there is increasing availability of competitive salaries and benefits such as medical insurance and paid time off, training and education opportunities, career progression, performance feedback, effective communication, and staff empowerment opportunities.<sup>##UREF##10##25##</sup></p>", "<title> Performance </title>", "<p> This review found significant issues with performance of HCWs in CAS, with issues around in-service training, supervision, performance management and task divisions worsening labour market inefficiencies and negatively impacting retention and motivation.</p>", "<p> We found that in-service training, supervision and continuous professional development opportunities were disrupted in conflict settings, leading to inequity in access to these job motivators among HCWs and, potentially, patient safety concerns. In CAR, refresher training was organized only irregularly for CHWs, and major discrepancies were found between districts in relation to supervision practices.<sup>##REF##31687768##28##</sup> In a study of surgical teams in DRC, all interviewees highlighted the need for continuous medical education while underscoring inequity in access to training. Some participants highlighted the increased risk of errors due to the lack of ‘supervision’ of inexperienced trainees in surgical care.<sup>##UREF##18##37##</sup> Non-governmental organizations (NGOs) sometimes filled the gap by providing in-service trainings, with evidence from South Sudan indicating that this led to variations in content and duration of training.<sup>##REF##34794466##16##</sup></p>", "<p> Several studies reported increased workload for HCWs remaining in position, often aggravated by the double impact of fewer colleagues to treat more and more complex cases (such as trauma cases after an attack, or increased levels of communicable diseases due to an influx of internally displaced persons [IDPs]).<sup>##REF##28314568##30##,##UREF##14##32##</sup> HCWs often took on tasks and roles that they were not trained for, leading to risks for quality of care and patient and HCW safety. An example was related to junior doctors being hurriedly employed in full service in Syria, and various specialists having to retrain in active conflict areas where HCWs were forced to re-specialise on triage and trauma.<sup>##UREF##11##27##</sup> In Syria, insufficient numbers of HCWs led to an increased focus on roles of non-physician HCWs and skill substitution. Bdaiwi et al reported that specialised dialysis nurses in Syria had been taking the roles of renal specialists: this was done with the support of the single remaining renal physician and a team of expatriate renal physicians providing training and advice.<sup>##REF##32665784##24##</sup> Despite all challenges facing them, studies widely report the importance of intrinsic factors such as humanitarianism and medical ethics as a strong motivating factor for HCWs to remain in position.<sup>##UREF##12##29##,##REF##34980205##34##</sup></p>", "<title> Contextual Factors Affecting HCWs in CAS</title>", "<p> This review identified many contextual challenges particular to CAS that impact the capacity and willingness of HCWs to operate as part of the workforce, including security-related issues, economic pressures and IDP movements. Changing dynamics around gender, ethnicity, race, class, ideology and other group dynamics impact HCWs and their patient relationships — with female HCWs notably facing many additional challenges in CAS.</p>", "<p> Insecurity of health workers, both due to targeting based on their professional status and more generally as a citizen living in a conflict zone, is tragically the most commonly reported theme throughout the literature reviewed.<sup>##REF##34933986##18##,##REF##33121500##22##,##UREF##10##25##, ####REF##28602556##26##, ##UREF##11##27####11##27##,##UREF##12##29##,##REF##28314568##30##,##UREF##14##32##, ####UREF##15##33##, ##REF##34980205##34####34980205##34##,##UREF##17##36##,##UREF##18##37##,##REF##33110596##41##,##REF##27332144##43##,##REF##29733267##44##,##REF##32514295##49##</sup> In Syria this included persecution for treating protestors,<sup>##UREF##11##27##,##REF##28314568##30##</sup> systematic attacks and bombings on health facilities in opposition held areas (including strategies such as chemical attacks and ‘double-tap’ attacks meant to specifically target onrushing aid personnel).<sup>##REF##28602556##26##,##REF##34458226##48##</sup> Fouad et al interpreted the many ways in which health and HCWs become active targets of conflict actors as a pattern of ‘weaponisation of health.’<sup>##REF##28314568##30##,##UREF##19##50##</sup> Security challenges required adjustments in the organization of and trust in healthcare, posing a challenging environment for HCWs. In Syria, the threats to HCWs and patients were so severe that they necessitated a re-organisation of healthcare infrastructure and staff. For example, various wards of hospitals were split among different (fortified) positions, and hospitals were placed underground to reduce risks of targeting and minimise potential for all services being interrupted.<sup>##UREF##12##29##,##REF##28314568##30##,##UREF##17##36##</sup> Field hospitals in homes, schools, basements, mosques, and caves were established to treat casualties before transporting patients to permanent medical facilities.<sup>##REF##28314568##30##</sup> Mowafi et al reported on the problem of transferring patients in need of specialty care between hospitals in active war zones in Syria.<sup>##REF##27332144##43##</sup> Insecurity and curfews could also force HCWs to change their working hours, with evidence from the DRC indicating shorter opening hours to avoid the need for HCWs to travel home at night.<sup>##REF##34933986##18##</sup> In Yemen and Nigeria, offering services in areas other than CHWs’ and supervisors’ village of residence, became a problem.<sup>##REF##35871004##38##,##REF##33110596##41##</sup> In Afghanistan, safety on the roads was a problem for particularly female CHWs.<sup>##REF##30728062##45##</sup> In DRC, ethnic grouping on either side of the conflict generated patient distrust of HCWs or between each other, which sometimes compromised HCWs’ attitudes towards particular ethnic groups.<sup>##UREF##18##37##</sup> Furthermore, for the predominantly female lay mental health workers in DRC, gender-based violence was a fear, as well as one of the biggest reasons for secondary trauma.<sup>##UREF##15##33##</sup></p>", "<p> The enormous stress and impact on mental health of HCWs is described in many studies.<sup>##REF##31034779##14##,##UREF##12##29##,##UREF##15##33##,##UREF##17##36##</sup> The stress of providing care was partly caused by the scarcity of HCWs, leading to heavy workload, an inability to “switch off” from work, and a feeling of helplessness because of the number of people they could not assist.<sup>##UREF##12##29##</sup> Moreover, delayed or non-payment of salaries and increasingly expensive cost of living could complicate HCWs home situation.<sup>##REF##31034779##14##,##REF##34458226##48##</sup> Psychological assistants (lay mental health workers) in DRC were susceptible to secondary trauma, as they may have been exposed, or were afraid to get exposed, to traumatic events their clients had experienced.<sup>##UREF##15##33##</sup> Footer et al reported on the stress of health workers, after being threatened being to prioritise the government forces, at the expense of the civilian population.<sup>##UREF##12##29##</sup> Provision of care to protestors was criminalized in Syria, and suspected sympathetic HCWs could be interrogated, disappeared or killed.<sup>##REF##28314568##30##,##UREF##17##36##</sup> In ISIS (Islamic State of Iraq and Syria) occupied Mosul (Iraq), the constant presence of morality police in clinics created a climate of fear and stress for HCWs, as even minor infractions of staff could be punished severely.<sup>##REF##31034779##14##</sup></p>", "<title> Healthcare Workforce Governance </title>", "<p> Available evidence suggests significant gaps and fragmentation in leadership and coordination, as well as institutional fragility at national and sub-national levels. In Syria, the de-facto autonomy of the Kurdish and rebel held areas spurred a fragmentation of HRH governance functions like regional healthcare workforce planning and a breakdown in coordination between decentralised structures.<sup>##REF##32665784##24##,##UREF##11##27##</sup> In Iraq, HCWs described the lack of flexibility of ministerial departments to adjust expectations for public health programme implementation to the realities in overstretched hospitals, resulting in tensions with patients and delays in critical care.<sup>##UREF##14##32##</sup> Several studies highlighted that inter-sectoral coordination was weak. Of particular note was the often dysfunctional relationship between the Ministry of Health and the Ministry of (higher) Education,<sup>##UREF##7##17##,##REF##30728062##45##</sup> that have shared responsibility for health sector education and/or accreditation. In South Sudan, implementation of CHW programmes was fragmented due to lack of coordination and regulatory frameworks.<sup>##REF##34794466##16##</sup> In the DRC, Labat and Sharma reported on increased corruption, organized crime (where people do not dare to take action because of their own safety), a lack of accountability of hospital management towards national health authorities, and patronage in human resource management (where people supportive of authorities are at higher levels).<sup>##UREF##18##37##</sup> In Nigeria, patent and proprietary medicine vendors – small owner operated drug retailers – provided services that went far beyond the role that was outlined by the pharmacy council of Nigeria.<sup>##REF##32960742##19##</sup> Co-ordination between the national level government and United Nations agencies and other development partners on health, including HRH, can be limited and uneven in CAS, as was the case in Nigeria.<sup>##REF##32960742##19##</sup> In South Sudan, a large influx of donor money in the context of inadequate funding resulted in overdependence on donors.<sup>##REF##34794466##16##</sup> In the most unstable (humanitarian) settings, the de-facto absence of government capacity in the health sector has created a scenario in which international non-governmental organizations (INGOs), faith-based organisations and non-profits have taken on increased responsibilities. Risk of parallel services was identified in some papers, as was donor rigidity in approach when more flexibility is required.<sup>##REF##32960742##19##,##REF##32665784##24##,##REF##29733267##44##,##REF##32641067##46##</sup></p>", "<p> The few studies that reported on HRH policy development showed capacity was low, and implementation (and financing) of existing policies was constrained.In DRC, the Ministry of Public Health developed national strategies to attract and retain different categories of HCWs. However, many of these strategies were either not implemented or only poorly implemented as Provincial Health Offices had limited control over the recruitment and deployment of health workers, which may be partly attributed to the HRH information system being unreliable. This resulted in inequitable distribution of HCWs across the districts.<sup>##REF##33148279##21##,##REF##33121500##22##</sup> Policy implementation gaps were also reported in a study from Burkina Faso,<sup>##REF##33028153##47##</sup> where implementation of a national-level policy on free prenatal consultations and provisions for obstetric emergencies was launched before the technical management and communication plan was ready. Not only did this prove problematic for attaining the policy goals, it also put HCWs in a difficult position where they were expected to deliver on the promises of the policy to patients, without the funding and resources to provide services. Amodu et al reported on low budgetary provisions for health in conflict affected areas of Northern Nigeria and highlighted a gap between budget allocation and actual release of the budget in CAS. Funding for IDP-related (health) concerns was lower than expected and insufficient to carry out the numerous activities that implementing agencies were saddled up with. The study identified links to “[broader] issues with trust, equity, and transparency in the government and health system especially where it concerns funding management.”<sup>##REF##32960742##19##</sup></p>", "<p> In CAS where non-state actors, such as insurgent groups or rebel movements, were in control, studies indicated their interest in also controlling the health workforce. Bdaiwi et al report that in Syria, both opposition-held and ISIS-held areas saw significant focus on attracting/retaining HCWs within a provisional health system to boost their legitimacy.<sup>##REF##32665784##24##</sup> However at the same time there are clear examples from ISIS distrusting and using harsh measures to control HCWs.<sup>##REF##31034779##14##,##UREF##17##36##</sup> In Myanmar’s ethnic regions ethnic health organisations (EHOs) emerged as a parallel, overlapping health systems model where national and more localised ethnic public models coexisted under a sustained cease-fire. In these regions, EHOs were the de-facto actors organising the formal health system, though other parallel structures also existed: some facilities from the central level ministry, INGOs and private providers. While the EHOs were trusted more than central ministry-led facilities, big concerns about quality issues persisted with regard to training of HCWs, poor financial protection mechanisms, resources and regulation.<sup>##REF##30938434##15##</sup> In Syria professional associations or expatriate groups took on governance functions in non-government-controlled areas. Bdaiwi et al highlighted the role of the Syrian Board of Medical Specialists, (a body composed of both in-country HCWs and diaspora specialists who had aligned themselves with the Syrian interim government), who actively took on roles beyond those normally taken by professional boards, eg, the coordination and certification of education programmes in the rebel held territories.<sup>##REF##32665784##24##</sup> The dominant presence of non-state actors in Syria, such as NGOs/donors/humanitarians/diaspora has led in some instances to a focus on empowering HCWs, enabling them to become potential advocates for peace and using healthcare as a potential avenue for peacebuilding after conflict, as well as emphasising the responsibility of governments to guarantee health worker safety.<sup>##UREF##12##29##,##REF##28314568##30##</sup></p>" ]	[ "<title>Discussion</title>", "<p> The evidence from the different settings and countries presented in this review highlights that dynamics of conflict both worsens ‘common’ HRH challenges found in LMICs and creates a unique set of additional challenges. The combination of these factors deepens existing disconnects between the education sector and HLM, leading to further weakened HRH in CAS. Using Syria as an example, the country already experienced a number of key HRH issues prior to the civil war, including maldistribution, high turnover of skilled staff and inadequate numbers of nurses.<sup>##REF##23826546##51##</sup> Once the civil war erupted, these existing issues were further exacerbated by HCWs fleeing the country/region, being arrested or even killed. Direct additional effects included non-qualified HCWs shifting to trauma care, need for concealment of facilities and fragmentation of the health system into several regionalised systems.<sup>##UREF##11##27##,##REF##34980205##34##</sup> So while some symptoms of disconnects in the education sector and HLM bear close resemblance to those in many other LMICs, we argue that conflict ‘multiplies’ negative workforce outcomes in CAS through more, and more complex, challenges for HCWs, governance dynamics and institutional constraints. In the next sections we discuss some of the key implications of our findings for HRH policy-making in CAS.</p>", "<p> HRH policies, programmes and interventions are embedded in, and have an impact on, the political and broader societal context.<sup>##REF##27443146##52##,##REF##30486844##53##</sup> Therefore, HRH policies must take into account the context, including the stage, severity and other dynamics of conflict. Depending on the dynamics of conflict, this highlights the vulnerability of the health workforce as visibly associated to the state or opposition (requiring protection), and the responsibility of governments to provide access to services to all its citizens (avoiding maldistribution of HCWs between favoured and non-favoured regions). Moreover, the effects of health workforce reforms on larger reconciliation and mid-to-long term reconstruction efforts needs to be considered. As little discussion has taken place on what HRH policy options work ‘best’ in CAS in general, or in specific CAS, feasibility assessments and a policy dialogue on how to best spend available resources are necessary first steps.</p>", "<p> Long-term HRH planning efforts in CAS are constrained by a lack of (financial and human) resources, instable institutions with limited capacity (and sometimes willingness) to implement, relatively strong but unpredictable donor influence, data limitations and by the uncertainties and disconnections between (systems in) geographical areas created by ongoing conflict. While not explicitly discussed in the studies included in this review, health is often not a priority of governments in CAS<sup>##REF##28115986##54##</sup> and countries’ constrained economic situations and increased population movements make long-term planning difficult. Filling immediate service gaps as a short-term approach to health systems relief appears to be a common trait of HRH policies and programmes in CAS. While this makes sense given the contextual challenges and urgency of the situation, it results in a lack of focus on sustaining quality of care and building and sustaining community trust. Short-term or too narrowly focused policy-making likely undermines the long-term sustainability and resilience of the health workforce, because HRH policy decisions (especially those focused on training and deploying new cadres, changing skills mix and distribution) have long-term impact and are not easily corrected.</p>", "<p> Many conflict-affected countries are formally ruled by contested, repressive or mistrusted governments. This in itself has major negative implications for governance, institutions, and the effective development and implementation of HRH policies and developments. In addition, it is not a simple “before and after” dichotomy. Many of these countries had governance issues before the conflict erupted (in some cases being causes of conflict). In these contexts, state withdrawal from a sector or region may actually open space and potential for innovation and improvement, for instance in terms of job descriptions, training programmes and task-shifting, where these had become ossified. One emerging issue from the literature is the potential to increase ‘value for money’ of HRH investments through strengthening financing and decision-making authority at sub-national levels to facilitate local training, recruitment, and support to HCWs.<sup>##REF##29149317##55##</sup></p>", "<p> Partly as a result of less central-level control this review found parallel systems in the education sector as well as in deployment and management of the health workforce in CAS – for instance, the lack of central planning and proliferation of commercial training institutions is likely to contribute to imbalances in the types of cadres trained and affect health workforce composition for many years. The policy implications for how governments should deal with the existence of a health workforce controlled by non-state actors are not straightforward. On the one hand, tacit support (eg, through continuation of certification or access to training) may strengthen the legitimacy of non-state actors through increased capacity to provide services to the population under their control. However on the other hand, active obstruction of HCWs undermines the obligation of the government to protect the right to health of all of its citizens. In the post-conflict period, attention should be paid to harmonizing the regulatory divergence or duplication and promoting integration those HCWs who did not have the ‘right’ qualifications or allegiance.<sup>##REF##21569435##56##</sup> A failure to adequately approach this may have implications for community trust in, and access to, services.</p>", "<p> Labour markets are dynamic in all countries and contexts, with changing patterns of HCW mobility being an ever-present factor that must be accounted for. However, in CAS, labour markets are likely to be more unstable and fractured. The evidence on HCW outflow within and out of CAS highlights the need for improved monitoring to understand variations in HCW mobility patterns between areas regarded as relatively more or less safe. In addition to geographic mobility, there can be sectoral mobility, with HCWs moving to NGO employment if this is perceived to be more attractive.<sup>##REF##26708245##57##</sup> A secondary issue related to outmigration is the potential to harness capacity support from HCW diaspora working in other countries.<sup>##REF##31307468##58##</sup> The overall understanding of the issue of internal and international flows of HRH in CAS is hampered by a lack of accurate, complete and up-to-date data on mobility patterns. This is not unique to CAS, but there is a risk of assumption, rather than analysis, directing policy focus. Individual country contexts, in terms of ease of travel and recognition of qualifications will be amongst the determining factors. In addition, the broader context of migration, its size and complexity will impact on health system and HRH demands. Somalia, for example, has been identified as a “country of origin, destination, transit and return for a large number of people moving across the Horn of Africa region and beyond,” with a 2016 report suggesting that remittances from the diaspora accounted for 35 per cent of gross domestic product in 2012, and were among the highest in the world.<sup>##UREF##20##59##</sup></p>", "<p> The evidence emphasises the need to address retention challenges with a co-ordinated policy response, using a bundle of different policy interventions. A systematic assessment is required to pinpoint which mix of interventions is likely to be most effective at supporting staff retention. The recently updated World Health Organization (WHO) Retention guidelines outline that community support in assuring security, housing and other livelihoods can improve HCWF retention.<sup>##UREF##21##60##</sup> Though little comprehensive evidence is available on this in CAS, the role of community protection to support HCWs to practice safely and remain in CAS seems important to focus on in policy development. Moreover, trust of communities in HCWs is an especially important focus for ensuring access to care<sup>##UREF##22##61##</sup>– despite severe challenges, civil society driven attempts to rebuild structures in places like Syria can give hope.<sup>##UREF##12##29##</sup></p>", "<p> The evidence highlights that the combination of under-resourcing, widespread societal trauma, and the (fear for) security threats facing facilities exacts a heavy toll on HCWs, highlighting the need for investments in mental health support services.<sup>##REF##22008428##62##</sup> In addition, the expansion of active monitoring of security incidents involving HCWs and patients’ needs to be supported to ensure perpetrators of violence are held to account.<sup>##REF##33962623##63##</sup> Particular attention must be paid to HCWs from different genders, ethnicities, ages and other intersecting characteristics that may increase vulnerability to violence.<sup>##UREF##23##64##</sup> Further research on this is needed.</p>", "<p> To enhance HCW motivation and performance, the use of technology has been progressing rapidly, accelerated by COVID-19, and needs full consideration within CAS; eg, m-health; paying staff via mobile phones, internet access as a method of keeping in touch, online continuous professional development and performance appraisal.<sup>##UREF##24##65##, ####REF##31157115##66##, ##REF##30305338##67####30305338##67##</sup> However, this review shows that there is little documented recent evidence on how technology could support HCWs in CAS, which could partly be because of problems with infrastructure and connectivity.</p>", "<p> Limitations of available workforce data constrain monitoring, planning and policy-making. Whilst this is not unique to CAS, the disruption and fragmentation of existing HRH information systems in CAS should be addressed. Where feasible, labour market analysis, underpinned by surveys of HCWs should be undertaken.<sup>##REF##27863499##68##</sup> The provision of digital HRH information systems is often part of donor-led post conflict re-building, and there is a need to ensure that the choice of systems is driven by user needs and policy priorities, and that local capacity to sustain the system is considered, with an emphasis on local “user” involvement during development, and on training of local operatives.</p>", "<p> Finally, investments in the health workforce will not be effective if not accompanied by investments in other elements of the health system. Effective governance is required to effectively implement the best human resources for health interventions and to co-ordinate across the other health system elements. The literature on health systems recovery after conflict often highlights that the immediate post-conflict period provides a unique opportunity for the government and development partners to increase efforts to rebuild health systems within the context of larger peace building efforts. The length, nature and challenges of a specific conflict — in addition to the specifics of the process of conflict resolution — all impact the likelihood and timing of such a window of opportunity.<sup>##REF##28115986##54##</sup> The implication for policy and strategy development processes is that this post-conflict opportunity cannot simply be presumed, and a clear understanding of political economy dynamics is required to better identify — and increase the chances of acting on – a window of opportunity.<sup>##REF##25075212##69##</sup> This is also an area that needs further research.</p>", "<title> Reflection on Available Evidence</title>", "<p> A key finding of the review is the relative lack broad based and policy relevant scientific evidence. In our sample studies, the HLM elements most reported on were related to individual performance or HCWs experiences, with governance aspects being least reported on. However, research gaps exist related to all elements of the HLM in CAS. The most important research gap is an absence of evidence taking a ‘long-term and broad-based view’ on the HLM dynamics in CAS. Most studies take a narrower entry point, and have a shorter horizon for their examination, such as a specific aspect of retention of one cadre in a localised area or region. There is a dearth of studies that look across the range of financial incentives available. Most studies take a narrow and incomplete focus, although a comprehensive approach is essential to investigate both the <italic toggle=\"yes\">causes</italic> (at individual and system level) of the fragmentation and variability in income levels and the <italic toggle=\"yes\">consequences</italic> of this fragmentation. In addition, the broader HLM dynamics and the connections between different labour market characteristics are usually not considered. Political economy analysis and related approaches could help to build a better understanding of power dynamics between stakeholders influencing these dynamics — and contextualise current market failures. Furthermore, studies that focus on HCWs in CAS usually focus on those workers who have stayed, not those who have left. The evidence available may therefore not fully represent considerations relevant for all HCWs, which in turn has implications for developing effective HRH policies. Moreover, there is a scarcity of evidence adequately considering gender and equity considerations in the health workforce in general,<sup>##UREF##23##64##</sup> but this is even more so the case for CAS. In addition, this review did not yield evidence on the impact of COVID-19, but the implications of the pandemic on HRH in CAS are important to consider. Some initial evidence describes enormous destabilising effects of the pandemic on health services in Yemen, where a perfect storm of intensifying conflict, a cholera epidemic linked to lack of services and COVID-19 threaten systems collapse.<sup>##REF##34294097##70##</sup> Whether COVID-19 becomes a new dimension of fragility or a test of the resilience of a health workforce already under pressure is something which needs further exploration. Future research could also consider including (quality assessed) grey literature.</p>", "<title> Limitations</title>", "<p> Our scoping review only considered English language, primary research peer reviewed publications — our goal was to specifically map scientific evidence but future reviews could consider further inclusion and quality assessment of grey literature. There are a wide range of CAS contexts, each presenting unique dynamics of conflict and their interaction with the socio-cultural context and labour market. This necessarily complicates relevance of findings across settings.</p>" ]	[ "<title>Conclusion</title>", "<p> Against a backdrop of growing conflict across the world, this scoping review has identified progress in generating evidence on HRH aspects of health and care systems in CAS. It has also identified continued gaps in knowledge, which limit the scope to identify and implement evidence-based policies. Whilst the HRH challenges may resemble those in many other LMICs, we argue that the unique set of societal drivers of conflict, governance dynamics and institutional constraints in CAS ‘multiply’ negative affects to the health workforce. Moreover, active conflict brings a set of additional HRH challenges, including the targeting of HCWs by combatants and effects of widespread societal trauma on the mental health of HCWs. HRH policies, programmes and interventions must be aligned with the political and broader societal context if they are to be successful. The post-conflict situation may present opportunities for improvement in HRH, but a clear understanding of political economy dynamics is required to better act on any such a window of opportunity.</p>" ]	[ "<p>\n<bold>Background:</bold> Conflict has devastating effects on health systems, especially on healthcare workers (HCWs) working in under-resourced and hostile environments. However, little evidence is available on how policy-makers, often together with development partners, can optimize the organization of the health workforce and support HCWs to deliver accessible and trustworthy health services in conflict-affected settings (CAS).\n</p>", "<p><bold>Methods:</bold> A scoping review was conducted to review recent evidence (2016-2022) on human resources for health (HRH) in CAS, and critically discuss HRH challenges in these settings. Thirty-six studies were included in the review and results were presented using an adapted version of the health labour market (HLM) framework.\n</p>", "<p><bold>Results:</bold> Evidence from CAS highlights that conflict causes specific constraints in both the education sector and in the HLM, and deepens any existing disconnect between those sectors. Parallel and inadequate education and performance management systems, attacks on health facilities, and increased workload and stress, amongst other factors, affect HCW motivation, performance, distribution, and attrition. Short-term, narrowly focused policy-making undermines the long-term sustainability and resilience of the health workforce in CAS, and also contributes to the limited and narrow available research base.\n</p>", "<p><bold>Conclusion:</bold> While HRH and workforce issues in CAS include those found in many other low- and middle-income countries (LMICs), an additional set of challenges for HCWs, governance dynamics and institutional constraints in CAS ‘multiply’ negative effects on the health workforce. HRH policies, programmes and interventions must be aligned with the political and broader societal context, including the stage, severity and other dynamics of conflict. During conflict, it is important to try to monitor in- and outflow of HCWs and provide HCWs the support they need at local level or through remote measures. The post-conflict situation may present opportunities for improvement in HRH, but a clear understanding of political economy dynamics is required to better act on any such a window of opportunity.</p>", "<p>\n<bold>Citation:</bold> Onvlee O, Kok M, Buchan J, Dieleman M, Hamza M, Herbst C. Human resources for health in conflict affected settings: a scoping review of primary peer reviewed publications 2016–2022. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7306. doi:10.34172/ijhpm.2023.7306</p>" ]	[ "<title>Acknowledgements</title>", "<p> This paper is an output of the Libya Health Sector Support Grant (P163565) program between the World Bank and Libya. Christopher H. Herbst, Mohini Kak, World Bank task led the overall work program. The team would also like to thank World Bank peer reviewers, Mickey Chopra (Lead Health Specialist) and Aarushi Bhatnagar (Economist). Moreover, the team would like to thank Jo Raven and Tim Martineau from Liverpool School of Tropical Medicine (LSTM) for their critical reflections.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This paper is an output of the Libya Health Sector Support Grant (P163565) program between the World Bank and Libya.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nFlowchart of Study Inclusion Process.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nHealth Labour Market Framework, Adapted to Emphasise Dynamics of Conflict and Health Workforce Governance. Abbreviations: CAS, conflict-affected settings; NSAs, non-state actors.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Publication Characteristics and Criteria\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Publication Characteristics</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Keywords</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Intervention characteristics</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Human resources for health, HRH, health workforce, health labour market, health [care] workers, cadre, doctors, nurses, midwives, community health workers, physicians</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Countries included in the World Bank financial year 21 high-intensity or medium-intensity conflict lists </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Afghanistan, Libya, Somalia, Syrian Arab Republic [Syria], Burkina Fa-so, Cameroon, CAR, Chad, DRC, Iraq, Mali, Mozambique, Myanmar, Niger, Nigeria, South Sudan, Yemen</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.75pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Dimensions of conflict</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.75pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Humanitarian, crisis, emergency, fragile and conflict affected [states/settings/situations/countries], post-conflict, conflict</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Exclusion criteria</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of specific reporting on dimensions of conflict when discussing HRH issues </td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Overview of Included Studies\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Author, Years and Citation</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Country</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Study Objective</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Study Methods</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Types of HCWs</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Main Reported Elements of the Adapted HLM Framework</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Al-Areibi (2019)<sup>##UREF##7##17##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Libya</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To examine the current Libyan medical education system, look at its positive and negative aspects, and to provide suggestions and recommendations that could help improve the quality of the system</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Descriptive/opinion</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medical workforce</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Altare et al (2021)<sup>##REF##34933986##18##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To identify operational challenges and investigate strategies and to maintain service delivery and quality in two health zones in North and two in South Kivu provinces in DRC in 2018</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Representatives of private and public healthcare providers. Staff of the Ministry of Health, UN agencies, NGOs, faith-based organizations as well as HCWs (chief midwives, chief nurses, and CHWs)</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance and motivation; inflows and outflows</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Amodu et al (2021)<sup>##REF##32960742##19##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Nigeria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To identify structural gaps influencing access to reproductive healthcare for women displaced by terrorism in Nigeria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: critical ethnography</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Primary health workers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: inflows and outflows, performance and motivation; contextual factors; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Atia et al (2020)<sup>##UREF##8##20##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Libya</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To assess the impacts of the accreditation process of the NCQAA on the quality of education in a private university in Libya</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: self-study report produced by the NCQAA accreditation committee during 2017-2019, using a standardized instrument</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medical students; staff working at educational institutes</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">HRH governance</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Baba et al (2020)<sup>##REF##33148279##21##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To identify strategies that can help to attract, support and retain midwives in the fragile and rural Ituri province</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: participatory workshop</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Midwives</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; labour market dynamics: inflows and outflows, performance and motivation; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Baba et al (2020)<sup>##UREF##9##23##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To understand skilled birth attendants’ availability and distribution in Ituri province, North Eastern DRC from 2013 to 2017, to understand how data can be used to support evidence-informed decisions about nurses and midwives in fragile contexts</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Quantitative: review of available routine data and data on local training output at provincial level</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Doctors, nurses and midwives (as skilled birth attendants)</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; labour market dynamics: inflows and outflows; contextual factors</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Barnett-Vanes et al (2016)<sup>##UREF##9##23##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Iraq</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To better understand the current resources and challenges facing medical schools, and the impacts of conflict on the training landscape and student experience, to provide evidence for further research and policy development</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mixed methods</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medical students; staff working at educational institutes</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Bdaiwi et al (2020)<sup>##REF##32665784##24##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore current initiatives present in the north west of Syria at both the undergraduate and postgraduate level for physician and non-physician HCWs and the challenges faced in providing undergraduate education and postgraduate training during the conflict</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mixed methods: narrative review complemented with brief interviews</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Allied health professionals including physiotherapists, nurses, specialist nurses, pharmacists, midwives, dentists, paramedics and emergency or anaesthetic technicians and doctors</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; labour market dynamics: inflows and outflows, performance and motivation; contextual factors; HRH governance</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Buny (2019)<sup>##UREF##10##25##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">South Sudan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore factors contributing to staff turnover and management strategies for recruiting and retaining professional aid workers within humanitarian and development NGOs in a conflict environment in South Sudan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: interviews and small group discussion with local and regional workers, NGO managers, expert practitioners</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Expatriate humanitarian aid workers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: inflows and outflows</td></tr><tr><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Elamein et al (2017)<sup>##REF##28602556##26##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To describe a new system used mainly in areas of Syria with a substantial presence of armed opposition groups since November, 2015, to detect and verify attacks on healthcare services and describe their effect</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Quantitative: based on a monitoring violence against healthcare alert network via (293-member) WhatsApp and an anonymised online data-entry tool for incident reporting</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various cadres</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Contextual factors</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Fardousi et al (2019)<sup>##UREF##11##27##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore health-worker perspectives on security, improving safety, managing constrained resources and handling mass casualties during besiegement in Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative study using semi-structured key informant interviews, conducted remotely over WhatsApp and Skype, and analysed thematically using inductive coding</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various both frontline and admin</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; Performance and motivation; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Ferdinand et al (2019)<sup>##REF##31687768##28##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CAR</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To evaluate the effectiveness of a 10-year CHW programme in CAR</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Quantitative: routine case management data from CHWs and structured interviews with beneficiaries, CHWs and health facility managers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Voluntary CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: performance and motivation; contextual factors; HRH governance</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Footer et al (2017)<sup>##UREF##12##29##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore the complex challenges health workers face in providing care when healthcare services and personnel are themselves subjected to violence and forced to operate in the midst of ongoing human rights violations and war crimes</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: interviews with health workers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various cadres</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: inflows and outflows, performance and motivation; contextual factors; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Fouad et al (2017)<sup>##REF##28314568##30##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To focus on four analytical themes: attacks on health-care facilities and targeting of health workers as part of a broader pattern of systematic violations of international humanitarian law, the attrition of health workers, the challenges facing health workers in different areas, and the evolving roles of health workers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mixed methods: scoping review, expert consultations, testimonials of health workers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various cadres</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector, labour market dynamics: inflows and outflows, performance and motivation; contextual factors; HRH governance</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Hamid et al (2020)<sup>##UREF##13##31##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore the impact of the provision of care of forcibly displaced Syrian MHPs to Syrian clients in the community, given shared experiences and backgrounds with clients</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: in-depth interviews with forcibly displaced Syrian MHPs across two cities in Turkey, Istanbul and Gaziantep, the latter being a city 97 km north of Aleppo, Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mental health professionals</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: inflows and outflows, performance and motivation; contextual factors</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Ibrahem and Morgan (2022)<sup>##UREF##14##32##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Iraq</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore the perspectives of healthcare professionals in Kirkuk in Iraq about the impact of the recent armed conflict (2014-2018) on their healthcare practice and training</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: Sixteen semi-structured interviews and purposive sampling of doctors and nurses who worked in conflict-affected areas in Kirkuk were selected</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Doctors and nurses</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; performance and motivation</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Jinor (2020)<sup>##UREF##15##33##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore the lived experiences of secondary trauma for psychological assistants in the DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: 13 in-depth interviews with psychological assistants</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Psychological assistants, a type of lay mental health worker</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; labour market dynamics: performance and motivation contextual factors</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Kallström et al (2022)<sup>##REF##34980205##34##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">This research aims to determine the motivations that influence the decision of HCWs to work in a country where the conflict has been raging for a decade</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative; research is based on 20 semi-structured interviews of Syrian HCWs </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various cadres</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance and motivation, contextual factors</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Kallström et al (2021)<sup>##UREF##16##35##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore the reasons why HCWs migrate from Syria, a country where conflict has been raging for over a decade</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A qualitative study was performed using semi-structured interviews</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various cadres</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Inflows and outflows, performance and motivation; contextual factors</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Kallström et al (2021)<sup>##UREF##17##36##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To describe violence against healthcare from the perspective of HCWs working in Syria during – at the time of writing – the ongoing conflict</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">This qualitative study is based on semi-structured interviews of 25, mostly Syrian, HCWs who worked in Syria after the conflict started in 2011</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various cadres</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance and motivation; contextual factors</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labat and Sharma (2016)<sup>##UREF##18##37##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To identify potential barriers to patient safety interventions from the perspective of surgical team members working in an operating theatre in Eastern DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: in-depth interviews with surgical health workers in a teaching hospital </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Surgical health workers, both expats and Congolese</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: performance and motivation; HRH governance; contextual factors</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lar et al (2022)<sup>##REF##35871004##38##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Nigeria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore the perceptions, experience, and performance of CHWs in the context of task sharing within communities in Bassa, Plateau State in Northcentral Nigeria and potentially to illuminate workforce dynamics in similar situations where regions experience conflict</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative; 18 interviews with CHVs and facility heads in rural communities</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CHVs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Inflows and outflows, performance and motivations; distribution</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lordfred et al (2022)<sup>##REF##34411878##39##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">This paper is a case presentation describing the process and lessons learned related to the introduction of the MISP into the first- and third-year pre-service midwifery curricula at multiple midwifery education facilities in the DRC</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative; case study approach</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Midwives</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance and motivation</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lorenzetti et al (2020)<sup>##REF##32429956##40##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Afghanistan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To evaluate a health video library intervention, a tablet-based tool to improve health promotion and counselling by CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: in-depth interviews with CHWs and CHW supervisors</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Voluntary CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Contextual factors </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lutwama et al (2021)<sup>##REF##34794466##16##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">South Sudan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore the characteristics, barriers, and facilitators to implementation of recent CHW programmes in the states supported by the HPF programme in South Sudan, in order to inform further scale-up of the BHI, and the design and implementation of CHW programmes in other low resource, CAS</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative, 26 key informant interviews and a scoping review </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance and motivation; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Michlig (2019)<sup>##REF##31034779##14##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Iraq</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To describe perceived changes and experiences of HCWs’ personal and professional lives in Mosul occurring during three years under ISIS</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative; IDIs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various cadres</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Inflows and outflows; performance and motivation; contextual factors</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Miller et al (2020)<sup>##REF##33110596##41##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Yemen</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To document the challenges to iCCM service delivery and to develop strategies for overcoming service delivery bottlenecks in conflict-affected areas of Yemen</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: in-depth interviews and focus group discussions</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: inflows and outflows, performance and motivation; contextual factors; HRH governance </td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mohamed (2021)<sup>##REF##33413470##42##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To estimate the prevalence of violence against resident doctors in Syria, investigate the association between exposure to workplace violence and health-related outcomes in terms of psychological stress, sleep quality, depression, and the overall subjective health of Syrian resident doctors, and suggest approaches to tackle this problem from the resident doctors' perspectives</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Quantitative: cross-sectional survey among resident doctors</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medical doctors</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: performance and motivation; contextual factors</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mowafi et al (2016)<sup>##REF##27332144##43##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Syria</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To identify the number of trauma hospitals operating in Syria and to delineate their capacities</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Quantitative: nationwide survey of 94 trauma hospitals </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Surgeons, nonsurgical physicians, nurses, other technical staff (both trainees and non-trainees)</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: performance and motivation; contextual factors</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Najafizada et al (2019)<sup>##REF##29733267##44##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Afghanistan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To apply a multi-layered gender analysis to explore gender dynamics within the CHW system in Afghanistan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: in-depth interviews with policy makers, health managers of NGOs implementing the programme in provinces, and CHWs and community members in villages</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: inflows and outflows, performance and motivation; contextual factors; HRH governance</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Najafizada et al (2019)<sup>##REF##30728062##45##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Afghanistan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To offer a descriptive qualitative analysis of how CHWs function as human resources for health in rural Afghanistan, and how they interact with both formal and informal health workers in the Afghan health system</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: participant observation and in-depth interviews</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Voluntary CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: inflows and outflows, performance and motivation; contextual factors; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Okunogbe et al (2019)<sup>##REF##32641067##46##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Afghanistan and South Sudan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The aim of the study is to examine the specific role of the Global Fund in strengthening HRH in the EMR. (1) What are the levels and composition of Global Fund investments in HRH in EMR countries? (2) What types of HRH activities have been supported by these investments? (3) In what ways have these investments contributed to health system strengthening in some of these countries?</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mixed methods: EMR-wide on quantitative data, qualitative case studies in Afghanistan and Sudan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Various cadres, such as: national and provincial programme officers, health management information systems officers, medical doctors, nurses, CHWs, community health supervisors, and lab technicians</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; labour market dynamics: performance and motivation; HRH governance</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Pare Toe and Samuelsen (2020)<sup>##REF##33028153##47##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Burkina Faso</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To explore how front-line health workers compensate for the many shortcomings they face and how the difficult working conditions affect their professional identity</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: anthropological field work, interviews with staff at dispensaries and medical centres</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Physicians, assistant-doctors, nurses, assistant-nurses, midwives and laboratory technicians</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Labour market dynamics: performance and motivation; contextual factors; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Parray (2021)<sup>##REF##34458226##48##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Afghanistan</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To discuss the motivations of Afghani women to become CHWs, their status in the community and within the health system, the threatening situations under which they operate, and the challenges they face as working women in a deeply patriarchal society within a conflict zone</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative; case study approach</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance and motivation; contextual factors</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tang and Zhao (2019)<sup>##REF##30938434##15##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Myanmar</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To audit the health systems and their performance of ethnic health organizations in selected ethnic-controlled, government-controlled or mixed-controlled areas and identify key challenges faced by the ethnic health systems in achieving universal health coverage</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative: in-depth interviews and focus group discussions</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Non-specific</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education sector; labour market dynamics: performance and motivation; contextual factors; HRH governance</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tappis et al (2020)<sup>##REF##32514295##49##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Yemen</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">This case study examines how RMNCAH+N services have been delivered since 2015, and identifies factors influencing implementation of these services in three governorates of Yemen</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualitative; thematic analysis and IDIs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Qualified health workers, managers and CHWs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance and motivation; contextual factors</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Summary of Main Review Findings\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Main Elements of the Adapted HLM Framework</bold>\n</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Main Review Findings</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Education sector</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Conflict resulted in a higher demand for HCWs and sometimes in increased numbers of schools and establishment of new universities, which often provided sub-standard training</p></list-item><list-item><p>A lack of, outdated or parallel accreditation mechanisms led to divergence in quality of services delivered by HCWs and non-recognition of trained HCWs</p></list-item><list-item><p>The content of existing curricula or training could, in certain cases, be inadequate for preparing HCWs to deliver quality of care in times of conflict</p></list-item><list-item><p>The quality of education was compromised by inadequate infrastructure and limited guidance and mentorship of interns</p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Inflows and outflows</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Limited recruitment and deployment of HCWs was caused by insufficient numbers of graduates or HCWs to meet demand, and limited motivation of potential or current HCWs to work in areas with high insecurity and workload</p></list-item><list-item><p>When it proved not possible to recruit specific cadres or types of HCWs, a common policy response was recruitment and deployment of CHWs</p></list-item><list-item><p>Conflict often led to the (forced) outflow of HCWs, both in terms of migration to more secure areas within or outside the country and leaving the profession all together</p></list-item><list-item><p>Besides insecurity, attrition was also caused by poor living and working conditions and in some cases, tension between locals, regional workers and expatriates</p></list-item><list-item><p>High workload and mental health issues among HCWs caused attrition</p></list-item></list>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Distribution</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Maldistribution of HCWs was associated with attractiveness of working areas (urban versus rural, stable versus instable/ in conflict)</p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Employment and remuneration</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>HCWs needed and/or requested more remuneration and other benefits than they were offered</p></list-item><list-item><p>There was some evidence about unequal payment of HCWs with similar functions, leading to demotivation and reduced performance</p></list-item></list>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Performance</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>In-service training, supervision and continuous professional development opportunities were disrupted, leading to inequity in access to these job motivators among HCWs and, potentially, patient safety concerns</p></list-item><list-item><p>HCWs often took on tasks and roles that they were not trained for, leading to risks for quality of care and patient and HCW safety</p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Contextual factors affecting HCWs in CAS </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Security challenges required adjustments in the organization of and trust in healthcare, posing a challenging environment for HCWs</p></list-item><list-item><p>Female health workers are more vulnerable in conflict areas</p></list-item><list-item><p>Mental health impacts on HCWs can be a significant issue</p></list-item></list>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">HRH governance </td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>There were significant gaps and fragmentation in leadership, HRH governance and regulation at national and regional levels</p></list-item><list-item><p>Conflict can intensify corruption, which can demotivate HCWs and compromise quality of care</p></list-item><list-item><p>Development partners’ short timelines of support and specific focus on certain activities or cadres, which might not be in line with government’s priorities, can disrupt HCWF composition over the medium to long term</p></list-item><list-item><p>HRH policy development capacity was low, and implementation (and financing) of existing policies was constrained</p></list-item><list-item><p>Non-state conflict actors, such as insurgent groups or rebel movements, are an actor group unique to CAS and bring with them serious ramifications for the health workforce</p></list-item><list-item><p>A few studies reporting on Syria showed that professional associations or expatriate groups took on governance functions in non-government-controlled areas</p></list-item></list>\n</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title><bold>Box 1.</bold> The Health Labour Market Framework</title><p> First developed by Sousa et al, the HLM framework takes a comprehensive view of the education sector and HLM dynamics (such as inflows and outflows of HCWs), including market failures, and links these to potential policy interventions.<sup>##REF##24347720##13##</sup> An important reason for us to choose this framework is its particular strength in visualizing how market disruptions within these sectors can compound issues in other parts of the framework affect workforce outcomes for years to come. This is especially relevant in CAS, as conflict causes specific disruptions across markets that further add to many difficulties already experienced in more stable LMICs.</p><p> We have chosen to further develop two elements of the HLM framework to better portray the devastating effects conflict has on the health workforce:</p><p>\n<bold>Emphasis on Dynamics of Conflict</bold></p><p> Current versions of the HLM framework do consider ‘economy, population, and broader societal drivers’ as influencing the education sector and labour market dynamics. However, the dynamics of conflict in CAS can have such far-reaching consequences for individual HCWs and the workforce that we added this specification in the framework. In our review, it becomes clear that conflict causes significant challenges for individual HCWs (including insecurity, displacement, and mental health) as well as shocks to institutions and functioning of health systems.</p><p>\n<bold>Addition of Focus on Health Workforce Governance</bold></p><p> While the HLM framework clearly addresses various entry points for policies, the authors felt that especially in CAS the underlying capacity and willingness of governments to fulfil key governance functions related to the health workforce cannot be taken for granted. As the review shows, in certain context the main coordinating function may fall to a non-state actor like ISIS in Syria and Iraq<sup>##REF##31034779##14##</sup> or ethnic health organizations in Myanmar.<sup>##REF##30938434##15##</sup> Moreover, in certain settings where governments are unable or unwilling to reach, development partners and/or civil society actors can take a bigger role.<sup>##REF##34794466##16##</sup> To highlight that an ideal stewardship role from a government cannot be presumed in CAS, we have added an additional box to highlight governance dynamics.</p><p>-----------------</p><p> Abbreviations: HRH, human resources for health; CAS, conflict-affected settings; HCWs, healthcare workers; ISIS, Islamic State of Iraq and Syria; HLM, health labour market; LMICs, low- and middle-income countries.</p></sec></boxed-text>", "<boxed-text id=\"BT2\" position=\"float\"><sec id=\"bx2\"><title>\n<bold>Box 2.</bold> Key Elements of the Adapted Health Labour Market Framework Used to Structure This Review</title><p>\n<bold>1. Education Sector</bold></p><p> The organisation, accessibility, and quality of pre-service education that affect production or supply of HCWs.</p><p>\n<bold>2. Labour market dynamics</bold></p><p>\n<italic toggle=\"yes\">\n<bold>Inflows and Outflows</bold>\n</italic>\n</p><p> The mobility of HCWs to enter and exit the labour market, and the ability of employing organisations to develop and implement policies that can shape and direct that mobility.</p><p>\n<italic toggle=\"yes\">\n<bold>Distribution</bold>\n</italic>\n</p><p> The (mal)distribution of the health workforce within a country, taking into account key factors such as urban/rural, level, cadre composition, age, and gender.</p><p>\n<italic toggle=\"yes\"><bold>Employment and Remuneration</bold></italic>\n</p><p> HCWs’ varying employment conditions, both official and de facto, including contractual conditions and remuneration (salary, stipends, and other).</p><p>\n<italic toggle=\"yes\">\n<bold>Performance</bold>\n</italic>\n</p><p> Various factors mediating HCWs’ (in)ability to perform, including challenges pertaining to in-service training, supervision, performance management and task divisions.</p><p>\n<bold>3. Contextual Factors Affecting HCWs in CAS</bold></p><p> Contextual challenges particular to CAS that impact the capacity and willingness of HCWs to operate as part of the workforce, including security-related issues, economic pressures and IDP movements. Changing dynamics around gender, ethnicity, race, class, ideology and other group dynamics can impact HCWs and patients.</p><p>\n<bold>4. Healthcare Workforce Governance</bold></p><p> The processesthat structure the roles and responsibilities of health systems stakeholders which influence if and how policies are enacted to achieve HCW outcomes (including administration of the workforce, regulation and accreditation, and policies to set and maintain strategic direction of the HCW). These processes are shaped by the interactions and relationshipsof a network of stakeholders with varying interests and power to influence governance outcomes.</p><p>-----------------</p><p> Abbreviations: HCW, healthcare worker; CAS, conflict-affected settings; IDP, internally displaced person.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Search String PubMed.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: HRH, human resources for health; DRC, Democratic Republic of Congo; CAR, Central African Republic.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: HRH, human resources for health; HCWs, healthcare workers; HLM, health labour market; DRC, Democratic Republic of Congo; CHW, community health worker; UN, United Nations; NCQAA, National Center for Quality Assurance and Accreditation; CAR, Central African Republic; MHPs, mental health professionals; ICCM, integrated community case management; NGO, Non-Governmental Organization; EMR, Eastern Mediterranean Region; ISIS, Islamic State of Iraq and Syria; RMNCAH+N, reproductive, maternal, new-born, child and adolescent health and nutrition; CHVs, community health volunteers; MISP, Minimum Initial Service Package for sexual and reproductive health in crisis settings; HPF, Health Pooled Fund; IDIs, in depth interviews; CAS, conflict-affected settings.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: HRH, human resources for health; HCWs, healthcare workers; CHWs, community health workers; CAS, conflict-affected settings; HLM, health labour market; HCWF, healthcare workforce.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7306-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7306-g002\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7306-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" Corral P, Irwin A, Krishnan N, Mahler DG, Vishwanath T. Fragility and Conflict: On the Front Lines of the Fight against Poverty. Washington, DC: World Bank; 2020. "]}, {"label": ["2"], "person-group": ["\n"], "surname": ["Haar", "Rubenstein"], "given-names": ["RJ", "LS"], "article-title": ["Health in fragile and post-conflict states: a review of current understanding and challenges ahead"], "source": ["Med ConflSurviv"], "year": ["2012"], "volume": ["28"], "issue": ["4"], "fpage": ["289"], "lpage": ["316"], "pub-id": ["10.1080/13623699.2012.743311"]}, {"label": ["3"], "person-group": ["\n"], "surname": ["Martineau", "McPake", "Theobald"], "given-names": ["T", "B", "S"], "article-title": ["Leaving no one behind: lessons on rebuilding health systems in conflict- and crisis-affected states"], "source": ["BMJ Glob Health"], "year": ["2017"], "volume": ["2"], "issue": ["2"], "fpage": ["e000327"], "pub-id": ["10.1136/bmjgh-2017-000327"]}, {"label": ["6"], "mixed-citation": [" World Health Organization (WHO). Guide to Health Workforce Development in Post-Conflict Environments. WHO; 2005. "]}, {"label": ["9"], "mixed-citation": [" World Health Organization (WHO). Analysing disrupted health sectors: a modular manual. Geneva: WHO; 2009. "]}, {"label": ["10"], "mixed-citation": [" WHO Alliance for Health Policy and Systems Research. Neglected health system research: health policy and systems research in conflict-affected fragile states. Geneva: WHO; 2008. "]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Arksey", "O\u2019Malley"], "given-names": ["H", "L"], "article-title": ["Scoping studies: towards a methodological framework"], "source": ["Int J Soc Res Methodol"], "year": ["2005"], "volume": ["8"], "issue": ["1"], "fpage": ["19"], "lpage": ["32"], "pub-id": ["10.1080/1364557032000119616"]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Al-Areibi"], "given-names": ["A"], "article-title": ["Medical education in Libya: challenges, hopes, and recommendations"], "source": ["Libyan Int Med Univ J"], "year": ["2019"], "volume": ["4"], "issue": ["1"], "fpage": ["3"], "lpage": ["9"]}, {"label": ["20"], "person-group": ["\n"], "surname": ["Atia", "Elfard", "Idbeaa", "Enjim"], "given-names": ["AE", "SA", "TF", "SE"], "article-title": ["Accreditation process and outcomes: experience of the University of Tripoli Alahlia, Libya"], "source": ["Open J Sociol Stud"], "year": ["2020"], "volume": ["4"], "issue": ["1"], "fpage": ["1"], "lpage": ["12"], "pub-id": ["10.32591/coas.ojss.0401.01001m"]}, {"label": ["23"], "person-group": ["\n"], "surname": ["Barnett-Vanes", "Hassounah", "Shawki"], "given-names": ["A", "S", "M"], "article-title": ["Impact of conflict on medical education: a cross-sectional survey of students and institutions in Iraq"], "source": ["BMJ Open"], "year": ["2016"], "volume": ["6"], "issue": ["2"], "fpage": ["e010460"], "pub-id": ["10.1136/bmjopen-2015-010460"]}, {"label": ["25"], "person-group": ["\n"], "surname": ["Buny"], "given-names": ["AA"], "article-title": ["Exploring factors influencing the decisions of professional aid workers to leave or stay in the humanitarian and development NGOs operating in War-torn societies: a lesson from South Sudan"], "source": ["J Contemp Sci Res"], "year": ["2019"], "volume": ["3"], "issue": ["10"], "fpage": ["1"], "lpage": ["12"]}, {"label": ["27"], "person-group": ["\n"], "surname": ["Fardousi", "Douedari", "Howard"], "given-names": ["N", "Y", "N"], "article-title": ["Healthcare under siege: a qualitative study of health-worker responses to targeting and besiegement in Syria"], "source": ["BMJ Open"], "year": ["2019"], "volume": ["9"], "issue": ["9"], "fpage": ["e029651"], "pub-id": ["10.1136/bmjopen-2019-029651"]}, {"label": ["29"], "person-group": ["\n"], "surname": ["Footer", "Clouse", "Rayes", "Sahloul", "Rubenstein"], "given-names": ["KHA", "E", "D", "Z", "LS"], "article-title": ["Qualitative accounts from Syrian health professionals regarding violations of the right to health, including the use of chemical weapons, in opposition-held Syria"], "source": ["BMJ Open"], "year": ["2018"], "volume": ["8"], "issue": ["8"], "fpage": ["e021096"], "pub-id": ["10.1136/bmjopen-2017-021096"]}, {"label": ["31"], "person-group": ["\n"], "surname": ["Hamid", "Scior", "de C Williams"], "given-names": ["A", "K", "AC"], "article-title": ["Qualitative accounts from Syrian mental health professionals: shared realities in the context of conflict and forced displacement"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["5"], "fpage": ["e034291"], "pub-id": ["10.1136/bmjopen-2019-034291"]}, {"label": ["32"], "person-group": ["\n"], "surname": ["Ibrahem", "Morgan"], "given-names": ["O", "J"], "article-title": ["Understanding the impact of the armed conflict (2014-2018) on healthcare professionals\u2019 practices and training: A qualitative study in Kirkuk, Iraq"], "source": ["International Public Health Journal"], "year": ["2022"], "volume": ["14"], "issue": ["1"], "fpage": ["75"], "lpage": ["83"]}, {"label": ["33"], "person-group": ["\n"], "surname": ["Jinor"], "given-names": ["J"], "article-title": ["Secondary trauma of lay mental health workers in low resource locations: Bukavu"], "source": ["J Soc Behav Health Sci"], "year": ["2020"], "volume": ["14"], "issue": ["1"], "fpage": ["2"], "pub-id": ["10.5590/jsbhs.2020.14.1.02"]}, {"label": ["35"], "person-group": ["\n"], "surname": ["Kallstr\u00f6m", "Al-Abdulla", "Parkki", "H\u00e4kkinen", "Juusola", "Kauhanen"], "given-names": ["A", "O", "J", "M", "H", "J"], "article-title": ["I had to leave I had to leave my clinic, my city, leave everything behind in Syria Qualitative research of Syrian healthcare workers migrating from the war-torn country"], "source": ["BMJ Open"], "year": ["2021"], "volume": ["11"], "issue": ["11"], "fpage": ["e049941"], "pub-id": ["10.1136/bmjopen-2021-049941"]}, {"label": ["36"], "person-group": ["\n"], "surname": ["Kallstr\u00f6m", "H\u00e4kkinen", "Al-Abdulla", "Juusola", "Kauhanen"], "given-names": ["A", "M", "O", "H", "J"], "article-title": ["Caught in crossfire: health care workers\u2019 experiences of violence in Syria"], "source": ["Med ConflSurviv"], "year": ["2021"], "volume": ["37"], "issue": ["1"], "fpage": ["34"], "lpage": ["54"], "pub-id": ["10.1080/13623699.2021.1889654"]}, {"label": ["37"], "person-group": ["\n"], "surname": ["Labat", "Sharma"], "given-names": ["F", "A"], "article-title": ["Qualitative study exploring surgical team members\u2019 perception of patient safety in conflict-ridden Eastern Democratic Republic of Congo"], "source": ["BMJ Open"], "year": ["2016"], "volume": ["6"], "issue": ["4"], "fpage": ["e009379"], "pub-id": ["10.1136/bmjopen-2015-009379"]}, {"label": ["50"], "person-group": ["\n"], "surname": ["Jabbour", "Fardousi"], "given-names": ["S", "N"], "article-title": ["Violence against health care in Syria: Patterns, meanings, implications"], "source": ["British Journal of Middle Eastern Studies"], "year": ["2022"], "volume": ["49"], "issue": ["3"], "fpage": ["403"], "lpage": ["417"], "pub-id": ["10.1080/13530194.2021.1916153"]}, {"label": ["59"], "mixed-citation": [" Avis W, Herbert S. Rapid fragility and migration assessment for Somalia.\u00a0Birmingham: GSDRC University of Birmingham; 2016. "]}, {"label": ["60"], "mixed-citation": [" World Health Organization (WHO). WHO Guideline on Health Workforce Development, Attraction, Recruitment and Retention in Rural and Remote Areas. WHO; 2021. "]}, {"label": ["61"], "person-group": ["\n"], "surname": ["Pallas", "Minhas", "P\u00e9rez-Escamilla", "Taylor", "Curry", "Bradley"], "given-names": ["SW", "D", "R", "L", "L", "EH"], "article-title": ["Community health workers in low- and middle-income countries: what do we know about scaling up and sustainability?"], "source": ["Am J Public Health"], "year": ["2013"], "volume": ["103"], "issue": ["7"], "fpage": ["e74"], "lpage": ["e82"], "pub-id": ["10.2105/ajph.2012.301102"]}, {"label": ["64"], "mixed-citation": [" World Health Organization (WHO). Delivered by women, led by men: a gender and equity analysis of the global health and social workforce. "], "uri": ["https://apps.who.int/iris/handle/10665/311322"]}, {"label": ["65"], "person-group": ["\n"], "surname": ["Yagos", "Tabo Olok", "Ovuga"], "given-names": ["WO", "G", "E"], "article-title": ["Use of information and communication technology and retention of health workers in rural post-war conflict Northern Uganda: findings from a qualitative study"], "source": ["BMC Med Inform DecisMak"], "year": ["2017"], "volume": ["17"], "issue": ["1"], "fpage": ["6"], "pub-id": ["10.1186/s12911-016-0403-3"]}]	{ "acronym": [], "definition": [] }	70	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 5; 12:7306	oa_package/ee/8d/PMC10590254.tar.gz
PMC10590255	0	[ "<title>Background</title>", "<p> Diets high in ultra-processed foods (UPFs) are linked to poor health due to their low nutritional value.<sup>##REF##32630022##1##, ####REF##32792031##2##, ##REF##33167080##3####33167080##3##</sup> UPFs are industrial formulations made of refined substances, such as sugars, oil and starches, as well as additives, and contain little or no whole foods.<sup>##REF##30744710##4##</sup> Increasingly, these products are cited in dietary guidelines to reduce their consumption in the population.<sup>##UREF##0##5##,##UREF##1##6##</sup> Public health researchers and advocates are also increasingly critical of the role of powerful food industry actors in producing, marketing, and selling UPF and shaping food environments and behaviors in ways that promote the consumption of these products.<sup>##REF##33619932##7##,##REF##23410611##8##</sup> To pursue financial growth, the food industry had, in the past and continues to, influence the information on diets and health by engaging and getting closer to health professionals such as dietitians and nutritionists.<sup>##UREF##2##9##,##REF##34935291##10##</sup> Industry interactions with nutrition professionals (NPs) could be profitable for NPs, as it could provide extra income and free or reduced rates for continuous education, for instance.<sup>##UREF##3##11##</sup> It is also beneficial for the industry to interact and maintain good relations with NPs, as it enhances its corporate image, promotes its products, and creates brand loyalty.<sup>##UREF##4##12##,##REF##21282309##13##</sup></p>", "<p> In recent years, however, the interactions between NPs and the industry have raised concerns, particularly their numerous partnerships and sponsorship arrangements, as these may undermine the trustworthiness, integrity, and credibility of the nutrition profession.<sup>##REF##33118920##14##, ####UREF##5##15##, ##UREF##6##16##, ##UREF##7##17##, ##UREF##8##18####8##18##</sup> Concerns have also been raised about health professional influencers – including NPs – receiving industry sponsorship to promote products/services, whether they disclose such funding or not.<sup>##UREF##5##15##,##UREF##9##19##,##REF##23547180##20##</sup> Such concerns about the interactions between industry and NPs have persisted for decades.<sup>##REF##11784415##21##</sup></p>", "<p> In the medical field, interactions with corporations and their associated risks have garnered much attention and reflection, and have prompted mechanisms to guard against such risks.<sup>##UREF##10##22##</sup> More broadly, a scoping review identified four main types of mechanisms for addressing and managing the influence of corporations on public health policy, research and practice (known as corporate political activity): (<italic toggle=\"yes\">a</italic>) transparency; (<italic toggle=\"yes\">b</italic>) management of interactions with industry and conflicts of interest (COIs); (<italic toggle=\"yes\">c</italic>) identification, monitoring and education about the practices of corporations and associated risks to public health; and (<italic toggle=\"yes\">d</italic>) prohibition of interactions with industry.<sup>##UREF##11##23##</sup> Recently, work has also been undertaken to develop guidelines for researchers’ interactions with the food industry.<sup>##REF##31437189##24##</sup> At the individual level, industry interactions with health professionals can create COIs, defined in law and public policy as a situation “where an individual has an obligation to serve a party or perform a role and the individual has either: (1) incentives or (2) conflicting loyalties, which encourage the individual to act in ways that breach his or her obligations” (it should be noted that alternative definitions are used in medicine).<sup>##UREF##12##25##</sup> The management of such COI is crucial for maintaining public trust.<sup>##REF##30657846##26##</sup> Consequently, NPs bodies have re-examined their partnership policies or introduced new guidance.<sup>##UREF##13##27##,##REF##32036995##28##</sup> For example, in 2018, Dietitians Australia ended its corporate sponsorship program with organizations within or related to food manufacturing and food industry associations or alcohol companies<sup>##UREF##14##29##</sup>; they have however been criticized for still allowing advertising by these industries.<sup>##UREF##15##30##,##UREF##16##31##</sup> Moreover, the International Confederation of Dietetic Associations’ International Code of Ethics and Code of Good Practice also explicitly states that NPs should be accountable to the public.<sup>##UREF##17##32##</sup></p>", "<p> While studies have been conducted on clinicians’ views of COI/industry interactions,<sup>##UREF##18##33##, ####REF##24671179##34##, ##UREF##19##35##, ##REF##26704824##36##, ##REF##24860060##37##, ##REF##30509273##38##, ##REF##32252743##39##, ##REF##28890928##40####28890928##40##</sup> to our knowledge, no review has examined the depth and breadth of interactions between NPs and industry and the perceived benefits, associated risks and solutions. A systematic review of interactions between non-physician clinicians and industry included 15 studies,<sup>##REF##24302892##41##</sup> only one of which included dietitians in its sample.<sup>##REF##17381952##42##</sup> As NPs have an important role in improving and maintaining the health of individuals and populations with their activities, it is urgent to examine the interactions between industry and NPs.</p>", "<p> Therefore, this scoping review aimed to map the literature concerning NPs–industry interactions in practice, NPs views or thoughts about those interactions, as well as the risks and solutions to address and manage these risks, and analyse and identify knowledge gaps.</p>" ]	[ "<title>Methods</title>", "<p> We conducted a scoping review following guidance from Arksey and O’Malley,<sup>##UREF##20##43##</sup> Levac et al,<sup>##REF##20854677##44##</sup> and the Joanna Briggs Institute.<sup>##REF##33570328##45##, ####UREF##21##46##, ##REF##33122034##47####33122034##47##</sup> The protocol for this study was pre-registered on Open Science Framework (osf.io/2wuda)<sup>##UREF##22##48##</sup> and a summary is provided below. The conduct and findings of this scoping review are reported following the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR).<sup>##REF##30178033##49##</sup></p>", "<title> Stage 1: Identifying the Research Question</title>", "<p> Our general research question was: <italic toggle=\"yes\">What is known from the existing scientific literature about the interactions between NPs and industry?</italic></p>", "<title> Sub-questions</title>", "<p>What is the nature of interactions between NPs, at the individual and institutional levels, and the industry, and how extensive are these interactions? </p>", "<p>What are the views of NPs towards those industry interactions, including perceived influence (eg, on professional practice, professional integrity), acceptability, and advantages/disadvantages? </p>", "<p>What are the perceived and observed risks associated with such interactions? </p>", "<p>What strategies/actions have been proposed/used to address and manage those risks? </p>", "<p> Our research question, search strategy, and inclusion/exclusion criteria were guided by the PCC (Population, Concept and Context) mnemonic<sup>##REF##33570328##45##</sup>; see ##TAB##0##Table 1##.</p>", "<title> Types of Sources of Evidence</title>", "<p> All scientific study designs were eligible, including those that used qualitative and/or quantitative methods, as well as non-empirical articles, including literature reviews, books, book chapters, guidelines, editorials, opinion pieces, and letters to the editor. Given the exploratory nature of this scoping review, we adopted a non-restrictive approach. We included documents funded by industry or whose authors were employed by industry, but these were analysed separately, given the inherent COI therein.</p>", "<title> Search Terms</title>", "<p> Title, abstract and keyword searches, using combinations of keywords and Medical Subject Headings (MeSH) (or equivalent), were used across the PCC outlined in ##TAB##0##Table 1##. The search strategy was developed in Medline (documented in protocol<sup>##UREF##22##48##</sup>), tailored for use within the other databases, and piloted before final searches were run. We developed the research strategy with the help of a librarian at the University of Montreal in Canada.</p>", "<title> Stage 2: Identifying Relevant Studies</title>", "<p> Between March 17, 2021 and March 21, 2021, VH and MH conducted electronic searches of the following databases/platforms: Scopus (Elsevier), CINAHL Complete (EBSCO host), Embase (OVID), Medline (OVID), CAB Abstracts (CABdirect) and Web of Science Core Collection. We searched for grey literature using Proquest Dissertations and Theses and Google Scholar. We also identified relevant resources through backward and forward citation searching of included records. Records were imported into Covidence software,<sup>##UREF##27##55##</sup> where duplicates were automatically identified and removed. We did not seek external expert input to complete the identification of relevant papers that might not have been found through database searches due to the expertise of two members of the review team (MM and JCM).</p>", "<title> Stage 3: Study Selection</title>", "<p> Title and abstract screening, and subsequent full text reviewing against our eligibility criteria, were conducted by two reviewers (VH and MH); any disagreements were resolved by consensus, or with a third reviewer when necessary (MM). Where full-text was not accessible to the research team, we contacted the author. Two authors were contacted, one did not respond and we finally had access to the other document through the University of Montreal’s library.</p>", "<title> Stage 4: Charting the Data</title>", "<p> Two reviewers (VH and MH) independently conducted data extraction/charting to reduce the probability of errors and bias<sup>##REF##33570328##45##</sup>; any disagreements were resolved by consensus or with a third reviewer (MM) when necessary. We used a modified version of the Joanna Briggs Institute template to assist with the charting of relevant data, such as author, origin, source type, and results or findings relevant to the review question(s).<sup>##REF##33570328##45##</sup> Initially, both reviewers independently extracted data from 10% of included records using the data charting table (see protocol<sup>##UREF##22##48##</sup>). They met to determine whether their approach to data extraction was consistent with the research question and purpose and if it captured the data appropriately.<sup>##REF##20854677##44##,##REF##33570328##45##</sup> Charting was an iterative process; the form was refined and updated accordingly<sup>##REF##33570328##45##</sup> – see final data extraction table in ##SUPPL##0##Supplementary file 1##.</p>", "<title> Stage 5: Collating, Summarizing, and Reporting the Results</title>", "<p> Following the completion of data charting from included records, we described and analysed the data in two ways. Firstly, we conducted a descriptive numerical summary analysis, encompassing the number and nature of records included in the review. Secondly, VH synthesized the qualitative data extracted for each of the four research sub-questions using content analysis<sup>##REF##16204405##56##</sup> with an inductive<sup>##UREF##28##57##,##UREF##29##58##</sup> and deductive approach based on previous work about solutions in COI in nutrition<sup>##UREF##11##23##</sup> for the sub-question on solutions used or proposed. Data from the results section of the documents, as well as the narrative content of publications, such as commentaries, were analysed qualitatively. We used NVivo software for data management. Finally, a verification of the clarity of the codes was carried out by JCM.<sup>##UREF##29##58##</sup> Any disagreements about the codes were discussed and resolved by consensus. Some quotes were categorised under several codes when quotes contained wording relevant to several categories.</p>" ]	[ "<title>Results</title>", "<p> The PRISMA flow diagram for our scoping review is presented in ##FIG##0##Figure 1##.<sup>##REF##33782057##59##</sup> In total, 7120 documents were identified through database/platform searches (excluding duplicates) and 2580 via other sources. After title and abstract screening of these 9700 records, and subsequent full-text review of 268 records, we included 115 documents for analysis covering 112 studies (Note: two documents were policy position papers that have been updated/revised; both versions were included<sup>##REF##7759752##60##, ####REF##11846124##61##, ##UREF##30##62##, ##UREF##31##63####31##63##</sup> — details in ##SUPPL##0##Supplementary file 1##). Overall, the majority of these documents were identified from original searches (n = 65), while others were obtained from backward citation mapping (n = 23) and forward citation mapping (n = 24), and three additional documents were identified after internal consultation with the team (expert input, ##FIG##0##Figure 1##).</p>", "<title> Characteristics of Included Documents</title>", "<p> Full details of included documents are provided in ##SUPPL##0##Supplementary file 1##; key characteristics are outlined in this section.</p>", "<title> Years</title>", "<p>\n##FIG##1##Figure 2## shows the included documents in the scoping review. These were published as early as 1980 with a growing trend, and a majority (90%) were published from 2000 onwards (##FIG##1##Figure 2##). There is also a significant growth since 2013.</p>", "<title> Type of Sources </title>", "<p> The majority of documents were journal articles (n = 91, 79%), including original manuscripts, commentaries, editorials, practice points, policy positions, and letters to editors. Other documents comprised doctoral theses (n = 6, 5%), reports (n = 5, 4%), published conference abstracts (n = 4, 3%), books (n = 3, 3%), book chapters (n = 3, 3%), newsletter articles (n = 1, 1%), and magazine articles (n = 2, 2%).</p>", "<title> Country of Origin</title>", "<p> Just over half of the documents (n = 59, 51%) were published in/focused on the United States, followed by the United Kingdom (n = 9, 8%), Canada (n = 7, 6%), and Australia (n = 6, 5%). Two documents were from Africa (Nigeria [n = 1, 1%] and South Africa [n = 3, 3%]). Six documents provided global perspectives (n = 6, 5%), while one focused on Europe (n = 1, 1%).</p>", "<title> Study Design</title>", "<p> Almost two in every three documents were classified as a narrative (n = 63, 55%) or position paper (n = 12, 10%). Only 32% (n = 37) of documents were empirical studies. Almost one in five was a documentary analysis (n = 21, 18%). Other categories of study design included mixed methods (n = 4, 3%), netnography (ie, “qualitative method investigating behaviors of cultures and communities present on the Internet”<sup>##UREF##32##64##</sup>) (n = 1, 1%), participant observation (n = 1, 1%), qualitative assessment (n = 10, 9%), quantitative and cross-sectional survey (n = 2, 2%) and systematic review (n = 1, 1%) (##SUPPL##1##Supplementary file 2##).</p>", "<title> Context</title>", "<p> Almost a third of the documents focused mostly on individual professional practice (n = 33, 29%). Individual professional practice in nutrition includes professional activities such as individual counselling and/or working in a hospital. ‘Sponsorship of professional body/organization’ was the second most frequent context studied or discussed in the literature (n = 26, 23%), followed by ‘corporate political activity’ (n = 21, 18%) and partnership/collaboration with a professional body (n = 26, 23%) (##TAB##1##Table 2##).</p>", "<title> Population</title>", "<p>\n##TAB##1##Table 2## presents the population studied in the documents analysed. Over half of the documents focused on more than one population (n = 62, 54%). More than half of the documents focused on nutrition and health organizations (including professional bodies, associations and societies) (n = 67, 59%) and NPs (n = 59, 52%).</p>", "<title> Type of Industry Studied or Discussed </title>", "<p> Most documents (n = 91, 79%) reported/discussed interactions between NPs and the food and beverage industry, followed by the pharmaceutical industry (n = 29, 25%). Other types of industry reported included the breastmilk substitutes (n = 18, 16%), biotechnology and agrochemical (n = 11, 10%), alcohol (n = 2, 2%) and medical technology (n = 1, 1%) sectors. The majority of documents mentioned more than one type of industry, while some were more general (ie, they did not mention any specific type of industry or company) (n = 15, 13%) (##SUPPL##0##Supplementary file 1##).</p>", "<title> Authors’ Industry Ties</title>", "<p> We examined industry involvement in included documents by analysing the affiliations, declared industry funding sources, and declared COIs. We identified industry ties with authors in 13 documents (11 %). For those papers where industry ties were identified, it was declared through the affiliation(s) of authors<sup>##REF##16442880##65##,##UREF##33##66##</sup>; in the funding section<sup>##REF##29540465##67##</sup>; the COI section<sup>##REF##32416734##68##,##UREF##34##69##</sup>; both the affiliation and funding section<sup>##UREF##35##70##,##REF##10083718##71##</sup>; both in the funding and COI sections<sup>##REF##33118920##14##,##REF##11784415##21##,##REF##32744984##72##</sup>; as well as through the affiliation, funding and declared COI sections.<sup>##REF##16002831##73##, ####UREF##36##74##, ##REF##16390663##75####16390663##75##</sup> In 24 documents, the information on both COI, funding and affiliations was not stated (it should be noted that the three books included in the review in which COI information is also absent are excluded from that count)<sup>##UREF##6##16##,##UREF##7##17##,##REF##7759752##60##, ####REF##11846124##61##, ##UREF##30##62##, ##UREF##31##63####31##63##,##UREF##37##76##, ####UREF##38##77##, ##UREF##39##78##, ##UREF##40##79##, ##UREF##41##80##, ##UREF##42##81##, ##UREF##43##82##, ##REF##11633356##83##, ##UREF##44##84##, ##UREF##45##85##, ##UREF##46##86##, ##REF##19476682##87##, ##UREF##47##88##, ##UREF##48##89##, ##UREF##49##90##, ##UREF##50##91##, ##REF##8906148##92##, ##UREF##51##93####51##93##</sup>; this included position papers/commentaries from professional bodies known to have had or for having relationships with industry (as declared in documents included or on their website) (ie, Academy of Nutrition and Dietetics [AND],<sup>##UREF##52##94##</sup> Society for Nutrition Education and Behavior, and Latin American Society of Nutrition).<sup>##REF##32036995##28##,##REF##7759752##60##,##UREF##30##62##,##UREF##31##63##,##UREF##38##77##,##UREF##40##79##,##UREF##41##80##,##UREF##43##82##,##UREF##45##85##,##UREF##48##89##,##REF##8906148##92##,##REF##20677413##95##, ####UREF##53##96##, ##REF##11794489##97##, ##UREF##54##98####54##98##</sup> Other documents from the AND, the Latin American Society of Nutrition, the British Nutrition Foundation and the Canadian Nutrition Society, who are known to have had or for having relationship(s) with industry (as declared in documents included or on their website<sup>##UREF##55##99##,##UREF##56##100##</sup>) have also not declared any industry ties or related COI.<sup>##REF##32036995##28##,##REF##21070977##101##, ####UREF##57##102##, ##UREF##58##103##, ##UREF##59##104##, ##UREF##60##105##, ##REF##30550121##106####30550121##106##</sup></p>", "<title> Qualitative Analysis</title>", "<p> We extracted and coded data about types of industry interactions experienced by NPs perceived risks, acceptability, and advantages of industry interactions, as well as strategies and actions used to manage such interactions (see codebooks for details of all codes, with illustrative quotes — Supplementary files 3, 4, and 5). Almost all documents outlined NPs experiences of industry interactions (n = 104, 90%) and perceived risk (n = 86, 75%). More than half of the documents discussed the acceptability and advantages of industry interactions (n = 64, 56% and n = 59, 51%, respectively). Finally, strategies and actions used to manage NPs and industry interactions were outlined in 69% of the documents (n = 79) (##SUPPL##1##Supplementary file 2##).</p>", "<title> Nutrition Professionals’ Experiences of Industry Interactions</title>", "<p> We identified seven channels through which NPs can interact directly or indirectly with industry. These included interactions through (1) NPs, (2) professional bodies or health and nutrition organizations, (3) educational institutions (eg, universities), (4) industry marketing and interactions in work settings, (5) colleagues or other health professionals (eg, physicians), (6) industry website or media advertising and promotional events, and (7) foreign aid context. In total, we identified 32 different categories of interactions between NPs and industry (presented in ##TAB##2##Table 3##). Details of these categories and illustrative quotes can be found in the ##SUPPL##2##Supplementary file 3##.</p>", "<p> When interacting directly with industry, NPs can have ‘active’ or ‘passive’ interactions. More ‘active’ interactions include endorsing industry products for compensation. Examples of active interactions were found in private practices, where NPs received compensation from companies in exchange for recommending their products to clients.<sup>##UREF##39##78##,##UREF##48##89##,##UREF##53##96##,##UREF##61##107##</sup> Other direct interactions with the industry that NPs do not necessarily seek out or for which they are not actively involved were also identified, such as receiving targeted communication from the industry (eg, via letter or email)<sup>##REF##14976167##111##,##UREF##66##116##,##REF##9847922##117##</sup> (##TAB##2##Table 3##).</p>", "<p> We identified that professional bodies and health organizations (with whom NPs interact frequently and in many ways) are important channels of influence for the industry through various interactions (##TAB##2##Table 3##). The most commonly reported interaction was industry participation in NPs continuing education within professional bodies and health and nutrition organizations. For example, 22 documents attested that the industry participated in various nutrition and scientific events around the world by having industry-sponsored or affiliated speakers and holding specific sessions, conferences and symposia.<sup>##REF##33118920##14##,##UREF##6##16##,##UREF##7##17##,##REF##11784415##21##,##UREF##51##93##,##UREF##59##104##,##UREF##62##110##,##REF##9847922##117##, ####UREF##67##118##, ##REF##33046110##119####33046110##119##,##REF##28689497##121##,##REF##19114408##123##, ####REF##32819452##124##, ##REF##29998811##125##, ##REF##33109216##126##, ##REF##27004957##127##, ##UREF##69##128##, ##REF##19298423##129##, ##UREF##70##130##, ##UREF##71##131##, ##UREF##72##132##, ##UREF##73##133####73##133##</sup> Other examples include industry involvement in seminars and training (continuing education) provided by professional bodies.<sup>##UREF##47##88##,##UREF##51##93##,##UREF##58##103##,##UREF##59##104##,##UREF##62##110##,##REF##30169613##135##</sup></p>", "<p> Partnerships between professional bodies or health and nutrition organizations and industry were reported in 39 documents, while sponsorship of these organizations was reported in 29 documents (##TAB##2##Table 3##). Sponsorship of the AND was mentioned in 18 of these documents,<sup>##UREF##2##9##,##REF##11784415##21##,##UREF##37##76##,##UREF##47##88##,##UREF##49##90##,##UREF##51##93##,##UREF##59##104##,##UREF##62##110##,##REF##9847922##117##,##UREF##67##118##,##REF##19298423##129##,##UREF##71##131##,##UREF##76##138##,##REF##20063212##147##,##REF##30232060##151##,##REF##18854543##153##,##REF##27745783##156##,##UREF##81##157##</sup> followed by the British Dietetic Association (BDA) (n = 3) <sup>##UREF##8##18##,##UREF##50##91##,##UREF##78##152##</sup> and the Dietitian Association of Australia (DAA) (n = 3).<sup>##UREF##6##16##,##REF##14976167##111##,##UREF##78##152##</sup> It was also reported in Canada,<sup>##UREF##80##155##</sup> New Zealand,<sup>##UREF##58##103##</sup> Spain,<sup>##REF##30169613##135##,##REF##24646823##145##</sup> and South Africa.<sup>##REF##32728853##122##</sup> Professional bodies and nutrition and health organizations also gave industry access to NPs through their actions, communications, and structures, by, for instance, advertising in journals, on the organization’s website and by direct mailing.<sup>##UREF##6##16##,##REF##11784415##21##,##UREF##49##90##,##UREF##50##91##,##UREF##51##93##,##UREF##58##103##,##UREF##62##110##,##REF##14976167##111##,##REF##1436768##115##,##UREF##67##118##,##REF##19298423##129##,##UREF##71##131##,##REF##30169613##135##,##REF##32660803##137##,##UREF##76##138##,##UREF##78##152##,##REF##33993793##158##</sup></p>", "<p> We identified three types of interaction that occurred within educational institutions, such as the provision or sponsorship of nutrition student educational materials, activities, events and internships<sup>##UREF##4##12##,##REF##10083718##71##,##REF##32819452##124##,##REF##33109216##126##,##UREF##72##132##,##UREF##82##159##</sup> (##TAB##2##Table 3##). Other channels through which the industry interacts with NPs are NPs workplace, NPs colleagues or other health professionals and industry websites and media advertising and promotional events. Finally, interactions with industry were also identified in the context of foreign aid.<sup>##UREF##67##118##,##UREF##83##160##</sup></p>", "<title> Nutrition Professional’s Acceptability of Industry Interactions </title>", "<p> Acceptability of industry interactions varied widely. Some authors, NPs (surveyed or interviewed), and organizations perceived interactions as acceptable,<sup>##UREF##2##9##,##REF##33118920##14##,##REF##17381952##42##,##UREF##30##62##,##UREF##38##77##,##UREF##47##88##,##UREF##49##90##,##UREF##50##91##</sup>, <sup>##UREF##51##93##,##UREF##59##104##,##UREF##66##116##, ####REF##9847922##117##, ##UREF##67##118####67##118##,##UREF##69##128##,##UREF##70##130##, ####UREF##71##131##, ##UREF##72##132####72##132##,##UREF##76##138##,##REF##19476684##142##,##UREF##81##157##,##REF##33993793##158##</sup> or even encouraged them.<sup>##REF##11784415##21##,##REF##7759752##60##,##REF##11846124##61##,##UREF##31##63##,##REF##16442880##65##,##REF##16002831##73##,##UREF##37##76##,##UREF##40##79##,##UREF##41##80##,##UREF##49##90##, ####UREF##50##91##, ##REF##8906148##92####8906148##92##,##REF##20677413##95##,##REF##11794489##97##,##UREF##54##98##,##REF##21070977##101##, ####UREF##57##102##, ##UREF##58##103##, ##UREF##59##104####59##104##,##UREF##66##116##,##UREF##71##131##,##UREF##72##132##,##REF##19476684##142##,##REF##1987003##161##,##REF##11115798##162##</sup> For those who actively encouraged these interactions, industry was considered an ally in promoting public health and developing such relationships. It is important to note that commentaries, position papers and letters of presidents from nutrition organizations and professional bodies (ie, AND, Canadian Nutrition Society and the British Nutrition Foundation) all encouraged interactions with industry,<sup>##REF##7759752##60##,##REF##11846124##61##,##REF##16442880##65##,##UREF##40##79##,##UREF##41##80##,##REF##8906148##92##,##REF##20677413##95##,##REF##11794489##97##,##UREF##54##98##,##REF##21070977##101##, ####UREF##57##102##, ##UREF##58##103##, ##UREF##59##104####59##104##</sup> or considered these as being acceptable.<sup>##UREF##30##62##,##UREF##38##77##,##UREF##59##104##</sup> Nevertheless, this review and further searches revealed that these organizations have several ties with industry, which could explain their stance.<sup>##UREF##52##94##,##UREF##55##99##,##UREF##56##100##</sup></p>", "<p> Some considered that acceptability was conditional on the type of industry.<sup>##UREF##40##79##,##UREF##42##81##,##UREF##50##91##,##UREF##51##93##,##UREF##62##110##,##UREF##66##116##,##UREF##76##138##</sup> For instance, some authors or NPs stated that industry’s mission should be consistent with their organization.<sup>##UREF##40##79##,##UREF##76##138##</sup> The nutritional values or level of processing of companies’ products were other conditions influencing acceptability. In a survey conducted with AND members,<sup>##UREF##76##138##</sup> “food growers and producers” were perceived the most acceptable to work with, while “food and drink manufacturers” were deemed the least acceptable. Acceptability could also be conditional on the type of interaction (eg, free travel and accommodation were acceptable, but involvement in nutrition/scientific events were not),<sup>##UREF##2##9##,##REF##11784415##21##,##UREF##49##90##,##UREF##50##91##,##UREF##67##118##</sup> or on other conditions such as following a code of ethics or being transparent.<sup>##REF##16390663##75##,##UREF##38##77##,##REF##11633356##83##,##REF##19476682##87##,##UREF##48##89##,##UREF##50##91##,##UREF##53##96##,##UREF##60##105##,##REF##1436768##115##,##UREF##72##132##,##REF##19476684##142##</sup> On the 11 documents that welcomed interactions with industry if a code of ethics is followed or if those are undertaken with transparency, five were documents from the AND.<sup>##REF##16390663##75##,##UREF##38##77##,##UREF##48##89##,##UREF##53##96##,##UREF##60##105##</sup></p>", "<p> Finally, the perception that interactions with industry were not acceptable was reported in 22 documents.<sup>##REF##33118920##14##,##UREF##6##16##,##UREF##8##18##,##UREF##39##78##,##UREF##45##85##,##UREF##47##88##,##UREF##49##90##,##UREF##50##91##,##UREF##51##93##,##REF##30550121##106##,##UREF##62##110##,##UREF##66##116##,##UREF##67##118##,##UREF##69##128##,##UREF##71##131##,##UREF##72##132##,##UREF##76##138##,##REF##25889468##140##,##REF##30232060##151##,##UREF##80##155##,##UREF##81##157##,##UREF##83##160##</sup> For instance, Bellatti<sup>##REF##30232060##151##</sup> reported that some members renounced their AND memberships because of its history of ties with the food industry, which demonstrates a high level of unacceptability. It may be noted that of the documents presenting an unfavourable stance about interactions with industry, none appear to have COI or indirect ties with industry through nutrition organizations like AND.</p>", "<title> Perceived Advantages of Industry Interactions </title>", "<p> A variety of advantages associated with industry interactions were perceived by some authors and NPs.</p>", "<title> Advantages for Organizations</title>", "<p> Interacting with the industry provided three benefits for organizations. First, interactions were perceived as beneficial for the financial survival of organizations.<sup>##UREF##6##16##,##REF##30657846##26##,##UREF##31##63##,##UREF##38##77##,##UREF##41##80##,##UREF##47##88##,##UREF##49##90##,##UREF##51##93##,##UREF##59##104##,##REF##14976167##111##,##REF##1436768##115##,##UREF##70##130##,##UREF##76##138##,##UREF##80##155##,##UREF##81##157##</sup> Second, others highlighted that sponsorship and funding were a way to earn additional income and accelerate business growth. For example, extra income could allow organizations to hold scientific events in a prestigious location or to offer more activities within those events.<sup>##UREF##59##104##,##UREF##67##118##,##UREF##76##138##,##REF##19476684##142##</sup> Third, it allowed organizations to fulfil their mission to a greater extent (eg, by having facilitated/funded educational programs or other activities that could not otherwise have happened).<sup>##UREF##30##62##,##UREF##31##63##,##UREF##37##76##,##REF##8906148##92##,##UREF##59##104##,##REF##19476684##142##</sup> In 1995, a past president of the AND (formerly called American Dietetic Association) highlighted that “[i]ndustry support makes an invaluable contribution toward fulfilling the mission and vision of American Dietetic Association, and can help accomplish many activities at the local level.”<sup>##UREF##31##63##</sup> Twenty years later, in 2015, NPs from the AND still endorsed this view.<sup>##UREF##59##104##</sup></p>", "<title> Advantages for Professionals and Organizations</title>", "<p> Advantages of industry interactions that apply to both professional bodies/organizations and professionals included improving public outreach,<sup>##UREF##30##62##,##UREF##31##63##,##UREF##41##80##,##UREF##59##104##,##REF##1436768##115##,##UREF##66##116##,##UREF##71##131##,##UREF##81##157##</sup> benefiting from industry’s expertise (eg, marketing and public relations expertise, skills and networks),<sup>##UREF##6##16##,##UREF##31##63##,##UREF##47##88##,##UREF##59##104##,##REF##19476684##142##</sup> building awareness of the professional body and its members to the public,<sup>##UREF##41##80##,##UREF##58##103##,##UREF##59##104##,##UREF##81##157##</sup> and enhancing credibility and reputation.<sup>##UREF##31##63##,##UREF##59##104##</sup></p>", "<title> Advantages for Individual Professionals</title>", "<p> Continuing education and information,<sup>##REF##17381952##42##,##REF##10083718##71##,##UREF##36##74##,##UREF##39##78##,##UREF##47##88##,##REF##11794489##97##,##UREF##54##98##,##UREF##59##104##,##REF##1436768##115##,##UREF##71##131##,##UREF##81##157##</sup> career and employment opportunities,<sup>##UREF##33##66##,##UREF##41##80##,##UREF##47##88##,##UREF##59##104##,##UREF##61##107##,##UREF##67##118##</sup> source of income<sup>##UREF##2##9##,##UREF##45##85##,##UREF##48##89##,##REF##14976167##111##, ####UREF##63##112##, ##UREF##64##113####64##113##,##REF##1436768##115##</sup> and prestige<sup>##UREF##53##96##,##REF##14976167##111##</sup> were reported benefits that professionals could personally gain from industry interactions.</p>", "<title> Advantages for the Public</title>", "<p> Some benefits that the public could gain from the interactions between industry and NPs were described. Indeed, it was argued that those interactions could positively influence industry actions and product development toward more healthy food products.<sup>##UREF##2##9##,##UREF##6##16##,##UREF##40##79##,##UREF##47##88##,##REF##20677413##95##,##REF##21070977##101##,##UREF##57##102##,##UREF##59##104##,##REF##1436768##115##,##UREF##71##131##,##REF##19476684##142##,##REF##23750980##148##,##UREF##81##157##</sup> For others, these interactions could shape public food choices and improve public health (eg, by combining resources,<sup>##UREF##81##157##</sup> “singles out products useful from standpoint of professionals”<sup>##REF##1436768##115##</sup> or “promot[ing] environments and messages that facilitate healthy food […] choices”<sup>##UREF##54##98##</sup>),<sup>##UREF##6##16##,##REF##11846124##61##, ####UREF##30##62##, ##UREF##31##63####31##63##,##REF##16002831##73##,##UREF##46##86##,##UREF##54##98##,##UREF##59##104##,##REF##1436768##115##,##REF##19298423##129##,##UREF##71##131##,##REF##24646823##145##,##REF##22420639##163##</sup> as well as offer better population nutrition education and information through partnerships (eg, by providing public with good nutrition materials at no charge).<sup>##UREF##6##16##,##REF##7759752##60##,##REF##11846124##61##,##UREF##31##63##,##REF##16442880##65##,##REF##8906148##92##,##REF##21070977##101##,##UREF##58##103##,##UREF##59##104##,##REF##1436768##115##,##UREF##66##116##</sup></p>", "<title> Perceived and Experienced Risks of Interacting With Industry</title>", "<p> Several risks were identified across the documents encompassing general risks and some specific to professionals, organizations, and the public.</p>", "<title> General </title>", "<p> According to the literature, relationships between NPs and industry actors could result in the public, NPs or their professional body refraining from criticizing industry actions or from encouraging people to engage in critical thinking around industry behavior and actions.<sup>##UREF##2##9##,##UREF##6##16##,##REF##11784415##21##,##UREF##42##81##,##UREF##51##93##,##UREF##62##110##,##REF##14976167##111##,##REF##9847922##117##,##UREF##67##118##,##REF##32728853##122##,##UREF##69##128##,##UREF##72##132##,##REF##31865949##143##,##REF##24330345##146##,##UREF##77##150##,##UREF##80##155##</sup> Interactions also represent a risk of being a vehicle for industry marketing and messaging<sup>##REF##33118920##14##,##UREF##6##16##,##UREF##7##17##,##REF##11784415##21##,##REF##24302892##41##,##UREF##51##93##,##REF##31180446##109##,##UREF##66##116##,##UREF##70##130##, ####UREF##71##131##, ##UREF##72##132##, ##UREF##73##133####73##133##,##REF##30169613##135##,##UREF##76##138##,##REF##24330345##146##,##UREF##81##157##</sup> and creating positive associations and credibility for industry brand(s).<sup>##UREF##4##12##,##REF##21282309##13##,##UREF##51##93##,##REF##30550121##106##,##REF##28110500##108##,##UREF##62##110##,##UREF##69##128##,##REF##30169613##135##,##UREF##75##136##,##REF##32268902##139##,##REF##27009056##141##,##REF##26259972##149##,##UREF##80##155##</sup></p>", "<title> For Health Policy</title>", "<p> Interactions between NPs and industry can also influence public health policies, given that professional bodies and nutrition and health organizations are respected and influential in their countries. For example, AND has a political action committee. Some NPs formally advise governments and advocate for nutrition policies.<sup>##UREF##51##93##,##UREF##84##164##</sup> Many authors pointed out that interactions could contribute to framing the debate around food and health in a way that could be favourable to the industry in two ways. First, by influencing NPs and professional bodies on food products and public health messages through industry-friendly narratives (eg, there are no good or bad foods, favouring energy balance and moderation, and focusing on individual choices)<sup>##UREF##6##16##,##REF##11784415##21##,##REF##32036995##28##,##REF##32416734##68##,##UREF##47##88##,##UREF##66##116##,##UREF##69##128##,##REF##19298423##129##,##UREF##72##132##,##REF##24330345##146##,##REF##20063212##147##,##REF##30232060##151##,##UREF##81##157##,##REF##11115798##162##,##REF##32520489##165##</sup> and second, shaping policy positions of professional bodies and health organizations.<sup>##UREF##6##16##,##UREF##7##17##,##UREF##51##93##,##UREF##67##118##,##REF##32660803##137##</sup> For instance, corporate sponsorship has shaped the policy positions of nutrition organizations, such as the Spanish Federation of Nutrition, Food and Dietetics Societies, which opposed the Nutri-Score front-of-pack labelling system, otherwise supported by health organizations across Europe. Interactions could also introduce bias in policies or dietary guidelines and programs<sup>##UREF##37##76##,##REF##27004957##127##,##UREF##69##128##,##REF##32268902##139##,##REF##27009056##141##</sup> and favour corporation lobby efforts aimed at delaying or neutralizing public health policies such as soda taxes or dietary guidelines (eg, by “invoking reciprocity and financial dependence on the part of national health organizations”<sup>##REF##27745783##156##</sup>).<sup>##REF##21282309##13##,##REF##32268902##139##</sup></p>", "<title> For Professionals and Organizations</title>", "<p> Risks of interacting with industry that apply to both organizations and professionals included image and reputational risks, including undermining trust, credibility, integrity and reputation<sup>##REF##33118920##14##,##UREF##6##16##,##UREF##7##17##,##REF##11784415##21##,##REF##30657846##26##,##REF##32036995##28##,##REF##16442880##65##,##REF##16390663##75##,##UREF##39##78##,##UREF##40##79##,##UREF##42##81##,##UREF##44##84##,##UREF##46##86##,##UREF##47##88##,##UREF##49##90##,##UREF##50##91##,##UREF##51##93##,##UREF##53##96##,##UREF##59##104##,##REF##28110500##108##,##UREF##62##110##,##REF##1436768##115##,##UREF##67##118##,##UREF##69##128##,##UREF##71##131##,##REF##19476684##142##,##REF##32517669##144##,##REF##18854543##153##,##UREF##80##155##,##UREF##81##157##,##REF##18060888##166##,##UREF##85##167##</sup> and appearance of endorsement of brands or products or commercial bias.<sup>##REF##11784415##21##,##UREF##38##77##,##UREF##49##90##,##UREF##50##91##,##REF##1436768##115##,##REF##9847922##117##,##UREF##76##138##,##REF##31865949##143##</sup> It can also compromise independence by impairing objectivity and judgement<sup>##UREF##2##9##,##REF##33118920##14##,##REF##11784415##21##,##REF##30657846##26##,##REF##32416734##68##,##REF##16390663##75##,##REF##11633356##83##,##UREF##45##85##,##UREF##50##91##,##UREF##53##96##,##REF##1436768##115##,##UREF##66##116##,##UREF##70##130##,##REF##32660803##137##,##REF##31865949##143##,##UREF##78##152##,##REF##18854543##153##,##UREF##80##155##,##UREF##85##167##</sup> and influencing decision-making or recommendations.<sup>##UREF##4##12##,##REF##21282309##13##,##REF##24302892##41##,##REF##16390663##75##,##UREF##38##77##,##UREF##49##90##,##UREF##51##93##,##UREF##53##96##,##UREF##60##105##,##REF##30550121##106##,##REF##14976167##111##,##REF##1436768##115##,##UREF##69##128##,##REF##32660803##137##,##REF##33993793##158##,##REF##32520489##165##,##UREF##85##167##</sup> Finally, interactions with industry can make the organization lose members<sup>##REF##30232060##151##</sup> and even contradict the organization’s and professional’s public health mission.<sup>##UREF##51##93##,##UREF##62##110##,##REF##1436768##115##,##REF##27009056##141##,##UREF##81##157##</sup></p>", "<title> For Professionals</title>", "<p> For individual NPs, interactions with industry could pose several risks, including the influence on the scientific content of nutrition events (eg, cancelling a debate on childhood obesity because it would cause inconvenience to potential sponsors<sup>##UREF##70##130##</sup> or providing educational flyers with commercial bias<sup>##UREF##69##128##</sup>).<sup>##UREF##51##93##,##UREF##62##110##,##REF##32660803##137##,##REF##25889468##140##,##REF##30232060##151##</sup> It can also influence the content of continuing education programs<sup>##UREF##47##88##,##UREF##51##93##,##UREF##62##110##,##UREF##85##167##</sup> and students’ training/teaching programs and careers.<sup>##UREF##4##12##</sup> This influence can be translated into a risk of commercial bias and incomplete education, as described by Simon: “Equally concerning, if registered dietitians are getting their continuing education units from the food industry, what messages are they missing? Coca-Cola or General Mills are not going to sponsor sessions on the harmful impacts of marketing to children despite the numerous studies demonstrating the connection.”<sup>##UREF##51##93##</sup> NPs’ practices and beliefs may also be unconsciously influenced.<sup>##UREF##62##110##,##REF##14976167##111##,##UREF##66##116##,##UREF##71##131##,##UREF##80##155##,##REF##27745783##156##</sup> This risk was illustrated in the context of collaboration between NPs and the food industry in school nutrition programs: “[…] these relationships leave NPs open to the charge that their lack of attention to food industry marketing efforts in elementary schools arises from their close ties to the food industry.”<sup>##UREF##66##116##</sup></p>", "<p> Two documents also reported that industry interactions with NPs and health and nutrition organizations could be misleading and result in confusion for NPs (eg, by confusing sponsorship and health promotion).<sup>##REF##14976167##111##,##UREF##67##118##</sup> Less frequently reported were risks of creating antagonism between health professionals<sup>##REF##28110500##108##</sup> and the revocation of licensure in case of ethical issues.<sup>##UREF##48##89##</sup></p>", "<title> For the Public</title>", "<p> NPs are respected professionals, capable of influencing population knowledge and perceptions about nutrition.<sup>##UREF##86##168##</sup> Our review suggests that interactions with industry may impact the public in three ways. First, interactions may mislead and confuse the public about nutrition knowledge (eg, by confusing nutritional advice with sponsor’s marketing or by not receiving all the information about foods).<sup>##REF##30657846##26##,##UREF##33##66##,##UREF##39##78##,##UREF##44##84##,##UREF##47##88##,##UREF##49##90##,##UREF##50##91##,##REF##28110500##108##,##UREF##62##110##,##REF##1436768##115##,##REF##9847922##117##,##UREF##67##118##,##UREF##68##120##,##REF##18854543##153##,##UREF##81##157##</sup> Second, they could undermine public health nutrition recommendations,<sup>##REF##21282309##13##,##UREF##8##18##,##REF##17381952##42##,##UREF##37##76##,##UREF##44##84##,##REF##9847922##117##,##UREF##67##118##,##UREF##70##130##,##UREF##73##133##,##REF##30169613##135##,##REF##32660803##137##,##REF##32268902##139##,##REF##27009056##141##,##REF##31865949##143##,##REF##32517669##144##,##REF##24330345##146##,##UREF##81##157##,##REF##33993793##158##,##UREF##83##160##,##REF##32520489##165##</sup> as illustrated by Potvin-Kent and al: “[…] [P]artnering with food companies, particularly those that largely produce and promote unhealthy food products, could confer an aura of healthfulness, goodwill and credibility to these industry partners while eclipsing the fact that many of the same companies or their industry associations persistently and aggressively push-back against government policies and the efforts of public health advocates aimed at improving diet and health.”<sup>##REF##32517669##144##</sup> Third, one document reported that “price of product may be increased (or not so low as it could be) due to costs of endorsement.”<sup>##REF##1436768##115##</sup></p>", "<title> Strategies and Actions, Proposed or Used to Address and Manage the Risks Associated With NPs and Industry Interactions</title>", "<p> We classified strategies and actions, proposed, used, or in use, to address and manage the risks associated with interactions between industry and NPs, according to whom these strategies or actions apply, either at the institution, individual or both levels. Five main categories of strategies were identified, namely (1) management, (2) education, (3) prohibition, (4) transparency, and disclosure (5) awareness-raising. ##TAB##3##Table 4## presents all these strategies. Further details on these strategies and illustrative quotations can be found in ##SUPPL##4##Supplementary file 5##.</p>", "<title> Institution/Organization/Professional Body Level </title>", "<title> Management </title>", "<p> Institutions, organizations and professional bodies use various management strategies to handle industry interactions. These include (1) codes, policies, and guidelines, (2) external and internal consultation, (3) alternative financial strategies, (4) compromise, and (5) other strategies (##TAB##3##Table 4##). The most commonly used strategy is to follow and develop codes, policies, and guidelines (and revise these if they are not considered strong enough or adequate). However, implementing these can be problematic, as some organizations have been found to deviate from their own established rules. Indeed, it was reported that the DAA, AND, and the BDA undertook activities that conflicted with or deviated from their own established code, guidelines, or policies.<sup>##UREF##6##16##,##UREF##50##91##,##UREF##51##93##</sup> For instance, Simon identified that “[…] [t]he DAA’s policy on brand endorsement is contradicted numerous times, for example, on the DAA’s Pinterest pages, with recipes credited to companies such as Unilever, Campbell’s, and Nestlé that list branded products as ingredients.”<sup>##UREF##6##16##</sup></p>", "<p> Otherwise, some authors suggest more selective criteria for choosing sponsors in industry partnerships with organizations.<sup>##UREF##70##130##,##UREF##76##138##,##REF##27009056##141##,##UREF##81##157##</sup> For instance, it was reported that the AND already had a list of “General Requirements for Acceptance of Corporate Relations Sponsors.” The list however did not appear to be used by the organization.<sup>##UREF##51##93##</sup> Moreover, whereas NPs surveyed by Reitshamer and colleagues in 2012 mentioned that AND must be more selective in choosing sponsors,<sup>##UREF##76##138##</sup> two other documents from the AND mentioned that the organization was already choosing their sponsors and partners based on “well-defined criteria” and “complex and rigorous scrutiny.”<sup>##UREF##31##63##,##UREF##59##104##</sup></p>", "<p> Other strategies proposed included structural changes at conferences/events<sup>##UREF##42##81##,##UREF##59##104##,##UREF##67##118##,##UREF##69##128##</sup> (eg, having a commercial area separate from the scientific content) and including additional sponsors to reduce specific industry influence (dilution principle).<sup>##UREF##50##91##,##UREF##76##138##</sup></p>", "<title> Education</title>", "<p> Educating professionals about the issue was another strategy proposed or used.<sup>##UREF##4##12##,##REF##24302892##41##,##UREF##33##66##,##UREF##42##81##,##UREF##47##88##,##UREF##61##107##,##UREF##71##131##,##UREF##72##132##,##REF##31865949##143##,##UREF##80##155##</sup> Some suggested that NPs should be “invited to discuss the moral and ethical implications of doing business with a variety of private food and pharmaceutical corporations”<sup>##UREF##80##155##</sup> and these “ethical implications should be problematized […] during continuing education.”<sup>##REF##24302892##41##</sup> In four documents, it was suggested that the issue should be included in courses and in projects within educational institutions where NPs are trained.<sup>##UREF##4##12##,##UREF##71##131##,##UREF##72##132##,##REF##31865949##143##</sup></p>", "<title> Individual Level</title>", "<title> Management</title>", "<p> We identified six main individual-level management strategies (##TAB##3##Table 4##). The most commonly suggested strategy was using tools like a code of ethics to manage COI when making decisions.<sup>##UREF##8##18##,##REF##11784415##21##,##UREF##33##66##,##REF##16390663##75##,##UREF##38##77##,##UREF##39##78##,##UREF##44##84##,##UREF##46##86##,##REF##19476682##87##,##UREF##48##89##,##UREF##49##90##,##UREF##53##96##,##UREF##58##103##,##UREF##61##107##,##UREF##63##112##,##UREF##65##114##,##UREF##81##157##,##REF##32520489##165##</sup> Balancing risks and benefits on a case-by-case basis (eg, in the context of corporate funding<sup>##UREF##2##9##,##REF##11784415##21##,##REF##32517669##144##</sup> or accepting gift or payment<sup>##REF##16390663##75##</sup>) is an example of the “individual discernment” strategy proposed. Another strategy proposed by an author with industry ties was that “[NPs] can ethically act as consultants and speak on behalf of a company or product as long as they retain control over the content and disclose their relationship with the company.”<sup>##REF##16390663##75##</sup></p>", "<title> Both Institution and Individual Level Strategy</title>", "<title> Prohibition: Prohibiting, Avoiding, and Refusing Interactions With Industry </title>", "<p> Some authors proposed prohibition as a strategy to deal with interactions with industry, including avoiding, refusing, and prohibiting all interactions. Some suggested refusing invitations and gifts from industry at the individual level (eg, declining invitations to attend or speak at sponsored meetings),<sup>##UREF##2##9##,##REF##16390663##75##,##UREF##38##77##,##UREF##39##78##,##REF##30550121##106##</sup> while others mentioned avoiding certain situations (eg, avoiding visiting industry booths at nutrition events or not attending a presentation that indirectly endorses certain products).<sup>##UREF##48##89##,##UREF##51##93##,##UREF##67##118##,##UREF##71##131##</sup></p>", "<title> Transparency: Disclosing Interactions With Industry and Related COI</title>", "<p> Transparency was proposed as a strategy for organizations and individuals to mitigate interactions with industry (##TAB##3##Table 4##). Nine documents highlighted the importance of transparency for institutions to be open with the public and members about their interactions with industry.<sup>##UREF##2##9##,##REF##30657846##26##,##REF##19476682##87##,##UREF##50##91##,##REF##32728853##122##,##REF##27004957##127##,##REF##32660803##137##,##REF##32268902##139##,##UREF##81##157##</sup> While these authors and NPs called for more transparency from some organizations such as the AND and the BDA, three documents from the AND emphasized ongoing efforts around transparency.<sup>##REF##32036995##28##,##UREF##40##79##,##UREF##53##96##</sup></p>", "<p> However, despite transparency being heavily discussed in documents where authors have industry ties (directly or through AND and the American Society of Nutrition),<sup>##REF##30657846##26##,##REF##32036995##28##,##UREF##33##66##,##REF##16390663##75##,##UREF##40##79##,##UREF##48##89##,##UREF##53##96##,##UREF##59##104##,##UREF##60##105##</sup> only one has declared their industry affiliation.<sup>##UREF##33##66##</sup> A lack of transparency from organizers of nutrition and scientific events about industry ties has also been identified in some documents.<sup>##REF##33118920##14##,##UREF##6##16##,##UREF##7##17##,##UREF##51##93##</sup> For instance, Mialon et al found that many conferences in Latin America and the Caribbean in 2018-2019 lacked information about food industry involvement.<sup>##REF##33118920##14##</sup></p>", "<title> Awareness-Raising: Advocating for COI Recognition and Action to Address COI by Institution</title>", "<p> Another reported strategy was for members of professional bodies and organizations to advocate for recognition of COI resulting from industry interactions.<sup>##UREF##4##12##,##UREF##42##81##,##REF##30550121##106##,##UREF##67##118##</sup> Two advocacy groups identified were Dietitians for Professional Integrity and a group of researchers and NPs who were members of the Latin American Society of Nutrition. They have both started a petition to ask for their organization to recognize COI and take necessary action. Finally, it was suggested that professionals and their organizations reflect on their existing interactions with industry to identify COI.<sup>##REF##11784415##21##,##UREF##39##78##,##REF##9847922##117##</sup> One author further proposed a framework to help with this work.<sup>##UREF##39##78##</sup></p>" ]	[ "<title>Discussion</title>", "<p> This scoping review aimed to map the literature on NPs–industry interactions in practice, as well as professionals’ views about the acceptability, advantages and risks of those interactions and the solutions to address and manage these risks. We identified numerous categories of interactions (n = 32) that can occur between NPs and different types of industry. Interactions were primarily with food and beverages industries, but other industries also interacted with NPs (eg, pharmaceutical and breastmilk substitutes). This review also highlights the need to consider various settings and points of influence in the career paths of NPs (eg, initial training, workplaces, etc) which can increase the risks identified in this review and discussed below. Some of these interactions, such as industry representatives visits, meals, product samples and gifts distribution, educational events and educational materials distribution, and payment for travel and accommodation attendance are not unique to NPs. These interactions have also been identified and discussed in other health sectors such as nursing, doctors of pharmacy, physiotherapists, and physicians.<sup>##UREF##10##22##,##REF##24302892##41##,##REF##31180446##109##,##REF##27043976##169##</sup></p>", "<p> We found that the acceptability of those interactions varied considerably among authors and NPs. While some authors and NPs encouraged or considered interactions with industry acceptable, others were more nuanced or considered them unacceptable. This review also revealed that documents from associations and professional bodies that had ties with industry tended to encourage and consider interactions with industry as being acceptable. On the other side, from all the documents revealing stances not favourable to these interactions, none have declared COI. Moreover, surveys<sup>##UREF##50##91##,##UREF##66##116##,##UREF##76##138##</sup> and interviews<sup>##UREF##47##88##,##UREF##71##131##,##UREF##81##157##</sup> from documents included in this review also showed that acceptability varied through members of the same association, such as AND and BDA. This variability is also reflected across other health professions. Indeed, in a systematic review of interactions between industry and other professionals than physicians (including NPs), Grundy<sup>##REF##24302892##41##</sup> identified that a majority of professionals held favourable views of industry interactions (such as sale representatives visits), while only a minority held negative views toward such interactions.</p>", "<p> We identified 14 advantages of interactions with industry perceived by different authors and NPs in the documents. Financial support was the most common benefit, aiding both organizations (financial survival, additional income and business growth) and NPs (source of income and career/employment). Similarly, Grundy and colleagues also reported that nurses believed it would be impossible to do their jobs without industry resources.<sup>##REF##27043976##169##</sup> Industry expertise is another advantage identified in our review. However, expertise transfer from industry is problematic because this expertise is oriented toward profit creation, marketing and brand loyalty.<sup>##UREF##87##170##</sup> Despite the benefits, it is important to note that risks also exist and can outweigh these advantages.</p>", "<p> Our review found risks associated with interactions between NPs, organizations, the public, and public policies. One frequently cited risk was the potential damage to the image and reputations of NPs and their professional organizations, which is also recognized in other professions.<sup>##UREF##10##22##,##UREF##87##170##,##UREF##88##171##</sup> These interactions also posed a risk for public health policies by introducing bias in public policies and programs and potentially favouring industry lobbying. These actions are part of a larger set of corporate political activity strategies that aim to influence policy in ways that benefit industry profitability at the expense of public health.<sup>##REF##28110500##108##,##REF##28689497##121##,##REF##29998811##125##,##REF##27004957##127##,##REF##30693564##172##, ####REF##27495802##173##, ##REF##26378841##174##, ##REF##31155001##175##, ##REF##29974816##176##, ##UREF##89##177####89##177##</sup> These strategies have been previously identified in tobacco research, which undermined and delayed public health policies aiming at controlling product sales, use and distribution.<sup>##REF##19298423##129##</sup> Although there is limited evidence of the actual effects of the interactions described here at the individual level, similar interactions in medicine have been shown to impact the behaviour and quality of prescription of medical doctors who engage with industry representatives.<sup>##UREF##90##178##</sup></p>", "<p> Many strategies were proposed or used to manage and address risks associated with interactions between NPs and industry. Transparency was the most frequently mentioned strategy for both individuals and institutions. However, this strategy alone might not be enough to mitigate the risks and ensure trustworthiness, indeed, it can also “guild the lily” even more.<sup>##UREF##87##170##,##UREF##91##179##</sup> Another questionable strategy identified in our review is the “dilution” strategy, which consists of having multiple partnerships or sponsors to reduce the influence of any single corporation. It is argued that this approach may exacerbate the framing effects by having a cumulative effect of influence, instead of reducing or diluting it.<sup>##UREF##87##170##</sup></p>", "<p> We did not assess the adequacy of the proposed solutions because it was beyond the scope of our review. However, as discussed above, some of these solutions are questionable. Notably, some of those were proposed by authors that had themselves COI or ties with industry, such as the author Woteki,<sup>##REF##16390663##75##</sup> who proposed managing interactions by retaining control over the content, and the documents from the AND who promoted transparency. Moreover, simply having a code of ethics and guidelines may not be enough to protect the profession, as implementation can be problematic. As mentioned above, some institutions deviated from their established code, guidelines, or policies and/or lacked transparency.<sup>##REF##33118920##14##,##UREF##6##16##,##UREF##7##17##,##UREF##50##91##,##UREF##51##93##</sup> To address this, recommendations include revising, evaluating and monitoring the respect of codes, guidelines and policies<sup>##REF##17381952##42##,##REF##19476682##87##,##REF##19476684##142##,##REF##31865949##143##</sup> and applying sanctions for non-compliance.<sup>##REF##33118920##14##</sup></p>", "<p> Evidence of the most effective strategies to mitigate COI and risks associated with interactions with industry within public health is still limited. One promising strategy to consider is prohibition, based on the effect it has had on tobacco control. Under the 5.3 Article of the World Health Organization (WHO) Framework Convention on Tobacco Control, which is adopted in national Law in 182 countries across the globe,<sup>##UREF##92##180##</sup> any individual working in the public sector and involved in tobacco control policies cannot interact with the tobacco industry.<sup>##REF##34897446##181##</sup> Some argued that national initiatives, ensuring independence and transparency of policy-making, such as the implementation of article 5.3 of the Framework by countries, have been effective.<sup>##REF##34897446##181##</sup> Thus, it has been suggested that this kind of initiative could be replicated for other industries which negatively impact health, such as the UPFs industry.<sup>##REF##34897446##181##</sup></p>", "<p> Education, another proposed solution, can be a first important step toward better independence, with lessons to draw from the medical field and pharmaceutical industry influence. One example of this type of strategy is the development of educational materials for medical students and practitioners made by the WHO and the Health Action International, <italic toggle=\"yes\">Understanding and Responding to Pharmaceutical Promotion - A Practical Guide, </italic>releasedin 2013.<sup>##UREF##10##22##</sup> More recently, the research team called “PEPITe santé” in France developed a training for critical analysis of pharmaceutical promotion for medical students.<sup>##UREF##93##182##, ####UREF##94##183##, ##UREF##95##184####95##184##</sup> These training programs could be adapted for NPs since many interactions and risks identified in this scoping were similar to those identified in this area.<sup>##UREF##10##22##</sup> Raising NPs awareness of the various interactions with industry and the risks attached is necessary and should be included in all dietetic programmes and continuous professional training.</p>", "<p> Some promising movements to counter inappropriate sponsorship of nutrition and health organizations had emerged in the past decade. In 2013, a grassroots organization, Dietitians for Professional Integrity, was formed to advocate for the AND to sever its ties with food industry partners and sponsors,<sup>##UREF##42##81##</sup> though the organization disbanded five years later as it failed to achieve its objectives. The Hunger and Environmental Nutrition Dietetic Practice Group of the AND has also publicly criticized the Academy’s sponsorship practices.<sup>##UREF##81##157##</sup> Although this advocacy resulted in toolkits for non-members and members<sup>##UREF##96##185##</sup> and guidance to help AND better choose sponsors,<sup>##UREF##96##185##</sup> the organization is still supported by corporations manufacturing UPF, such as Mondelēz International.</p>", "<title> Implications for Research</title>", "<p> This review found that NPs-industry interactions are gaining attention in the literature, but empirical studies are limited and mainly focus on the United States. More research is needed to systematically document industry interactions with NPs and the impacts and risks associated with these. Research on strategies to manage NPs-industry interactions and COI is needed as fewer studies have focused on this area.<sup>##UREF##11##23##</sup> Future research in the area should focus on media, particularly social media (including blogs), given the rise in their prominence<sup>##REF##29463487##186##</sup> and also examine industry documents to gain insights on this issue from an industry perspective.</p>", "<title> Strengths and Limitations </title>", "<p> This study has several strengths. Firstly, our scoping review presents a comprehensive overview of the literature on NPs interactions with the industry. A further strength of the study is the synthesis and reporting of the qualitative data from the scoping review, which goes beyond the traditional scope of a review. This provides valuable evidence on which to base future research and inform practice.</p>", "<p> We did not assess the quality of the included documents. However, this was not our focus or within the remit of a scoping review per se, as we set out to map the literature in this area to inform future research. Lastly, it is important to note that we captured some hypothetical situations in our analysis which illustrated existing types of interactions between NPs and industry, ie, authors did not provide actual examples and/or citations.<sup>##UREF##33##66##,##REF##16390663##75##,##UREF##38##77##,##UREF##39##78##,##UREF##44##84##,##UREF##46##86##,##UREF##49##90##,##UREF##53##96##</sup></p>", "<title> Deviations From Protocol</title>", "<p> First, we planned to search professional bodies’ websites, selecting the most relevant ones based on the initial findings from the previous searches. However, we did not proceed with this approach due to the high volume of records identified. We also initially planned to extract data regarding the ‘disadvantages of industry interactions’; however, on piloting, there was an overlap between this and ‘perceived risks,’ so we merged it into the latter column. There was also an overlap between the ‘Views of NPs towards the perceived influence of industry interactions’ and advantages and risks; we amended the former to general views.</p>" ]	[ "<title>Conclusion</title>", "<p> NPs have a crucial role in identifying and addressing inappropriate commercial practices, while promoting nutrition for health.<sup>##REF##32184211##187##</sup> Our scoping review identified several areas for future research, such as exploring the impact of these interactions on nutrition practice and public health policies. Finally, to better manage the COI resulting from these interactions, reviewing and monitoring existing institutional policies and guidelines and evaluating the effectiveness of current solutions through research could be first steps to enhance transparency, accountability, and ultimately the quality of nutrition care.</p>" ]	[ "<p>\n<bold>Background:</bold> In recent years, interactions between nutrition professionals (NPs) and the food industry, such as sponsorship arrangements, have raised concerns, particularly as these may negatively impact the trustworthiness and credibility of the nutrition profession. This study aimed to map the literature and identify knowledge gaps regarding interactions between NPs and industry. We sought to examine the nature of such interactions and NPs perspectives about these, as well as the risks and solutions.\n</p>", "<p><bold>Methods:</bold> We conducted a scoping review according to a pre-registered protocol, searching eight electronic databases and grey literature sources in March 2021 to identify documents for inclusion. Two independent reviewers screened citations for inclusion and conducted data extraction. Quantitative and qualitative syntheses were conducted. </p>", "<p><bold>Results:</bold> We identified 115 documents for analysis, published between 1980 to 2021, with a majority from the United States (n=59, 51%). Only 32% (n=37) were empirical studies. The food industry was the most frequent industry type discussed (n=91, 79%). We identified 32 types of interactions between NPs and industry, such as continuing education provided by industry and sponsorship of professional bodies and health and nutrition organizations. The financial survival of nutrition organizations and continuing education access for NPs were the most frequently cited advantages of industry-NPs interactions. On the other hand, undermining public trust, NPs credibility and public health nutrition recommendations were pointed out as risks of these interactions. Following a code of ethics, policies, or guidelines was the most frequently proposed solution for managing these interactions.</p>", "<p><bold>Conclusion:</bold> Despite the increasing attention given to this issue, few empirical papers have been published to date. There is a need for more research to better and systematically document industry interactions with NPs and the impacts associated with these, as well as more research on effective management strategies. </p>", "<p><bold>Registry Name and Number:</bold> Interactions between nutrition professionals and industry actors: A scoping review protocol. doi:10.17605/OSF.IO/Q6PUA</p>", "<p>\n<bold>Citation:</bold> Hamel V, Hennessy M, Mialon M, Moubarac JC. Interactions between nutrition professionals and industry: a scoping review. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7626. doi:10.34172/ijhpm.2023.7626</p>" ]	[ "<title>Acknowledgements</title>", "<p> We wish to thank Myrian Grondin, Librarian at the University of Montreal, for her assistance in the development of the search strategy.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> There was no dedicated funding for this review. VH received financial support from the Centre de Recherche en Santé Publique (CReSP) when this study was conducted and is financially supported by the Fonds de Recherche du Québec – Santé [Grant Number: BF2 – 319234]. MH was a postdoctoral researcher funded by the Health Research Board-Ireland [Grant Number: ILP-HSR-2019-011] when this study was conducted. MM is funded by the Health Research Board-Ireland [Grant Number: ARPP-2020-002]. JCM is funded by the Canadian Institutes of Health Research, the International Development Research Center (IDRC) and Heart & Stroke Canada [Grant Numbers: RNI00488, RY000380, RQ000690].</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nPRISMA Flow Diagram for Our Scoping Review. Abbreviation: PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nNumber of Documents by Year of Publication.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Inclusion and Exclusion Criteria\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Inclusion Criteria</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Exclusion Criteria</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Population</td><td style=\"border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Nutrition/dietetic professionals (students/qualified); nutrition/dietetic professional bodies and associations.<break/>NPs are “individuals who pursue a professional career in nutrition, such as dietitians or nutritionists, and are trained sufficiently in nutrition practice to demonstrate defined competencies and to meet the certification or registration requirements of national or global nutrition/dietetics professional organizations.”<sup>##UREF##17##32##</sup><break/>A professional body is “an organization of people with particular professional qualifications. May seek to set standards of professional competence, to control entry to ensure that its members are able to maintain professional standards to monitor the conduct of members to ensure that they maintain these standards, and to exclude them if they do not.”<sup>##UREF##23##50##</sup><break/>National dietetics associations “are professional societies whose members have education qualifications in food, nutrition and dietetics recognized by a national authority and whose members apply the science of nutrition to the feeding and education of groups of people and individuals, in health and disease.”<sup>##UREF##24##51##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">-</td></tr><tr><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Concept</td><td rowspan=\"1\" colspan=\"1\">Industry interactions<break/>Industry is defined as companies/corporations that produce food and drink/healthcare goods and services, as well as third parties working for such entities, including their trade associations, public relations firms and associated scientific entities.<sup>##REF##24302892##41##,##UREF##25##52##</sup> Pharmaceutical and alcohol industries also, given their presence at nutrition conferences in many countries and their influence on other parts of NPs’ practice.<sup>##REF##33118920##14##</sup><break/>Interactions are defined as any industry exposure such as meetings with sales representatives; receipt of gifts, payments, or promotional materials, including samples; or attendance at industry-sponsored education.<sup>##REF##24302892##41##</sup><break/>Risks are defined as unintended, negative consequences of an event for public health, NPs, organization and public policies.<sup>##UREF##26##53##</sup></td><td style=\"text-align:left;\" rowspan=\"1\" colspan=\"1\">Records focusing on views and experiences of interactions between professionals and industry concerning research as this has been the subject of more recent studies.<sup>##REF##30968553##54##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Context</td><td style=\"border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Professional practice, not limited by geographic location, language, or year.</td><td style=\"text-align:left;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Documents solely focusing on NPs working for/in the industry.</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Documents by Context and by Population\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Context</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>No. of Articles </bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>%</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Professional practice</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">33</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">29</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Sponsorship of professional body/organization</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">26</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">23</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Corporate political activity</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">21</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">18</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Partnership/collaboration with a professional body</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">21</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">18</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Sponsorship and involvement in scientific events</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">15</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Management of COI by professional body/nutrition organization</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">NPs education/continuing professional development</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Ethics</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public nutrition education</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Sponsorship of health professional</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Management of conflict of interest by academia</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Sponsorship/advertising</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Population </bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>No. of Articles </bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>%</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Nutrition and health organization</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">67 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">59</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">NPs</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">59</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">52</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Policy-makers</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">30</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">26</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Health professionals</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">28</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">25</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Academics</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">24</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">21</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Community</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Academia</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Journalists</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Advertisers/publishers</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Opinion leaders</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Nutrition Professionals’ Experiences of Industry Interactions According to the Channels Through Which the Industry Interacts With Them\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Channels Through Which the Industry Interacts With NPs </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Nature of Interactions</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Interactions with individual NPs</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Active (solicited or implying involvement from individuals)\n<list list-type=\"bullet\"><list-item><p>Employment by or consultation service for industry<sup>##REF##11784415##21##,##REF##16390663##75##,##UREF##44##84##,##UREF##53##96##,##UREF##61##107##, ####REF##28110500##108##, ##REF##31180446##109##, ##UREF##62##110####62##110##</sup></p></list-item><list-item><p>Having stock holding or ownership in an industry<sup>##REF##16390663##75##,##UREF##48##89##</sup></p></list-item><list-item><p>Endorsement of a company and its brands</p><p><list list-type=\"simple\"><list-item><p>♦ Endorsement of products or industry in the public sphere<sup>##UREF##48##89##,##REF##14976167##111##, ####UREF##63##112##, ##UREF##64##113##, ##UREF##65##114##, ##REF##1436768##115####1436768##115##</sup></p></list-item><list-item><p>♦ ndorsement of products in private practice or in the office<sup>##UREF##39##78##,##UREF##48##89##,##UREF##53##96##,##UREF##61##107##</sup></p></list-item><list-item><p>♦ Endorsement and/or co-creation of educational material<sup>##UREF##49##90##,##UREF##50##91##,##UREF##66##116##</sup></p></list-item></list></p></list-item></list>\nOther direct interactions\n<list list-type=\"bullet\"><list-item><p>Receiving travel and conference attendance funding<sup>##UREF##8##18##,##REF##30657846##26##,##REF##17381952##42##,##UREF##33##66##,##REF##16390663##75##,##UREF##50##91##,##UREF##51##93##,##REF##9847922##117##, ####UREF##67##118##, ##REF##33046110##119####33046110##119##</sup></p></list-item><list-item><p>Continuing education directly provided by industry<sup>##UREF##36##74##,##REF##11633356##83##,##UREF##68##120##, ####REF##28689497##121##, ##REF##32728853##122####32728853##122##</sup></p></list-item><list-item><p>Receiving targeted communication from industry (eg, via letter or email)<sup>##REF##14976167##111##,##UREF##66##116##,##REF##9847922##117##</sup></p></list-item></list></td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Interaction with professional bodies or nutrition and health organizations</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NPs education\n<list list-type=\"bullet\"><list-item><p>Involvement in NPs and scientific events</p><p>\n<list list-type=\"simple\"><list-item><p>\n♦ Industry participation in scientific event(s)<sup>\n##REF##33118920##14##,##UREF##6##16##,##UREF##7##17##,##REF##11784415##21##,##UREF##51##93##,##UREF##59##104##,##UREF##62##110##,##REF##9847922##117##, ####UREF##67##118##, ##REF##33046110##119####33046110##119##,##REF##28689497##121##,##REF##19114408##123##, ####REF##32819452##124##, ##REF##29998811##125##, ##REF##33109216##126##, ##REF##27004957##127##, ##UREF##69##128##, ##REF##19298423##129##, ##UREF##70##130##, ##UREF##71##131##, ##UREF##72##132##, ##UREF##73##133####73##133##\n</sup>\n</p></list-item><list-item><p>\n♦ Exhibit booths<sup>\n##REF##33118920##14##,##REF##11784415##21##,##UREF##41##80##,##UREF##42##81##,##UREF##49##90##,##UREF##59##104##,##UREF##62##110##,##REF##1436768##115##,##REF##33046110##119##,##REF##27004957##127##,##UREF##69##128##,##UREF##70##130##, ####UREF##71##131##, ##UREF##72##132####72##132##,##UREF##74##134##, ####REF##30169613##135##, ##UREF##75##136####75##136##\n</sup>\n</p></list-item><list-item><p>\n♦ Industry promotional and educational materials distribution <sup>\n##REF##33118920##14##,##REF##11784415##21##,##UREF##42##81##,##UREF##51##93##,##REF##1436768##115##,##UREF##66##116##,##UREF##69##128##,##UREF##70##130##\n</sup>\n</p></list-item><list-item><p>\n♦ Provision of meals/beverages/food samples<sup>\n##REF##33118920##14##,##REF##11784415##21##,##REF##16390663##75##,##UREF##47##88##,##UREF##51##93##,##REF##9847922##117##,##UREF##69##128##,##UREF##70##130##\n</sup>\n</p></list-item><list-item><p>\n♦ Sponsorship of nutrition events/conferences<sup>\n##UREF##2##9##,##REF##33118920##14##,##REF##30657846##26##,##UREF##39##78##,##UREF##46##86##,##UREF##47##88##,##UREF##51##93##,##REF##28110500##108##,##UREF##66##116##,##UREF##67##118##,##REF##33046110##119##,##REF##33109216##126##,##UREF##69##128##,##UREF##70##130##,##UREF##73##133##,##REF##30169613##135##,##REF##32660803##137##, ####UREF##76##138##, ##REF##32268902##139##, ##REF##25889468##140##, ##REF##27009056##141##, ##REF##19476684##142####19476684##142##\n</sup>\n</p></list-item></list>\n</p></list-item><list-item><p>Continuing education provided/sponsored by industry<sup>##UREF##47##88##,##UREF##51##93##,##UREF##58##103##,##UREF##59##104##,##UREF##62##110##,##REF##30169613##135##</sup></p></list-item></list>\n<p>Partnership and sponsorship</p>\n<list list-type=\"bullet\"><list-item><p>Partnership on programs or advocacy<sup>##UREF##2##9##,##REF##21282309##13##,##UREF##6##16##,##REF##11784415##21##,##UREF##31##63##,##REF##29540465##67##,##REF##32416734##68##,##REF##32744984##72##,##REF##16002831##73##,##UREF##41##80##,##UREF##45##85##,##UREF##49##90##, ####UREF##50##91##, ##REF##8906148##92##, ##UREF##51##93####51##93##,##REF##11794489##97##,##UREF##58##103##,##UREF##59##104##,##UREF##62##110##,##REF##1436768##115##, ####UREF##66##116##, ##REF##9847922##117##, ##UREF##67##118####67##118##,##REF##32728853##122##,##REF##33109216##126##,##REF##27004957##127##,##REF##19298423##129##,##UREF##71##131##,##REF##30169613##135##,##REF##32268902##139##,##REF##31865949##143##, ####REF##32517669##144##, ##REF##24646823##145##, ##REF##24330345##146##, ##REF##20063212##147##, ##REF##23750980##148##, ##REF##26259972##149##, ##UREF##77##150##, ##REF##30232060##151####30232060##151##</sup></p></list-item><list-item><p>Sponsorship of professional bodies and health and nutrition organizations<sup>##UREF##2##9##,##UREF##6##16##, ####UREF##7##17##, ##UREF##8##18####8##18##,##REF##11784415##21##,##UREF##37##76##,##UREF##47##88##,##UREF##49##90##,##UREF##50##91##,##UREF##58##103##,##UREF##59##104##,##UREF##62##110##,##REF##14976167##111##,##REF##9847922##117##,##UREF##67##118##,##REF##32728853##122##,##REF##19298423##129##,##UREF##71##131##,##REF##30169613##135##,##REF##32660803##137##,##UREF##76##138##,##REF##20063212##147##,##REF##30232060##151##, ####UREF##78##152##, ##REF##18854543##153##, ##UREF##79##154##, ##UREF##80##155##, ##REF##27745783##156##, ##UREF##81##157####81##157##</sup></p></list-item></list><p>Other interactions with professional bodies or nutrition and health organizations</p><list list-type=\"bullet\"><list-item><p>Advertising through journal(s), direct mailing, and website<sup>##UREF##6##16##,##REF##11784415##21##,##UREF##49##90##,##UREF##50##91##,##UREF##51##93##,##UREF##58##103##,##UREF##62##110##,##REF##14976167##111##,##REF##1436768##115##,##UREF##67##118##,##REF##19298423##129##,##UREF##71##131##,##REF##30169613##135##,##REF##32660803##137##,##UREF##76##138##,##UREF##78##152##,##REF##33993793##158##</sup></p></list-item><list-item><p>Endorsement of food products (such as food certification)<sup>##UREF##6##16##,##REF##30657846##26##,##UREF##59##104##,##REF##14976167##111##,##REF##1436768##115##</sup></p></list-item><list-item><p>Prizes and awards sponsored by or from industry<sup>##REF##33118920##14##,##UREF##6##16##,##REF##30657846##26##,##UREF##50##91##,##UREF##59##104##</sup></p></list-item><list-item><p>Leaders or committee members with industry's ties or affiliation in the organization<sup>##UREF##6##16##,##UREF##49##90##,##REF##32268902##139##</sup></p></list-item><list-item><p>Networking opportunities (such as membership networking events)<sup>##REF##30657846##26##,##UREF##36##74##,##REF##19476684##142##</sup></p></list-item><list-item><p>Industry-led surveys and focus groups with members<sup>##REF##21282309##13##,##UREF##50##91##</sup></p></list-item></list>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Interaction with or within educational institutions (eg, universities)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Provision/sponsorship of student educational materials/activities/events/internships<sup>##UREF##4##12##,##REF##10083718##71##,##REF##32819452##124##,##REF##33109216##126##,##UREF##72##132##,##UREF##82##159##</sup></p></list-item><list-item><p>Scholarships, sponsorship, awards, and prizes for students<sup>##UREF##4##12##,##REF##33118920##14##,##REF##11633356##83##,##REF##33109216##126##</sup></p></list-item><list-item><p>Sponsored continuing education<sup>##REF##33109216##126##,##REF##31865949##143##</sup></p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Industry marketing/interactions in a work setting</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Industry marketing/interactions in a work setting <list list-type=\"bullet\"><list-item><p>Sales representative visits<sup>##REF##17381952##42##,##UREF##49##90##,##UREF##61##107##</sup></p></list-item><list-item><p>Gifts, samples, and educational material<sup>##REF##17381952##42##,##UREF##49##90##</sup></p></list-item><list-item><p>Attending lunchtime meetings (industry representative speaking)<sup>##UREF##50##91##</sup></p></list-item><list-item><p>Industry marketing<sup>##UREF##68##120##</sup></p></list-item></list>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Interactions through colleagues or other professionals</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>Indirect influence from industry through colleagues or other professionals (eg, physicians)<sup>##UREF##39##78##,##UREF##61##107##,##UREF##66##116##</sup></p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Industry website, media advertising and promotional events</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>\nEducational materials and information for professionals and consumers created by the industry and delivered via the web/television advertising or other promotional events (eg, industry had a specific website for health professionals and publishing educational materials for professionals)<sup>\n##UREF##62##110##,##UREF##67##118##,##REF##28689497##121##,##REF##32728853##122##,##REF##29998811##125##\n</sup>\n</p></list-item></list>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Foreign aid</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n<list list-type=\"bullet\"><list-item><p>\nInteractions with industry in the context of foreign aid NPs implication<sup>\n##UREF##67##118##,##UREF##83##160##\n</sup>\n</p></list-item></list>\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T4\"><label>Table 4</label><caption><title>Strategies and Actions, Proposed or Used to Address and Manage the Risks Associated With Nutrition Professionals and Industry Interactions\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Type of Strategy</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Sub-categories of Strategy</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Institution/Organization/Professional Body Level</bold>\n</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Management</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.1) Codes, policies, and guidelines<sup>##UREF##2##9##,##UREF##4##12##,##UREF##6##16##,##UREF##8##18##,##REF##11784415##21##,##REF##30657846##26##,##REF##32036995##28##,##REF##24302892##41##,##REF##17381952##42##,##REF##16390663##75##,##UREF##40##79##,##UREF##42##81##,##UREF##43##82##,##UREF##45##85##,##UREF##47##88##,##UREF##49##90##,##UREF##51##93##,##UREF##53##96##,##REF##30550121##106##,##REF##31180446##109##,##UREF##64##113##,##REF##1436768##115##,##REF##32728853##122##,##REF##29998811##125##,##UREF##71##131##,##REF##30169613##135##,##UREF##76##138##,##REF##31865949##143##,##UREF##78##152##,##UREF##80##155##,##UREF##81##157##,##REF##32520489##165##</sup>\n<list list-type=\"bullet\"><list-item><p>\nMonitoring and evaluation of its respect<sup>\n##REF##17381952##42##,##REF##19476682##87##,##REF##19476684##142##,##REF##31865949##143##\n</sup>\n</p></list-item><list-item><p>\nSanction when non-compliance observed<sup>\n##REF##33118920##14##\n</sup>\n</p></list-item><list-item><p>\nHaving or developing more selective criteria for choosing sponsors<sup>\n##UREF##31##63##,##UREF##51##93##,##UREF##59##104##,##UREF##70##130##,##UREF##76##138##,##REF##27009056##141##,##UREF##81##157##\n</sup>\n</p></list-item><list-item><p>\nDissemination of codes and guidelines to mitigate or manage COI<sup>\n##REF##30657846##26##,##UREF##40##79##,##REF##30550121##106##,##UREF##81##157##\n</sup>\n</p></list-item><list-item><p>\nInvest in human resources to assist with COI management<sup>\n##UREF##47##88##\n</sup>\n</p></list-item></list>\n<p>1.2) External and internal consultation</p>\n<list list-type=\"bullet\"><list-item><p>\nConsider members’ opinions regarding institutional sponsorship<sup>\n##UREF##47##88##,##UREF##50##91##,##UREF##67##118##,##UREF##76##138##,##UREF##81##157##\n</sup>\n</p></list-item><list-item><p>\nCreating a COI/ethics committee<sup>\n##UREF##4##12##,##UREF##42##81##,##UREF##43##82##,##REF##30550121##106##,##UREF##69##128##,##UREF##70##130##,##UREF##73##133##\n</sup>\n</p></list-item><list-item><p>\nIndependent advisory group to assist with COI management<sup>\n##UREF##47##88##\n</sup>\n</p></list-item></list>\n<p> 1.3) Alternative financial strategies</p>\n<list list-type=\"bullet\"><list-item><p>Seek alternative/non-conflicted sponsorship or funding<sup>##UREF##6##16##,##REF##32036995##28##,##UREF##47##88##,##UREF##67##118##,##UREF##70##130##,##REF##19476684##142##,##REF##32517669##144##,##UREF##81##157##</sup></p></list-item><list-item><p>Cut down expenses and revise priorities<sup>##REF##33118920##14##,##UREF##42##81##,##UREF##47##88##,##UREF##67##118##,##REF##33109216##126##,##REF##19476684##142##,##UREF##81##157##</sup></p></list-item><list-item><p>Increase membership fee revenue<sup>##UREF##42##81##,##UREF##76##138##</sup></p></list-item></list>\n<p>1.4) Compromise and other strategies</p>\n<list list-type=\"bullet\"><list-item><p>\nStructural changes at conferences/events<sup>\n##UREF##39##78##,##REF##21070977##101##,##REF##1436768##115##,##REF##29998811##125##\n</sup>\n</p></list-item><list-item><p>\nAccept less risky interactions<sup>\n##UREF##2##9##,##UREF##50##91##,##REF##31865949##143##\n</sup>\n</p></list-item><list-item><p>\nEnsure the educational materials used are free of explicit or implicit bias<sup>\n##REF##1436768##115##\n</sup>\n</p></list-item><list-item><p>\nDilution principle<sup>\n##UREF##50##91##,##UREF##76##138##\n</sup>\n</p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.5) Educate NPs about industry interactions and related COI<sup>##UREF##4##12##,##REF##24302892##41##,##UREF##33##66##,##UREF##42##81##,##UREF##47##88##,##UREF##61##107##,##UREF##71##131##,##UREF##72##132##,##REF##31865949##143##,##UREF##80##155##</sup><break/>1.6)Strategies to favor independence in educational settings\n<list list-type=\"bullet\"><list-item><p>\nIndependent accreditation of university dietetic training<sup>\n##UREF##6##16##\n</sup>\n</p></list-item><list-item><p>\nUse independent documentation, references, and teaching materials<sup>\n##UREF##49##90##\n</sup>\n</p></list-item><list-item><p>\nPresent a variety of products instead of a particular brand<sup>\n##UREF##49##90##\n</sup>\n</p></list-item></list>\n</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Individual Level</bold>\n</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Management</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2.1) Tools or resources for decision-making\n<list list-type=\"bullet\"><list-item><p>\nCode of ethics and guidelines<sup>\n##UREF##8##18##,##REF##11784415##21##,##UREF##33##66##,##REF##16390663##75##,##UREF##38##77##,##UREF##44##84##,##REF##19476682##87##,##UREF##48##89##,##UREF##49##90##,##UREF##53##96##,##UREF##58##103##,##UREF##61##107##,##UREF##63##112##,##UREF##65##114##,##UREF##81##157##,##REF##32520489##165##\n</sup>\n</p></list-item><list-item><p>\nOther tools (DORM and Nolan principles)<sup>\n##UREF##39##78##,##UREF##46##86##\n</sup>\n</p></list-item></list>\n2.2) Individual discernment\n<list list-type=\"bullet\"><list-item><p>\nBalance risks and benefits on a case-by-case basis<sup>\n##UREF##2##9##,##REF##11784415##21##,##REF##16390663##75##,##REF##32517669##144##\n</sup>\n</p></list-item><list-item><p>\nFact and references checking and follow up<sup>\n##UREF##6##16##,##UREF##49##90##,##UREF##71##131##\n</sup>\n</p></list-item><list-item><p>\nRely on professional judgment<sup>\n##UREF##38##77##,##UREF##71##131##\n</sup>\n</p></list-item></list>\n2.3) External consultation and advice on COI<sup>##UREF##38##77##,##UREF##39##78##,##UREF##53##96##,##REF##30550121##106##,##UREF##72##132##</sup><break/>2.4) Accepting funding through third-party<sup>##REF##9847922##117##</sup><break/>2.5) Retain control over content<sup>##REF##16390663##75##</sup><break/>2.6) Document COI management<sup>##UREF##39##78##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Institution/Organization/Professional Body and Individual Level</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Prohibition</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.1) Prohibiting, avoiding, and refusing all interactions with industry</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Transparency</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.2) Transparency and disclosure\n<list list-type=\"bullet\"><list-item><p>\nTransparency of institution vis-à-vis the public and members<sup>\n##UREF##2##9##,##REF##30657846##26##,##REF##19476682##87##,##UREF##50##91##,##REF##32728853##122##,##REF##27004957##127##,##REF##32660803##137##,##REF##32268902##139##,##UREF##81##157##\n</sup>\n</p></list-item><list-item><p>\nTransparency in conferences and nutrition and scientific events<sup>\n##REF##16390663##75##,##UREF##49##90##,##UREF##53##96##,##UREF##59##104##,##UREF##60##105##,##UREF##67##118##,##UREF##69##128##,##UREF##70##130##,##REF##19476684##142##,##REF##32520489##165##\n</sup>\n</p></list-item><list-item><p>\nSigned agreement or contract with industry to manage/guide interactions around conference sponsorship or general sponsorship<sup>\n##UREF##6##16##,##UREF##67##118##,##REF##32660803##137##\n</sup>\n</p></list-item><list-item><p>\nTransparency of NPs vis-à-vis the clients and the public<sup>\n##REF##11784415##21##,##UREF##33##66##,##REF##16390663##75##,##UREF##39##78##,##UREF##48##89##,##UREF##53##96##,##REF##31180446##109##,##UREF##63##112##,##UREF##65##114##,##REF##9847922##117##,##REF##31865949##143##\n</sup>\n</p></list-item></list>\n</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Awareness-raising</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.3) Identification and awareness-raising\n<list list-type=\"bullet\"><list-item><p>\nAdvocating for COI recognition and action by institutions<sup>\n##UREF##4##12##,##UREF##42##81##,##REF##30550121##106##,##UREF##67##118##\n</sup>\n</p></list-item><list-item><p>\nIdentifying COI<sup>\n##REF##11784415##21##,##UREF##39##78##,##REF##9847922##117##\n</sup>\n</p></list-item></list>\n</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 1. Data Extraction Table.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 2. Overview of Included Documents in This Scoping Review.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 3. Codebook With Illustrative Quotes – Nutrition Professionals Experiences of Industry Interactions and Acceptability.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl4\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 4. Codebook With Illustrative Quotes – Perceived Advantages and Risks.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl5\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 5. Codebook With Illustrative Quotes – Strategies and Actions Proposed or Used, to Address and Manage the Risks Associated With Nutrition Professionals and Industry Interactions.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviation: NPs, nutrition professionals.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: NPs, nutrition professionals; COI, conflict of interest.</p><p> Note: Documents could be categorised under multiple categories; numbers do not add up to 100%. Academia and academics were coded to references to institutions (eg, universities) and individuals, respectively. Nutrition and health organizations were coded for professional bodies, societies, non-profit health organizations and medical associations. Health professionals can include NPs, but these were categorised separately, where possible.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviation: NPs, nutrition professionals.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: NPs, nutrition professionals; COI, conflict of interest; DORM, Disclosure, Options, Reassurance, Modification.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7626-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7626-g002\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7626-s001.xlsx\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7626-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7626-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7626-s004.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7626-s005.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["5"], "mixed-citation": [" Minist\u00e9rio da Sa\u00fade do Brasil. Guiaalimentar para a popula\u00e7\u00e3obrasileira: promovendo a alimenta\u00e7\u00e3osaud\u00e1vel. Bras\u00edlia: Minist\u00e9rio da Sa\u00fade; 2014. "]}, {"label": ["6"], "mixed-citation": [" Government of Canada. Canada\u2019s Food Guide, Limit Highly Processed Foods. Government of Canada; 2019. "]}, {"label": ["9"], "mixed-citation": [" Nestle M. Food Politics: How the Food Industry Influences Nutrition and Health. 3rd ed. Berkley, Los Angeles, CA: University of California Press; 2013. "]}, {"label": ["11"], "mixed-citation": [" Nestle M. Unsavory Truth: How Food Companies Skew the Science of What We Eat. New York: Basic Books; 2018. "]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Pereira", "do Nascimento", "Bandoni"], "given-names": ["TN", "FA", "DH"], "article-title": ["[Conflict of interest in the training and practices of nutritionists: regulation is necessary]"], "source": ["CienSaude Colet"], "year": ["2016"], "volume": ["21"], "issue": ["12"], "fpage": ["3833"], "lpage": ["3844"], "pub-id": ["10.1590/1413-812320152112.13012015"]}, {"label": ["15"], "mixed-citation": [" Simmons E. Exposed: How NHS Doctors Are Making Thousands of Pounds by Plugging BMWs, Deodorant, Sun Cream and Snacks on Instagram. 2020. "], "uri": ["https://www.dailymail.co.uk/health/article-7981869/NHS-doctors-making-thousands-plugging-BMWs-deodorant-snacks-Instagram.html"]}, {"label": ["16"], "mixed-citation": [" Simon M. Is the Dietitians Association of Australia in the Pocket of Big Food? Oakland, CA: Eat Drink Politics; 2015. "]}, {"label": ["17"], "mixed-citation": [" Simon M. Nutrition scientists on the take from Big Food. In: Has the American Society for Nutrition Lost All Credibility? Eat Drink Politics; 2015. "]}, {"label": ["18"], "person-group": ["\n"], "surname": ["van Tulleken"], "given-names": ["C"], "article-title": ["Overdiagnosis and industry influence: how cow\u2019s milk protein allergy is extending the reach of infant formula manufacturers"], "source": ["BMJ"], "year": ["2018"], "volume": ["363"], "fpage": ["k5056"], "pub-id": ["10.1136/bmj.k5056"]}, {"label": ["19"], "person-group": ["\n"], "surname": ["Chretien", "Azar", "Kind"], "given-names": ["KC", "J", "T"], "article-title": ["Physicians on Twitter"], "source": ["JAMA"], "year": ["2011"], "volume": ["305"], "issue": ["6"], "fpage": ["566"], "lpage": ["568"], "pub-id": ["10.1001/jama.2011.68"]}, {"label": ["22"], "mixed-citation": [" World Health Organization (WHO), Health Action International (HAI). Understanding and Responding to Pharmaceutical Promotion. HAI; 2009. "]}, {"label": ["23"], "person-group": ["\n"], "surname": ["Mialon", "Vandevijvere", "Carriedo-Lutzenkirchen"], "given-names": ["M", "S", "A"], "article-title": ["Mechanisms for addressing and managing the influence of corporations on public health policy, research and practice: a scoping review"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["7"], "fpage": ["e034082"], "pub-id": ["10.1136/bmjopen-2019-034082"]}, {"label": ["25"], "person-group": ["\n"], "surname": ["Rodwin"], "given-names": ["MA"], "article-title": ["Conflicts of interest in medicine: should we contract, conserve, or expand the traditional definition and scope of regulation?"], "source": ["J Health Care Law Policy"], "year": ["2018"], "volume": ["21"], "issue": ["2"], "fpage": ["157"], "lpage": ["187"]}, {"label": ["27"], "mixed-citation": [" Association for Nutrition. NPs: Working with Industry or Campaign Groups. 2020. "], "uri": ["https://www.associationfornutrition.org/latest-news/nutrition-professionals-working-with-industry-or-campaign-groups"]}, {"label": ["29"], "mixed-citation": [" Dietitians Australia. Public Announcements: Conclusion of DA\u2019s Corporate Partnership Program. 2018. "], "uri": ["https://dietitiansaustralia.org.au/voice-of-daa/public-statements/"]}, {"label": ["30"], "mixed-citation": [" Demasi M. Dietitians Backslide - Dump Corporate Sponsorships, Invite Ads Instead. 2019. "], "uri": ["https://www.michaelwest.com.au/dietitians-backslide-dump-corporate-sponsorships-invite-ads-instead/"]}, {"label": ["31"], "mixed-citation": [" Dietitians Australia. Showcase Your Product or Service. 2020. "], "uri": ["https://dietitiansaustralia.org.au/marketplace/advertise-with-us/"]}, {"label": ["32"], "mixed-citation": [" International Confederation of Dietetic Associations (ICDA). International Competency Standards for Dietitian-Nutritionists. ICDA; 2016. "]}, {"label": ["33"], "person-group": ["\n"], "surname": ["Chimonas", "DeVito", "Rothman"], "given-names": ["S", "NJ", "DJ"], "article-title": ["Bringing transparency to medicine: exploring physicians\u2019 views and experiences of the sunshine act"], "source": ["Am J Bioeth"], "year": ["2017"], "volume": ["17"], "issue": ["6"], "fpage": ["4"], "lpage": ["18"], "pub-id": ["10.1080/15265161.2017.1313334"]}, {"label": ["35"], "person-group": ["\n"], "surname": ["Kim", "Mumm", "Korenstein"], "given-names": ["A", "LA", "D"], "article-title": ["Routine conflict of interest disclosure by preclinical lecturers and medical students\u2019 attitudes toward the pharmaceutical and device industries"], "source": ["JAMA"], "year": ["2012"], "volume": ["308"], "issue": ["21"], "fpage": ["2187"], "lpage": ["2189"], "pub-id": ["10.1001/jama.2012.25315"]}, {"label": ["43"], "person-group": ["\n"], "surname": ["Arksey", "O\u2019Malley"], "given-names": ["H", "L"], "article-title": ["Scoping studies: towards a methodological framework"], "source": ["Int J Soc Res Methodol"], "year": ["2005"], "volume": ["8"], "issue": ["1"], "fpage": ["19"], "lpage": ["32"]}, {"label": ["46"], "mixed-citation": [" Peters MD, Godfrey C, McInerney P, Munn Z, Trico A, Khalil H. Scoping Reviews. In: JBI Manual for Evidence Synthesis. Adelaide: JBI Global Wiki; 2020. "]}, {"label": ["48"], "mixed-citation": [" Hamel V. Interactions between NPs and industry actors: A scoping review protocol. 2021, May 21, 2021. "], "uri": ["https://osf.io/2wuda"]}, {"label": ["50"], "mixed-citation": [" Oxford Reference. Overview - professional body 2022; "], "uri": ["https://www.oxfordreference.com/display/10.1093/oi/authority.20110803100348288"]}, {"label": ["51"], "mixed-citation": [" International Confederation of Dietetic Associations. National Dietetic Associations (NDAs). 2022. "], "uri": ["https://www.internationaldietetics.org/NDAs.aspx"]}, {"label": ["52"], "person-group": ["\n"], "surname": ["Hennessy", "Cullerton", "Baker"], "given-names": ["M", "K", "P"], "article-title": ["Time for complete transparency about conflicts of interest in public health nutrition research"], "source": ["HRB Open Res"], "year": ["2019"], "volume": ["2"], "fpage": ["1"], "pub-id": ["10.12688/hrbopenres.12894.1"]}, {"label": ["53"], "mixed-citation": [" Aven T, Ben-Haim Y, Andersen HB, et al. Society for Risk Analysis Glossary. Society for Risk Analysis; 2018. "]}, {"label": ["55"], "mixed-citation": [" Covidence systematic review software [computer program]. Melbourne, Australia Version. Accessed March 2021. "]}, {"label": ["57"], "person-group": ["\n"], "surname": ["Thomas"], "given-names": ["DR"], "article-title": ["A general inductive approach for analyzing qualitative evaluation data"], "source": ["Am J Eval"], "year": ["2006"], "volume": ["27"], "issue": ["2"], "fpage": ["237"], "lpage": ["246"], "pub-id": ["10.1177/1098214005283748"]}, {"label": ["58"], "person-group": ["\n"], "surname": ["Blais", "Martineau"], "given-names": ["M", "S"], "article-title": ["L\u2019analyse inductive g\u00e9n\u00e9rale: description d\u2019une d\u00e9marche visant \u00e0 donner un sens \u00e0 des donn\u00e9es brutes"], "source": ["RecherchesQualitatives"], "year": ["2006"], "volume": ["26"], "issue": ["2"], "fpage": ["1"], "lpage": ["18"], "pub-id": ["10.7202/1085369ar"]}, {"label": ["62"], "person-group": ["\n"], "surname": ["Derelian"], "given-names": ["D"], "article-title": ["President\u2019s page: nutrition education philosophies--why we do the things we do"], "source": ["J Am Diet Assoc"], "year": ["1996"], "volume": ["96"], "issue": ["2"], "fpage": ["191"], "pub-id": ["10.1016/s0002-8223(96)00054-5"]}, {"label": ["63"], "person-group": ["\n"], "surname": ["Derelian", "Schwartz", "Wright"], "given-names": ["D", "N", "A"], "article-title": ["President\u2019s page: extending our messages for the good of the public and the profession"], "source": ["J Am Diet Assoc"], "year": ["1995"], "volume": ["95"], "issue": ["4"], "fpage": ["497"], "pub-id": ["10.1016/s0002-8223(95)00131-x"]}, {"label": ["64"], "person-group": ["\n"], "surname": ["Kozinets"], "given-names": ["RV"], "article-title": ["On netnography: initial reflections on consumer research investigations of cyberculture"], "source": ["Adv Consum Res"], "year": ["1998"], "volume": ["25"], "issue": ["1"], "fpage": ["366"], "lpage": ["371"]}, {"label": ["66"], "person-group": ["\n"], "surname": ["Helm", "Jones"], "given-names": ["J", "RM"], "article-title": ["Practice paper of the Academy of Nutrition and Dietetics: social media and the dietetics practitioner: opportunities, challenges, and best practices"], "source": ["J AcadNutr Diet"], "year": ["2016"], "volume": ["116"], "issue": ["11"], "fpage": ["1825"], "lpage": ["1835"], "pub-id": ["10.1016/j.jand.2016.09.003"]}, {"label": ["69"], "person-group": ["\n"], "surname": ["Stover", "Ohlhorst", "Field", "Garza"], "given-names": ["P", "S", "M", "C"], "article-title": ["Nutrition science at a cross-road best practices from the ASN committee on public trust"], "source": ["Ann NutrMetab"], "year": ["2017"], "volume": ["71"], "issue": ["Suppl 2"], "fpage": ["142"], "pub-id": ["10.1159/000480486"]}, {"label": ["70"], "person-group": ["\n"], "surname": ["Calder", "Feskens", "Kraneveld", "Plat", "van\u2019t Veer", "de Vries"], "given-names": ["PC", "EJM", "AD", "J", "P", "J"], "article-title": ["Towards \u201cImproved Standards in the Science of Nutrition\u201d through the Establishment of Federation of European Nutrition Societies Working Groups"], "source": ["Ann NutrMetab"], "year": ["2020"], "volume": ["76"], "issue": ["1"], "fpage": ["2"], "lpage": ["5"], "pub-id": ["10.1159/000506325"]}, {"label": ["74"], "person-group": ["\n"], "surname": ["de Oliveira Martins", "Leroy", "Verstraeten", "Lartey"], "given-names": ["F", "J", "R", "A"], "article-title": ["Global nutrition leadership: perspectives from the corporate sector"], "source": ["Ann NutrMetab"], "year": ["2017"], "volume": ["71"], "issue": ["Suppl 2"], "fpage": ["194"], "lpage": ["195"], "pub-id": ["10.1159/000480486"]}, {"label": ["76"], "person-group": ["\n"], "surname": ["Aksnes", "Alvim", "Gardu\u00f1o Diaz"], "given-names": ["B", "M", "S"], "article-title": ["The normalization of conflicts of interest in the USA and their potential impact on public health nutrition"], "source": ["World Nutr"], "year": ["2017"], "volume": ["8"], "issue": ["1"], "fpage": ["123"], "lpage": ["127"]}, {"label": ["77"], "person-group": ["\n"], "surname": ["Boyce"], "given-names": ["B"], "article-title": ["The balance of professional ethics"], "source": ["J AcadNutr Diet"], "year": ["2017"], "volume": ["117"], "issue": ["7"], "fpage": ["1120"], "lpage": ["1123"], "pub-id": ["10.1016/j.jand.2017.01.019"]}, {"label": ["78"], "mixed-citation": [" Cohen D. Conflict of Interest & RD Practice. College of Dietitians of Ontario; 2009. "]}, {"label": ["79"], "person-group": ["\n"], "surname": ["Connor"], "given-names": ["SL"], "article-title": ["The role of sponsorship in achieving our mission"], "source": ["J AcadNutr Diet"], "year": ["2015"], "volume": ["115"], "issue": ["5"], "fpage": ["691"], "pub-id": ["10.1016/j.jand.2015.03.007"]}, {"label": ["80"], "person-group": ["\n"], "surname": ["Diekman"], "given-names": ["CB"], "article-title": ["Sponsors, partners, alliances: \u201cWhat\u2019s in it for me?\u201d"], "source": ["J Am Diet Assoc"], "year": ["2007"], "volume": ["107"], "issue": ["8"], "fpage": ["1281"], "pub-id": ["10.1016/j.jada.2007.05.440"]}, {"label": ["81"], "mixed-citation": [" Dietitians for Professional Integrity. The food ties that bind: The Academy of nutrition & dietetic\u2019 2013 Conference & Expo; November 2013. "]}, {"label": ["82"], "person-group": ["\n"], "surname": ["Garcia Chavez", "Sanchez-Bazan", "Barquera"], "given-names": ["CG", "K", "S"], "article-title": ["Position of the Latin American society for nutrition on conflict of interest"], "source": ["Ann NutrMetab"], "year": ["2017"], "volume": ["71"], "issue": ["Suppl 2"], "fpage": ["801"], "pub-id": ["10.1159/000480486"]}, {"label": ["84"], "person-group": ["\n"], "surname": ["Hermann"], "given-names": ["MG"], "article-title": ["Ethics in the business of nutrition"], "source": ["Top Clin Nutr"], "year": ["1992"], "volume": ["7"], "issue": ["3"], "fpage": ["1"], "lpage": ["5"]}, {"label": ["85"], "person-group": ["\n"], "surname": ["Jarratt", "Mahaffie"], "given-names": ["J", "JB"], "article-title": ["Key trends affecting the dietetics profession and the American Dietetic Association"], "source": ["J Am Diet Assoc"], "year": ["2002"], "volume": ["102"], "issue": ["12"], "fpage": ["S1821"], "lpage": ["S1839"], "pub-id": ["10.1016/s0002-8223(02)90392-5"]}, {"label": ["86"], "mixed-citation": [" Kunneke E, Swart R, Nortj\u00e9 N. Ethics for the dietetic profession\u2013a South African perspective. In: Nortj\u00e9 N, De Jongh JC, Hoffmann WA, eds. African Perspectives on Ethics for Healthcare Professionals. Cham: Springer; 2018. p. 91-105. "], "pub-id": ["10.1007/978-3-319-93230-9_7"]}, {"label": ["88"], "person-group": ["\n"], "surname": ["Palmer"], "given-names": ["S"], "article-title": ["Corporate sponsorships"], "source": ["Today\u2019s Dietitian"], "year": ["2015"], "volume": ["17"], "issue": ["1"], "fpage": ["34"], "lpage": ["39"]}, {"label": ["89"], "person-group": ["\n"], "surname": ["Fieber"], "given-names": ["LK"], "article-title": ["Ethical considerations in dietetics practice"], "source": ["J Am Diet Assoc"], "year": ["2000"], "volume": ["100"], "issue": ["4"], "fpage": ["454"], "pub-id": ["10.1016/s0002-8223(00)00138-3"]}, {"label": ["90"], "mixed-citation": [" Avoiding conflict of interest: a challenge for leaders in all professions. Health Care Food Nutr Focus. 2005;22(11):9-12."]}, {"label": ["91"], "mixed-citation": [" Professional Associations Research Network. Member Attitudes to Commercial Collaborations and Partnerships. British Dietetic Association (BDA); 2017. "]}, {"label": ["93"], "mixed-citation": [" Simon M. Are America\u2019s NPs in the Pocket of Big Food? Eat Drink Politics; 2013. "]}, {"label": ["94"], "mixed-citation": [" Academy of Nutrition and Dietetics. Meet Our Sponsors. 2022. Academy Supporters, Fiscal Year 2022 and 2023. "], "uri": ["https://www.eatrightpro.org/about-us/advertising-and-sponsorship/meet-our-sponsors"]}, {"label": ["96"], "person-group": ["\n"], "surname": ["Peregrin"], "given-names": ["T"], "article-title": ["Identifying and managing conflicts of interest"], "source": ["J AcadNutr Diet"], "year": ["2020"], "volume": ["120"], "issue": ["3"], "fpage": ["445"], "lpage": ["447"], "pub-id": ["10.1016/j.jand.2019.12.014"]}, {"label": ["98"], "person-group": ["\n"], "surname": ["Freeland-Graves", "Nitzke"], "given-names": ["JH", "S"], "article-title": ["Position of the academy of nutrition and dietetics: total diet approach to healthy eating"], "source": ["J AcadNutr Diet"], "year": ["2013"], "volume": ["113"], "issue": ["2"], "fpage": ["307"], "lpage": ["317"], "pub-id": ["10.1016/j.jand.2012.12.013"]}, {"label": ["99"], "mixed-citation": [" British Nutrition Foundation. Current Members. 2022. "], "uri": ["https://www.nutrition.org.uk/our-work/support-what-we-do/corporate-partnerships/current-members/"]}, {"label": ["100"], "mixed-citation": [" Canadian Nutrition Society. CNS Commitment to Working with Industry Partners and Sponsors. 2022. "], "uri": ["https://cns-scn.ca/organization/principles-for-working-with-industry-and-sponsors"]}, {"label": ["102"], "person-group": ["\n"], "surname": ["Gramlich"], "given-names": ["L"], "article-title": ["Health organizations and the food industry"], "source": ["CMAJ"], "year": ["2011"], "volume": ["183"], "issue": ["8"], "fpage": ["934"], "pub-id": ["10.1503/cmaj.111-2048"]}, {"label": ["103"], "person-group": ["\n"], "surname": ["Wynne"], "given-names": ["A"], "article-title": ["The New Zealand Dietetic Association"], "source": ["Nutr Bull"], "year": ["2003"], "volume": ["28"], "issue": ["4"], "fpage": ["376"], "lpage": ["380"], "pub-id": ["10.1046/j.1467-3010.2003.00352.x"]}, {"label": ["104"], "person-group": ["\n"], "surname": ["Stein"], "given-names": ["K"], "article-title": ["Advancing health through sustained collaboration: how the history of corporate relations extended the Academy\u2019s reach"], "source": ["J AcadNutr Diet"], "year": ["2015"], "volume": ["115"], "issue": ["1"], "fpage": ["131"], "lpage": ["142"], "pub-id": ["10.1016/j.jand.2014.10.024"]}, {"label": ["105"], "person-group": ["\n"], "surname": ["Tappenden"], "given-names": ["KA"], "article-title": ["A unifying vision for scientific decision making: the Academy of Nutrition and Dietetics\u2019 scientific integrity principles"], "source": ["J AcadNutr Diet"], "year": ["2015"], "volume": ["115"], "issue": ["9"], "fpage": ["1486"], "lpage": ["1490"], "pub-id": ["10.1016/j.jand.2015.06.372"]}, {"label": ["107"], "mixed-citation": [" Fornari AB. The Development of an Ethics Curriculum for Dietetics Students Utilizing Learner-Centered Pedagogy [thesis]. Ann Arbor, Teachers College, Columbia University; 2001. "]}, {"label": ["110"], "mixed-citation": [" Nestle M. Supporting Worthy Causes, Health Professionals and Research. In: Soda Politics: Taking on Big Soda (And Winning). United States: Oxford University Press; 2015: 252-267. "]}, {"label": ["112"], "person-group": ["\n"], "surname": ["Chan", "Drake", "Vollmer"], "given-names": ["T", "T", "RL"], "article-title": ["A qualitative research study comparing nutrition advice communicated by registered dietitian and non-registered dietitian bloggers"], "source": ["J CommunHealthc"], "year": ["2020"], "volume": ["13"], "issue": ["1"], "fpage": ["55"], "lpage": ["63"], "pub-id": ["10.1080/17538068.2020.1749351"]}, {"label": ["113"], "person-group": ["\n"], "surname": ["Saboia", "Pisco Almeida", "Sousa", "Pernencar"], "given-names": ["I", "AM", "P", "C"], "article-title": ["I am with you: a netnographic analysis of the Instagram opinion leaders on eating behavior change"], "source": ["Procedia Comput Sci"], "year": ["2018"], "volume": ["138"], "fpage": ["97"], "lpage": ["104"], "pub-id": ["10.1016/j.procs.2018.10.014"]}, {"label": ["114"], "person-group": ["\n"], "surname": ["Inan-Eroglu", "Buyuktuncer"], "given-names": ["E", "Z"], "article-title": ["What images and content do professional dietitians share via Instagram?"], "source": ["Nutr Food Sci"], "year": ["2018"], "volume": ["48"], "issue": ["6"], "fpage": ["940"], "lpage": ["948"], "pub-id": ["10.1108/nfs-03-2018-0087"]}, {"label": ["116"], "mixed-citation": [" Levine J. Creating Consumers (How the Food Industry Delivers its Products and Messages to Elementary School Students and What NPs Know and Think About it) [thesis]. Ann Arbor: Teachers College, Columbia University; 1998. "]}, {"label": ["118"], "person-group": ["\n"], "surname": ["Gomes"], "given-names": ["F"], "article-title": ["Words for our sponsors"], "source": ["World Nutr"], "year": ["2013"], "volume": ["4"], "issue": ["8"], "fpage": ["618"], "lpage": ["644"]}, {"label": ["120"], "mixed-citation": [" Wallace CL. Learning to Practice: A Case Study of the Experiences of Public Health Registered Dietitians in Professional Lifelong Learning [thesis]. Ann Arbor: The University of Memphis; 2014. "]}, {"label": ["128"], "person-group": ["\n"], "surname": ["Piaggio", "Solans"], "given-names": ["LR", "AM"], "article-title": ["Corporate sponsorship and health halo for ultra-processed products"], "source": ["World Nutr"], "year": ["2020"], "volume": ["11"], "issue": ["1"], "fpage": ["18"], "lpage": ["41"], "pub-id": ["10.26596/wn.202011118-41"]}, {"label": ["130"], "person-group": ["\n"], "surname": ["Canella", "Martins", "Silva", "Passanha", "Louren\u00e7o"], "given-names": ["DS", "AP", "HF", "A", "BH"], "article-title": ["Food and beverage industries\u2019 participation in health scientific events: considerations on conflicts of interest"], "source": ["Rev PanamSalud Publica"], "year": ["2015"], "volume": ["38"], "issue": ["4"], "fpage": ["339"], "lpage": ["343"]}, {"label": ["131"], "mixed-citation": [" Portman EC. Making the Healthy Choice: Exploring Health Communication in the Food System [thesis]. Vermont: The University of Vermont and State Agricultural College; 2016. "]}, {"label": ["132"], "mixed-citation": [" Scheffer P. Formation des di\u00e9t\u00e9ticiens et esprit critique: comment favoriserl\u2019ind\u00e9pendanceprofessionnelle et une pratique r\u00e9flexive du m\u00e9tier? France: L\u2019Harmattan; 2015. "]}, {"label": ["133"], "person-group": ["\n"], "surname": ["Dumbili"], "given-names": ["EW"], "article-title": ["Heightened hypocrisy: a critical analysis of how the alcohol industry-sponsored \u2018\u2018Nigerian Beer Symposium\u2019\u2019 jeopardises public health"], "source": ["Drugs (Abingdon Engl)"], "year": ["2019"], "volume": ["26"], "issue": ["3"], "fpage": ["287"], "lpage": ["291"], "pub-id": ["10.1080/09687637.2017.1421144"]}, {"label": ["134"], "mixed-citation": [" Morssink CB. Testing the Feasibility of Friedson\u2019s Professionalization Model: The Case of Dietetics in the Domain of Nutrition [thesis]. Ann Arbor: University of Illinois at Chicago, Health Sciences Center; 2001. "]}, {"label": ["136"], "person-group": ["\n"], "surname": ["Wilkins"], "given-names": ["JL"], "article-title": ["Civic dietetics: opportunities for integrating civic agriculture concepts into dietetic practice"], "source": ["Agric Human Values"], "year": ["2009"], "volume": ["26"], "issue": ["1"], "fpage": ["57"], "lpage": ["66"], "pub-id": ["10.1007/s10460-008-9177-2"]}, {"label": ["138"], "person-group": ["\n"], "surname": ["Reitshamer", "Schrier", "Herbold", "Metallinos-Katsaras"], "given-names": ["E", "MS", "N", "E"], "article-title": ["Members\u2019 attitudes toward corporate sponsorship of the Academy of Nutrition and Dietetics"], "source": ["J Hunger Environ Nutr"], "year": ["2012"], "volume": ["7"], "issue": ["2-3"], "fpage": ["149"], "lpage": ["164"], "pub-id": ["10.1080/19320248.2012.704748"]}, {"label": ["150"], "person-group": ["\n"], "surname": ["Wilkins", "Lapp", "Tagtow", "Roberts"], "given-names": ["JL", "J", "A", "S"], "article-title": ["Beyond eating right: the emergence of civic dietetics to foster health and sustainability through food system change"], "source": ["J Hunger Environ Nutr"], "year": ["2010"], "volume": ["5"], "issue": ["1"], "fpage": ["2"], "lpage": ["12"], "pub-id": ["10.1080/19320240903573983"]}, {"label": ["152"], "person-group": ["\n"], "surname": ["Malhotra", "Schofield", "Lustig"], "given-names": ["A", "G", "RH"], "article-title": ["The science against sugar, alone, is insufficient in tackling the obesity and type 2 diabetes crises-we must also overcome opposition from vested interests"], "source": ["Journal of the Australasian College of Nutritional and Environmental Medicine"], "year": ["2019"], "volume": ["38"], "issue": ["1"], "fpage": ["4"], "lpage": ["11"]}, {"label": ["154"], "person-group": ["\n"], "surname": ["Clapp", "Scrinis"], "given-names": ["J", "G"], "article-title": ["Big food, nutritionism, and corporate power"], "source": ["Globalizations"], "year": ["2017"], "volume": ["14"], "issue": ["4"], "fpage": ["578"], "lpage": ["595"], "pub-id": ["10.1080/14747731.2016.1239806"]}, {"label": ["155"], "person-group": ["\n"], "surname": ["Gingras"], "given-names": ["J"], "article-title": ["Evoking trust in the nutrition counselor: why should we be trusted?"], "source": ["J Agric Environ Ethics"], "year": ["2005"], "volume": ["18"], "issue": ["1"], "fpage": ["57"], "lpage": ["74"], "pub-id": ["10.1007/s10806-004-3092-3"]}, {"label": ["157"], "mixed-citation": [" Smith KK. Turf Wars and Corporate Sponsorship: Challenges in the Food System and the Academy of Nutrition and Dietetics [thesis]. Ann Arbor: The University of Vermont and State Agricultural College; 2014. "]}, {"label": ["159"], "person-group": ["\n"], "surname": ["Karim"], "given-names": ["NA"], "article-title": ["Past experiences and future prospects on nutrition higher education collaboration in Asia: a Malaysian perspective from a public university"], "source": ["Ann NutrMetab"], "year": ["2019"], "volume": ["75"], "issue": ["3"], "fpage": ["40"], "pub-id": ["10.1159/000501751"]}, {"label": ["160"], "mixed-citation": [" Palmer G. The Politics of Breastfeeding: When Breasts Are Bad for Business. Pinter & Martin Publishers; 2009. "]}, {"label": ["164"], "person-group": ["\n"], "surname": ["Wassef", "Champagne", "Farand"], "given-names": ["J", "F", "L"], "article-title": ["Nutritionists as policy advocates: the case of obesity prevention in Quebec, Canada"], "source": ["Public Health Nutr"], "year": ["2021"], "volume": ["25"], "issue": ["7"], "fpage": ["1"], "lpage": ["14"], "pub-id": ["10.1017/s1368980021004997"]}, {"label": ["167"], "person-group": ["\n"], "surname": ["Marks", "Thompson"], "given-names": ["JH", "DB"], "article-title": ["Shifting the focus: conflict of interest and the food industry"], "source": ["Am J Bioeth"], "year": ["2011"], "volume": ["11"], "issue": ["1"], "fpage": ["44"], "lpage": ["46"], "pub-id": ["10.1080/15265161.2011.556979"]}, {"label": ["168"], "mixed-citation": [" Dietitians of Canada. Learn About Dietitians. 2022. "], "uri": ["https://www.dietitians.ca/About/Learn-About-Dietitians?lang=en-CA"]}, {"label": ["170"], "mixed-citation": [" Marks JH. The Perils of Partnership: Industry Influence, Institutional Integrity, and Public Health. United States: Oxford University Press; 2019. "]}, {"label": ["171"], "mixed-citation": [" Scheffer P. Les m\u00e9tiers de la sant\u00e9 face aux industries pharmaceutique, agroalimentaire et chimique: quelles formations critiques? Paris: L\u2019Harmattan; 2015. "]}, {"label": ["177"], "person-group": ["\n"], "surname": ["Vandenbrink", "Pauz\u00e9", "Potvin Kent"], "given-names": ["D", "E", "M"], "article-title": ["Strategies used by the Canadian food and beverage industry to influence food and nutrition policies"], "source": ["Int J BehavNutr Phys Act"], "year": ["2020"], "volume": ["17"], "issue": ["1"], "fpage": ["3"], "pub-id": ["10.1186/s12966-019-0900-8"]}, {"label": ["178"], "mixed-citation": [" Grenouilleau AS. Interactions des professionnels de sant\u00e9 avec les repr\u00e9sentants de l\u2019industrie. France: Haute Autorit\u00e9 de Sant\u00e9; 2022. "]}, {"label": ["179"], "person-group": ["\n"], "surname": ["Goldberg"], "given-names": ["DS"], "article-title": ["The shadows of sunlight: why disclosure should not be a priority in addressing conflicts of interest"], "source": ["Public Health Ethics"], "year": ["2019"], "volume": ["12"], "issue": ["2"], "fpage": ["202"], "lpage": ["212"], "pub-id": ["10.1093/phe/phy016"]}, {"label": ["180"], "mixed-citation": [" Who Framework Convention on Tobacco Control. Who Framework Convention on Tobacco Control Parties. 2021. "], "uri": ["https://fctc.who.int/who-fctc/overview/parties"]}, {"label": ["182"], "mixed-citation": [" Delwarde T. Impact de la FACRIPP (Formation \u00e0 l\u2019Analyse CRitique de la Promotion Pharmaceutique): vers plus d\u2019ind\u00e9pendance? [thesis]. M\u00e9decine humaine et pathologie, Universit\u00e9 de Bordeaux; 2019. "]}, {"label": ["183"], "mixed-citation": [" Lalanne R. Elaboration et mise en place d\u2019une formation a l\u2019analyse critique de la promotion pharmaceutique [thesis]. M\u00e9decine humaine et pathologie, Universit\u00e9 de Bordeaux; 2016. "]}, {"label": ["184"], "mixed-citation": [" PEPITe sant\u00e9. Formation \u00e0 l\u2019Analyse Critique de la Promotion Pharmaceutique. 2020. "], "uri": ["https://www.pepite-sante.fr/activites/facripp"]}, {"label": ["185"], "mixed-citation": [" Dietitians for Professional Integrity. Dietitian resources for non-and members - A DFPI Tolkit. 2016. "], "uri": ["https://integritydietitians.org//wp-content/uploads/2015/07/June2016RT.pdf"]}]	{ "acronym": [], "definition": [] }	187	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 22; 12:7626	oa_package/b1/ee/PMC10590255.tar.gz
PMC10590256	0	[ "<title>Background</title>", "<p> Stillbirth is a global health crisis that affects millions of families each year. Globally, 1 in 72 babies are stillborn, amounting to around 2 million stillbirths annually.<sup>##UREF##0##1##</sup> Over the last twenty years, the stillbirth rate (SBR) has declined by only 2.3% compared annually to a 2.9% reduction in neonatal mortality, 4.3% in mortality among children aged 1–59 months and 2.9% for maternal mortality.<sup>##UREF##0##1##</sup> The stagnating trend has resulted in calls for increased investment at global and national levels. Several global publications, initiatives and networks have emerged to amplify and accelerate progress on reducing stillbirths. These include the<italic toggle=\"yes\"> Every Newborn Action Plan (ENAP)</italic><sup>##REF##26249104##2##,##UREF##1##3##</sup>; <italic toggle=\"yes\">Global Strategy for Women and Child Health</italic><sup>##UREF##2##4##</sup>; <italic toggle=\"yes\">the Network for Improving Quality of Care ( QoC ) for maternal, newborn, and child health (MNCH)</italic><sup>##UREF##3##5##</sup>; and the <italic toggle=\"yes\">Core Stillbirth Estimation Group of the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME)</italic>.<sup>##UREF##4##6##</sup> SBR is also part of the World Health Organization (WHO) <italic toggle=\"yes\">Global Reference List of 100 Core Health Indicators. </italic>Within ENAP, a prominent target is for countries to achieve SBRs of 12 or fewer stillbirths per 1000 total births by 2030 and to close equity gaps.</p>", "<p> There is an acknowledgment that the unequal gains witnessed in stillbirth compared to other MNCH outcomes require further investment.<sup>##UREF##0##1##,##REF##26249104##2##,##REF##24853600##7##</sup> Many stillbirths are preventable through improved peri-conceptual health and nutrition, high quality antenatal and delivery care, and improved health systems.<sup>##REF##24853600##7##</sup> Health systems also provide the foundations needed to deliver quality care.<sup>##UREF##5##8##</sup> Health systems building blocks including leadership and governance are required to drive action and investment at the point of care. Information systems allow for evidence-informed decision-making. Financing arrangements remove barriers to health service access. Essential commodities and a skilled, motivated health workforce support the delivery of QoC interventions.</p>", "<p> As a critical function of health systems, leadership and governance are vital roles governments play in the stewardship of health systems. The central role of governments is to provide policy guidance underpinned by oversight, collaboration and coalition, regulation, and accountability.<sup>##UREF##5##8##</sup> ENAP has issued a call to action to governments to review and sharpen national strategies, policies, and guidelines for newborns and stillbirths. Prioritizing and establishing national targets for SBR reduction provides direction to sub-national and facility teams for better reporting and measurement on the neglected burden of stillbirth, drives the identification of measures to achieve the stated target, and holds governments accountable. Prioritization of stillbirths within national plans also creates awareness for health workers to document better and can drive increased investments into stillbirth measurement and reporting infrastructure.</p>", "<p> This paper seeks to provide an overview of the policy environment in countries to understand stillbirths recording and reporting. The policy instruments used in this paper refer to policies, strategies, laws, plans, and guidelines. Specifically, we aimed to: understand the governance related to stillbirths; assess processes established for maternal deaths, stillbirths, and neonatal deaths; identify health information systems commonly used for data collection on maternal and perinatal mortality; understand availability of essential commodities for maternal and perinatal services; explore national health workforce policies for stillbirth reporting; and finally, examine national-level policies and processes on death registration and stillbirths. The selection of objectives was informed by the WHO Health Systems Framework.<sup>##UREF##5##8##</sup></p>" ]	[ "<title>Methods</title>", "<title> Design </title>", "<p> The continuum of services across reproductive, maternal, neonatal, child and adolescent health (RMNCAH) is key for QoC in a country. Country responses to the global 2018-2019 WHO RMNCAH Policy Survey were reviewed to understand the policy environment for stillbirth.<sup>##UREF##7##13##,##UREF##8##14##</sup> The survey, distributed to all 194 Member States of WHO via email, tracked country progress in adopting WHO recommendations in national health policies, strategies and guidelines related to RMNCAH.<sup>##UREF##7##13##</sup> The survey was communicated by WHO, with an indicated timeframe, for WHO country offices to complete with relevant Ministry of Health and other United Nations (UN) agencies. Country responses to the survey were validated against national documents submitted by countries to WHO, with the required follow-up done by WHO. WHO conducted an analysis and published the results of the broader RMNCAH survey in the <italic toggle=\"yes\">International Journal of Health Policy and Management.</italic><sup>##UREF##9##15##</sup> This report did not systematically focus on, or review critically stillbirths.</p>", "<title> Survey Question Selection – Inclusion and Exclusion Process </title>", "<p> The policy survey was modular and included 331 questions and associated sub-questions. Thematic areas for the survey included cross-cutting RMNCAH issues, maternal and newborn health, child health, adolescent health, reproductive health, and gender-based violence.<sup>##REF##34861763##16##</sup></p>", "<p> For inclusion in this review, the two survey modules with content on stillbirths were examined: firstly, the cross-cutting RMNCAH module, and secondly, the maternal and newborn health module.</p>", "<p> From the two relevant survey modules, a systematic three-step process was conducted to determine study questions to be included in the study. In the first step, we (the authors of this paper) reviewed all 160 questions and sub-questions captured within the cross-cutting, and maternal and newborn health modules of the RMNCAH policy survey questionnaire. We identified questions related to stillbirth or influencing stillbirth outcomes using three perspectives. For inclusion, first, all questions that specifically mention stillbirth. Second, questions related to health systems building blocks that are essential facilitators for creating an enabling environment for stillbirth reduction<sup>##UREF##5##8##</sup>; and finally, questions on stillbirth-related areas such as neonatal and maternal deaths which are highly correlated to SBR. We excluded questions about clinical interventions and preventive measures for perinatal and maternal health. Twenty-four questions were identified from this step (##FIG##0##Figure 1##).</p>", "<p> We submitted a data sharing request form to WHO outlining the scope and intended output of the research. We obtained from WHO, secondary data including the original country responses to the 24 questions, catalogued national policy documents submitted by countries to validate and substantiate the survey responses, protocols for validation of country survey responses against national documents, and information from WHO on any data quality concerns relating to these questions.</p>", "<p> As a second step, once the data was received for the 24 questions, data verification was undertaken. Three questions for which responses could not be verified through the national documents were excluded. These included a question that required verification in the national health management information system and two questions on the frequency of death review panel meetings. Five questions that addressed general human resources were dropped, as more focused responses were available in a specific question on human resources for stillbirths (See Table S1 of ##SUPPL##0##Supplementary file 1##). National documents were reviewed to ensure that countries that indicated “yes” to established stillbirth targets had stated targets.</p>", "<p> Overall, 16 questions (See Table S2 of ##SUPPL##0##Supplementary file 1##) were included in this study: one question relating to national targets for SBR, under-five mortality rate (U5MR), and neonatal mortality rate (NMR); four questions on policies for death registration processes (birth registrations were not accounted for in this study as the term is used to refer to registration of live births, not stillbirths or fetal deaths<sup>##REF##33557862##17##</sup>); two questions on essential medicines and equipment; one question on surveys and health management information systems; and eight questions on death reviews. From the 16 questions, original country responses to 12 questions submitted by the 155 responding countries in all languages were included for the global review. For the remaining four questions, the questions had relevance to stillbirth, but stillbirth was not directly mentioned, for example, “is there a national policy/law that requires every death to be registered?” These four questions were adjusted to make them stillbirth specific eg, “is there a national policy/law that requires every death including [stillbirth or fetal death] to be registered?”</p>", "<p> For the third step, national documents for the sixty-six countries who submitted documents in English (Table S3, ##SUPPL##0##Supplementary file 1##) were then examined to answer the four adjusted questions (Table S2, ##SUPPL##0##Supplementary file 1##) using a defined search protocol. A response to the adjusted questions was then recorded. Responses to these four questions served as primary data. Search terms used for this analysis included: still, stillbirth, still birth, fetal, foetus, fetus, and foetal. Associated definitions for the search terms are reflected in Table S4 of ##SUPPL##0##Supplementary file 1##.</p>", "<p> Limitations to this approach are further expanded upon in the limitations section.</p>", "<title> Analysis</title>", "<p> The WHO Health Systems Framework was most appropriate to our study as it allows for a description of the various organizations, institutions, resources and people that work together to reduce SBRs. Past studies have also highlighted the usefulness of applying this framework to achieve health goals.<sup>##REF##23902601##18##, ####REF##24666579##19##, ##REF##24560261##20####24560261##20##</sup> The WHO Health Systems Framework guided the framing of study objectives and presentation of results. Country responses were recorded for each objective in a data tracking sheet to determine if stillbirth was addressed (Table S2, ##SUPPL##0##Supplementary file 1##). These responses were then analysed using the WHO regional groupings as the primary level of analysis. Countries also identified as fragile, conflict-affected, and vulnerable (FCV) settings, and the 2021 World Bank country income classification were used as an additional level of analysis.<sup>##UREF##10##21##,##UREF##11##22##</sup> STATA 16 was used for data cleaning and analyses. Descriptive analyses were used to identify and describe the results across regions.</p>" ]	[ "<title>Results</title>", "<title> A Global Perspective on National Stillbirth Policy Environment </title>", "<p> The following results were obtained from 155 countries (80% of WHO Member State countries) who responded to the wider RMNCAH survey. This captured 95.2% of the current burden of stillbirths in 2019.</p>", "<title> Governance for Stillbirths: Mortality Targets</title>", "<p> A national target for SBR was developed in 32 countries (21.9%). No established SBR target was reported in 114 countries and 9 countries did not respond to the question (##FIG##1##Figure 2##). Two regions accounted for over 60% of countries with a national target for SBR (Africa 40.6% [n = 13] and South-East Asia 21.9% [n = 7]). This is partly due to the large number of reporting countries in the African region.</p>", "<p> In comparison, three quarters of countries (n = 110) reported having set a national target for U5MR, and 68.5% (n = 102) reported a national NMR target (##FIG##2##Figure 3##). Results from the survey indicate that for countries with an established SBR target, 28.1% (n = 9) had set these greater than the ENAP target of 12 or fewer stillbirths per 1000 total births. Nearly half of all countries with identified NMR and U5MR targets, these were set at greater than the ENAP target of 12 or fewer deaths per 1000 live births and the Sustainable Development Goal target of 25 or fewer deaths per 1000 live births, respectively.</p>", "<p> Of the 32 countries reporting having a national target for SBR, 15.6% (n = 5) are high-income, 18.8% (n = 6) are upper-middle-income, 40.6% (n = 13) reported as lower-middle-income, and 25.0% (n = 8) are classified as low-income countries. Among the 39 globally recognized FCV countries, 29 completed the survey. A third of FCV countries who responded to the survey, reported having set a SBR target.</p>", "<title> Review Processes ( eg, Panels or Committees) Established for Maternal Deaths, Neonatal Deaths, and Stillbirths</title>", "<title> Review Processes Established for Maternal Deaths Including Stillbirths</title>", "<p> Maternal death review panels provide an opportunity to learn from the circumstances surrounding the death of a woman. Two-thirds of countries reported a national maternal death review panel or committee, and no information was available for 8.4% (n = 13) (##FIG##3##Figure 4##). Of the 102 countries with maternal death review, over half (59.8%, n = 61) reported that stillbirth and neonatal death reviews were integrated in the system. Integrated systems, defined as the investigation into a stillbirth or neonatal death should they have occurred alongside with a maternal death, were most common in Africa (39.3% of countries, n = 24), the Americas (23.0%, n = 14), Europe (13.1%, n = 8), and South-East Asia (13.1%, n = 8).</p>", "<title> Review Processes Established Specifically for Stillbirths </title>", "<p> A little less than half (n = 68) of countries have a national policy that requires stillbirth causes to be reviewed. Of this number, 62 countries have a policy requiring stillbirth review supported by an established operational facility-level review process. This approach was more common in Africa and the Americas compared to other regions. A further six countries reported having a national policy to review stillbirths but no facility-level review processes in place. No national policy was available in 43.9% (n = 68) of countries, however, facility-level review mechanisms exist in 13 of these countries. Only 3.9% (n = 6) of countries reported unknown or no information.</p>", "<title> Review Processes Established Specifically for Neonatal Deaths </title>", "<p> Two-thirds of countries (n = 105) have a national policy requiring review of neonatal deaths. Of this number, 95 countries have a national policy/guideline/law requiring neonatal death reviews alongside a facility neonatal death review process. This was common in Africa, the Americas and Europe compared to other regions. A national policy requiring neonatal death review was available in 10 countries, but no facility-level processes exist. No national policy for neonatal death review was reported in 5.2% (n = 8) of countries, however facility review processes existed. Only 3.9% (n = 6) of countries responded having no information.</p>", "<title> Health Information Systems Commonly Used for Data Collection on Maternal and Perinatal Rates</title>", "<p> The relevant survey question on health information systems looked into data sources for comparison. Across countries, the four most used data sources to compare maternal, newborn, child, and adolescent mortality rates, in descending order were: WHO websites and reports; national health statistics databases; national population-based surveys (eg, Demographic and Health Surveys and Multiple Indicator Cluster Surveys); and civil registration and vital statistics systems (##FIG##4##Figure 5##).</p>", "<title> Essential Commodities for Quality of Care for Maternal and Perinatal Services</title>", "<p> Globally, more than 90.3% of countries had a national policy or guideline for essential medicines and equipment. Over 80% of countries had key commodities including oxygen supply, blood and blood products, self-inflating bag with neonatal and paediatric masks of different size, for pregnancy and childbirth care which are required for stillbirth prevention and resuscitation of babies who are apnoeic at birth and would otherwise be classified as a ‘fresh stillbirth.’</p>", "<title> A Focused Perspective on National Policy Documents and Stillbirth </title>", "<p> The following results are obtained from the document review of the 66 countries (out of 155) that submitted documents in English on content relevant to stillbirths, using the four stillbirth-specific adjusted questions. 885 documents (31.4% of those submitted for the cross-cutting, and maternal and newborn thematic areas) were examined as part of the primary data review.</p>", "<p> Among national policies reviewed, 45.5% (n = 30) mention registering stillbirths, according to established national guidelines or protocols. Just 12.1% (n = 8) of countries reported a national policy/law that requires the cause of death registration for stillbirth or fetal death to be in line with the WHO International Classification of Diseases (ICD)-10.<sup>##UREF##12##23##</sup> When cause of death was mentioned for stillbirths, ICD-10 was rarely referenced. 24.3% (n = 16) of countries have a policy/law that requires a routine audit and review of death certification for stillbirth or fetal death. Across countries, when certificates were mentioned in the context of stillbirths, countries did not differentiate between death or medical certificates.</p>", "<p> Training of health workers in filling out death certificates using ICD-10 classification for stillbirths was reported in 5 out of the 66 countries. When training of health workers was mentioned, it generally entailed communication and counselling to the mother/family after a stillbirth.</p>", "<p> Between national agencies, 32% (n = 21) of countries require death data recorded on stillbirth at health facility or at the community-level be provided to the national statistics office, civil registration system, or equivalent bodies. 30.3% (n = 20) of countries required sharing individual death records on stillbirth between central and district/regional health directorate levels. Reporting stillbirth data that occurred in private facilities was mentioned by two countries in national documents.</p>" ]	[ "<title>Discussion</title>", "<p> In the post Millennium Development Goals era, focus on stillbirth has improved.<sup>##UREF##13##24##</sup> A coalition of agencies and initiatives including the <italic toggle=\"yes\">Network for improving QoC for MNCH, the UN IGME, ENAP, </italic>and<italic toggle=\"yes\"> the Global Strategy for Women and Child Health</italic> are coordinating action by providing guidance on stillbirth reduction. These initiatives have exerted influence on the political priority for stillbirth.<sup>##REF##26249104##2##,##UREF##1##3##,##REF##24853600##7##,##REF##30820319##25##, ####UREF##14##26##, ##UREF##15##27##, ##UREF##16##28####16##28##</sup> Since its launch in 2014, countries who signed onto the ENAP,<sup>##UREF##17##29##</sup> committed to end preventable newborn mortality and stillbirths. ENAP is further underpinned by periodic monitoring processes to ensure countries are on track to achieve the 12 per 1000 total births goal by 2030.<sup>##UREF##18##30##</sup> The success made by ENAP is clear, countries who actively report to ENAP have established stillbirth targets. Similarly, the eleven countries who are the founding members of the QoC Network for MNCH, all have established SBR targets.<sup>##UREF##3##5##</sup></p>", "<p> In October 2020, with the launch of the global report on <italic toggle=\"yes\">A Neglected Tragedy: The global burden of stillbirths</italic><sup>##UREF##0##1##</sup> by the UN IGME, there was consensus and acknowledgement by international agencies and networks that further work is required to include stillbirths in all relevant maternal and newborn health policies. Implementing the actions shared in the global report will require involvement of actors at the country and local levels to make sustainable improvements.</p>", "<p> Stillbirths are not prioritized in most countries when compared to other child health indicators.<sup>##REF##21496917##10##,##REF##26794078##12##,##UREF##19##31##</sup> Only 21.9% of countries have established a national target for SBR (compared to 68.5% for NMR and 73.8% for U5MR), and less than half of countries have a national policy for stillbirths to be reviewed. This lower proportion of countries signals that stillbirths continue to be relegated to a “not now” agenda. Though in 2019, an estimated 2.0 million babies were stillborn roughly similar to the number of neonatal deaths.<sup>##UREF##0##1##</sup> The gains reported in child health<sup>##REF##21496917##10##,##REF##26794078##12##</sup> (2.9% reduction in neonatal mortality and 4.3% among children aged 1–59 months annually over the last 20 years) are consistent with findings from this policy review and align with the historical increase in global calls for standardized and improved measurement on newborns.<sup>##REF##26530604##32##</sup> An increased number of countries have established a national NMR target (and a higher number of countries reported neonatal death review processes at national and facility-level) and U5MR target.</p>", "<p> Some factors that play a role in why stillbirth prioritization lags at the country-level compared to other child health areas. First, definitions for stillbirths vary. Whilst standard definitions for stillbirth are included in WHO’s ICD, including a standard definition for international comparison, these definitions are not consistently applied.<sup>##REF##27431422##33##</sup> Universal application of these definitions is essential to enable accurate comparisons between countries and within countries over time and to identify where the need is greatest. Second, the literature on stillbirth has predominately focused on clinical interventions<sup>##REF##19426469##34##, ####REF##26390820##35##, ##REF##19426465##36##, ##REF##29193794##37##, ##REF##20233385##38####20233385##38##</sup> with very little information positioning the stillbirth agenda in a way that is understood by and attracts attention of policy-makers, rather than just clinicians.<sup>##REF##24853600##7##</sup> This affects how stillbirths are portrayed and prioritized internally within the policy community.<sup>##REF##24122129##39##</sup> Third, culture, taboo and misconception about stillbirths remain a big barrier.<sup>##REF##26794074##40##</sup></p>", "<p> Contextual factors play a role in how stillbirth policies and strategies are acted upon at country-level. Few (15.6%) high-income countries have established a SBR target. This may be due to increased focus being placed on low- and middle-income countries where overall national SBRs frequently remain greater than the 12 per 1000 total births ENAP targets.<sup>##UREF##0##1##</sup> However, ENAP targets also include a requirement to close equity gaps in SBR in all contexts. This will require focus on the highest risk groups in every country in terms of improving equity of access and use of essential health services to end preventable deaths.<sup>##UREF##1##3##</sup> In low-income countries where the risk of stillbirth is on average 7.6 times higher than in high-income countries,<sup>##UREF##0##1##</sup> 25% of low-income countries in this study have set a SBR target. This is likely due in part to more active engagement in ENAP and active WHO and the United Nations International Children’s Emergency Fund (UNICEF) support of country implementation and monitoring of ENAP in high mortality settings, including support for target setting.<sup>##UREF##1##3##,##UREF##15##27##,##UREF##16##28##</sup> For low-income countries that have not set a stillbirth target, these countries could benefit from increased investments into stillbirth policy setting and data strengthening. Further, national policies and strategies to reduce stillbirths would benefit from scaling up QoC interventions, which are often the same interventions to reduce maternal and neonatal mortality and improve well-being.<sup>##UREF##0##1##,##REF##24853600##7##</sup></p>", "<p> In FCV settings where health systems face complexity with service delivery resourcing, organization, access, and use,<sup>##UREF##11##22##,##REF##31909791##41##,##REF##31902953##42##</sup> 29 countries responded to the survey. The 10 countries classified as FCV settings with an established SBR target are all signatories to the ENAP, signaling commitment by national governments to prevent newborn deaths and stillbirths. Some FCV settings do not have an established stillbirth target. This can be attributed to the significant health and development needs, competing priorities, service delivery disruption, and unpredictable resourcing streams witnessed in such settings.<sup>##REF##31909791##41##, ####REF##31902953##42##, ##UREF##20##43####20##43##</sup> To achieve the global target of 12 or less stillbirths per 1000 total births by 2030, careful attention will need to be given to FCV settings, which account for significant health burden globally.<sup>##UREF##20##43##</sup> This will require accelerating access to essential quality care<sup>##REF##25974281##44##</sup>; improving health workforce competencies<sup>##UREF##21##45##</sup>; addressing systems redesign, infrastructure and essential commodities in health facilities and at the community level<sup>##REF##31909791##41##, ####REF##31902953##42##, ##UREF##20##43####20##43##</sup>; and improving data on stillbirths to address inequities in these settings.</p>", "<p> National policies need to be grounded by operational mechanisms at the sub-national and facility-level to facilitate the achievement of national goals.<sup>##REF##23221008##46##,##UREF##22##47##</sup> Setting a national approach to review stillbirths is a step in the right direction by countries, with 40% of all countries indicating that they have national policies to review stillbirth grounded by facility-level review processes to understand the causes and address gaps in service delivery, to improve QoC. A small number of countries (n = 13) indicated that there are facility-level review processes but no national policies. Contributing factors to the differences reported within countries could include varying forms of decentralized health planning and management systems within countries, which may result in greater delegation of power, community participation, and flexibility in planning to address urgent health needs in a local community<sup>##UREF##22##47##,##REF##28327123##48##</sup>; extended time to translate policies into practice<sup>##REF##22179294##49##</sup>; sub-national commitment and ownership to curb SBRs; and funding from global-level initiatives and point-of-care efforts to improve SBRs.<sup>##REF##32470901##50##</sup></p>", "<p> Globally, 56 countries are off track to meet the SBR ENAP target by 2030.<sup>##UREF##23##51##</sup> At the country-level, several challenges remain to record and report a stillbirth: First, due to the varied definitions on stillbirths, countries use different criteria, including gestational age and birthweight for stillbirth measurement.<sup>##REF##29193794##37##,##REF##26794077##52##</sup> Second, misclassification of antepartum and intrapartum stillbirths,<sup>##UREF##24##53##,##UREF##25##54##</sup> differentiating between intentional late term induced abortion and stillbirth,<sup>##REF##26400645##55##</sup> and distinguishing stillbirth and early neonatal death,<sup>##UREF##6##11##,##REF##24050480##56##, ####REF##33765942##57##, ##UREF##26##58####26##58##</sup> further compromises data quality of stillbirth reporting. Third, challenges persist in reporting stillbirths within health information systems. Only 32% of surveyed countries require death data recorded on stillbirths at health facilities or by community health workers be provided to the national statistics office, civil registration system, or equivalent bodies. This finding warrants further research at country-level to understand and close the evidence-gap on how the policy environment affects reporting of stillbirths into health information systems. When data is reported on stillbirth, noted challenges include under-reporting, omission or misclassification of deaths in civil registration systems,<sup>##REF##25971218##59##</sup> and limited information on birthweight, gestational age, and stillbirth type in the health management information systems.<sup>##REF##29347930##60##,##REF##15522924##61##</sup> Further, socio-cultural and spiritual beliefs in some countries are identified barriers for mothers underreporting stillbirths or hindering families to register a stillbirth in demographic health surveys.<sup>##REF##26794074##40##,##REF##33557858##62##</sup></p>", "<p> A key intervention proposed to improve stillbirth recording and reporting are death reviews. Maternal and perinatal death surveillance and response (MPDSR) has expanded in recent years,<sup>##UREF##27##63##, ####REF##33712840##64##, ##UREF##28##65##, ##UREF##29##66####29##66##</sup> with a view to learning about causes and promoting successful partnerships at different levels that can lead to real change for communities and nations. Globally, only 39.4% of countries have identified the inclusion of stillbirth or neonatal death reviews as part of national committees on maternal death reviews, resulting in missed opportunities for an efficient and integrated review process alongside identifying the high-yield QoC intervention packages to save both mother and baby. Further missed opportunities were reported where very few countries had mechanisms to review causes of death for stillbirth. Some reasons for countries reporting no review or lack of an integrated review process may include policy and planning environment, resource support, historical focus by external actors on the implementation of MPDSR, political prioritization, pressures to implement, and the level of connectedness and networks between health system levels.<sup>##REF##33712840##64##,##UREF##29##66##</sup></p>", "<p> Stillbirths remain invisible in most national documents. Less than half of reviewed national policy documents made mention of registering stillbirths and just 12.1% made mention of identifying stillbirth causes according to ICD-10. A systematic classification<sup>##REF##21496912##67##,##REF##27634615##68##</sup> such as ICD-10, supports national tracking, provides in-depth investigation, grounds research, and identifies areas of greatest need. Low utilization of classification systems in facilities may be due to scarce national resourcing thereby affecting coverage and lack of required data.<sup>##REF##27634615##68##</sup> Several studies have called on training of health workers on management related to stillbirth<sup>##REF##26794074##40##,##REF##26810220##69##,##REF##33430858##70##</sup> to address the gaps related to health worker skills for perinatal death reviews. Properly identifying the causes of stillbirth is important for women to know why their baby died, to reduce blame and stigma and take positive action for the next pregnancy.<sup>##REF##27905202##71##</sup></p>", "<title> Limitations </title>", "<p> This study has some limitations. The study is a policy review and does not assess the level of implementation of the various policies. Additionally, the document reviews were conducted only in English. Documents submitted in the other five official UN languages were excluded, in addition to those in local national languages. Though the document reviews, were only conducted in English, this was the highest share of documents submitted in official UN languages. We recommend that further reviews in other UN official languages be conducted to augment these findings.</p>", "<p> Reliability of country responses can be a problem as this is based on the knowledge of the individuals reporting the data at country-level. The situation in the country may have changed since the time of the survey with new guidelines having been released from WHO on MPDSR (2021) and the COVID-19 pandemic. The nature in which questions were framed within the WHO RMNCAH survey may have influenced the responses by country. For example, “what is the target” does not indicate if it is a current or future target.</p>", "<title> Recommendations</title>", "<p> The following recommended actions for policy-makers could improve prioritization of stillbirths within national policies and plans, ahead of the 2030 Sustainable Development Goal deadline. First, close the large gaps in stillbirth registration by using a standard definition for stillbirths and explicitly incorporating stillbirth into RMNCAH policies and plans. The WHO ICD-11 (released 2022) is now updated with a revised standard definition for stillbirth.<sup>##UREF##30##72##</sup> Where stillbirth is not included, include stillbirth registration as part of plans for stillbirth reduction. Second, undertake reviews of RMNCAH plans and guidelines, with a specific reference to the training of health workers to record and register stillbirths and their causes according to internationally recognized standards such as ICD-11. This action should apply to all health facilities including public and private facilities and at the community-level. Third, develop simple communication and advocacy materials making the case for stillbirth policy improvements for policy-makers. Fourth, improve the reporting infrastructure at the country level with clear protocols for health workers and ensure data on stillbirths is shared between different actors. Data is needed to develop sound policies. Finally, ensure policies do not remain detached from frontline efforts by including adequately financed implementation plans at the facility and district levels.</p>", "<p> At the global level, we suggest improvements to the WHO RMNCAH policy survey to address the urgent need for stillbirth reduction and better reporting, including a dedicated thematic area on stillbirth. Integration of the additional four adjusted questions on stillbirth into the WHO RMNCAH policy survey could provide a better picture of the policy landscape for stillbirths and allow for useful information for policy tracking in addition to the data collected by the ENAP. We suggest that international agencies increase investments in stillbirth by expanding upon countries participating in global initiatives (such as ENAP and the QoC Network) to advance the stillbirth agenda. We also urge global and implementing partners to provide guidance and training for how governments can incorporate stillbirths in national policies and plans on RMNCAH and strengthen data systems to record and report on stillbirths.</p>" ]	[ "<title>Conclusion</title>", "<p> Networks and global initiatives play a key role in supporting the policy environment to reduce stillbirths. The findings from this global policy review highlight great gaps exist in setting national direction for stillbirth reduction. Without improving the policy environment which directs how stillbirths are acted upon at country-level, the global goal of reducing the SBR to 12 or less stillbirths in every country per 1000 total births will remain aspirational.</p>" ]	[ "<p>\n<bold>Background:</bold> Globally, data on stillbirth is limited. A call to action has been issued to governments to address the data gap by strengthening national policies and strategies to drive urgent action on stillbirth reduction. This study aims to understand the policy environment for stillbirths to advance stillbirth recording and reporting in data systems.</p>", "<p><bold>Methods:</bold> A systematic three-step process (survey tool examination, identifying relevant study questions, and reviewing country responses to the survey and national documents) was taken to review country responses to the global 2018-2019 World Health Organization (WHO) Reproductive, Maternal, Neonatal, Child and Adolescent Health (RMNCAH) Policy Survey. Policy Survey responses were reviewed to identify if and how stillbirths were included in national documents. This paper uses descriptive analyses to identify and describe the relationship between multiple variables.\n</p>", "<p><bold>Results:</bold> Responses from 155 countries to the survey were analysed, and over 800 national policy documents submitted by countries in English reviewed. Fewer than one-fifth of countries have an established stillbirth rate (SBR) target, with higher percentages reported for under-5 (71.0%) and neonatal mortality (68.5%). Two-thirds (65.8%) of countries reported a national maternal death review panel. Less than half (43.9%) of countries have a national policy that requires stillbirths to be reviewed. Two-thirds of countries have a national policy requiring review of neonatal deaths. WHO websites and national health statistics reports are the common data sources for stillbirth estimates. Countries that are signatories to global initiatives on stillbirth reduction have established national targets. Globally, nearly all countries (94.8%) have a national policy that requires every death to be registered. However, 45.5% of reviewed national policy documents made mention of registering stillbirths. Only 5 countries had national policy documents recommending training of health workers in filling out death certificates using the International Classification of Diseases (ICD)-10 for stillbirths. </p>", "<p><bold>Conclusion:</bold> The current policy environment in countries is not supportive for identifying stillbirths and recording causes of death. This is likely to contribute to slow progress in stillbirth reduction. The paper proposes policy recommendations to make every baby count.</p>", "<p>\n<bold>Citation:</bold> Mensah Abrampah NA, Okwaraji YB, You D, et al. Global stillbirth policy review – outcomes and implications ahead of the 2030 Sustainable Development Goal agenda. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7391. doi:10.34172/ijhpm.2023.7391</p>" ]	[ "<title>Acknowledgements</title>", "<p> We gratefully acknowledge the contributions of Allyson Moran and Elizabeth Katwan. Further thanks to the Stillbirths Advocacy and Research in Africa Hub (SARAH). We also acknowledge the country survey respondents and WHO for enumeration of the survey, cleaning of data and cataloguing the national source documents that enabled this review. No specific funding was provided for the analyses in this paper, however, funding for DJ was provided by the Takeda Foundation as part of the Takeda Chair in Global Child Health at the London School of Hygiene and Tropical Medicine.</p>", "<title>Ethical issues</title>", "<p> Ethics approval was received from the London School of Hygiene and Tropical Medicine to conduct the policy review. Additionally, we submitted a data sharing request form to WHO outlining the scope and intended output of the research. Approval was obtained and we received from WHO all national policies and documents submitted to the global 2018-2019 WHO RMNCAH Policy Survey.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nMethodology Flow Chart. Abbreviations: Abbreviations: UN, United Nations; HMIS, Health Management Information Systems.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nCountries That Have Developed a National Target for Stillbirth Rate, as Reported on the 2018-2019 RMNCAH Policy Survey. Abbreviation: RMNCAH, Reproductive, Maternal, Neonatal, Child and Adolescent Health.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nCountries That Have Developed a National Stillbirth Rate Target Compared to Neonatal Mortality Rate and Under-Five Mortality Rate Targets, Grouped by WHO Region. Abbreviation: WHO, World Health Organization.</p></statement></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4</label><statement><p>\nNational Review Processes Established for Maternal Deaths, Stillbirths and Neonatal Deaths, as Reported on the 2018-2019 WHO RMNCAH Policy Survey. Abbreviation: RMNCAH, Reproductive, Maternal, Neonatal, Child and Adolescent Health.</p></statement></fig>", "<fig position=\"float\" id=\"F5\"><label>Figure 5</label><statement><p>\nTop Five Data Sources Used by Countries to Compare Child and Maternal Mortality Rates. Each box is proportional to its value, meaning that bigger boxes have bigger proportions. Abbreviations: WHO, World Health Organization; DHS, Demographic and Health Surveys; MICS, Multiple Indicator Cluster Surveys; CRVS, Civil Registration and Vital Statistics; Nat Health statistics, National Health Statistics.</p></statement></fig>" ]	[]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><p> National policy-makers should:</p><list list-type=\"bullet\"><list-item><p>Establish a standard national definition for stillbirths and include stillbirth registration as part of strategies to accelerate progress to end preventable stillbirths. </p></list-item><list-item><p>Undertake reviews of reproductive, maternal, newborn, child and adolescent health plans and guidelines, and include specific reference to the training of health workers to record and register stillbirths and their causes according to internationally recognized standards. </p></list-item><list-item><p>Improve the reporting infrastructure at country level with clear protocols for health workers and ensure data on stillbirths is shared between different actors and health system levels. </p></list-item><list-item><p>Consider joining global initiatives that aim to reduce stillbirth rates (SBRs) such as the <italic toggle=\"yes\">Every Newborn Action Plan (ENAP)</italic> and the <italic toggle=\"yes\">Quality of Care ( QoC ) Network for Maternal, Newborn and Child Health (MNCH)</italic>. </p></list-item><list-item><p>Ensure policies do not remain detached from frontline efforts by including adequately financed implementation plans at the facility and district levels. </p></list-item></list><p> The highlighted recommendations are applicable to health providers and stakeholders involved in stillbirth prevention. It is essential to ensure that policies, training and reporting infrastructure on stillbirth are available and sensitized within countries.</p><p>\n<bold>Implications for the public</bold>\n</p><p> Findings from 155 countries and over 800 national policy documents reveal stillbirths remain invisible in national policies. Countries that responded to the survey prioritized child health mortality indicators (such as under-five mortality rate [U5MR] and neonatal mortality rate [NMR]), three-times more than stillbirths. The regions with the highest burden of stillbirth, Africa and South-East Asia, accounted for more than half of all established stillbirth rate (SBR) targets. 40.6% of reporting countries in Africa and 21.9% of reporting countries in South-East Asia had established SBR targets. Greater than half of all reporting countries with established SBR targets are middle-income, with gaps reported in countries facing fragility, vulnerability, and conflict. Overall, more countries reported review processes for maternal (65.8%) and neonatal deaths (67.7%) compared to stillbirth (43.9%). Improving the policy environment which directs how stillbirths are acted upon at country-level is an essential step in creating the enabling environment needed to make every baby count.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1 contains Tables S1-S4.\n</p></caption></supplementary-material>" ]	[]	[ "<graphic xlink:href=\"ijhpm-12-7391-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7391-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7391-g003\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7391-g004\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7391-g005\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7391-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" UNICEF, World Health Organization, World Bank Group, United Nations. A Neglected Tragedy: The Global Burden of Stillbirths. Report of the UN Inter-Agency Group for Child Mortality Estimation. UNICEF, World Health Organization, World Bank Group, United Nations; 2020. "]}, {"label": ["3"], "mixed-citation": [" World Health Organization (WHO), UNICEF. Every Newborn: An Action Plan to End Preventable Deaths. Luxembourg: WHO, UNICEF; 2014. "]}, {"label": ["4"], "mixed-citation": [" World Health Organization (WHO), United Nations. Global Strategy for Women\u2019s, Children\u2019s and Adolescents Health 2016-2030. Geneva: WHO; 2016. "]}, {"label": ["5"], "mixed-citation": [" World Health Organization (WHO). Quality, Equity, Dignity: The Network to Improve Quality of Care for Maternal, Newborn and Child Health. WHO; 2017. "]}, {"label": ["6"], "mixed-citation": [" United Nations Inter-Agency Group for Child Mortality Estimation (UN-IGME) Summary of recommendations regarding pregnancy losses, terminations of pregnancy, stillbirths, fetal and neonatal deaths in ICD-11. [Unpublished manuscript]. "]}, {"label": ["8"], "mixed-citation": [" World Health Organization (WHO). Strengthening Health Systems to Improve Health Outcomes: WHO\u2019s Framework for Action. Geneva: WHO; 2007. "]}, {"label": ["11"], "mixed-citation": [" Blencowe H. Counting the Smallest: Data to Estimate Global Stillbirth, Preterm Birth and Low Birthweight Rates [dissertation]. London School of Hygiene & Tropical Medicine; 2020. "], "pub-id": ["10.17037/pubs.04655794"]}, {"label": ["13"], "mixed-citation": [" World Health Organization (WHO). Reproductive, Maternal, Newborn, Child, and Adolescent Health Policy Survey. Geneva: WHO; 2018. "]}, {"label": ["14"], "mixed-citation": [" World Health Organization (WHO). Maternal, Newborn, Child and Adolescent Health and Ageing. Data Portal. "], "uri": ["https://platform.who.int/data/maternal-newborn-child-adolescent-ageing/national-policies?selectedTabName=Reports"]}, {"label": ["15"], "mixed-citation": [" World Health Organization (WHO). Sexual, Reproductive, Maternal, Newborn, Child and Adolescent Health Policy Survey, 2018-2019: Report. Geneva: WHO; 2020. "]}, {"label": ["21"], "mixed-citation": [" Word Bank Group. World Bank Country and Lending Groups. "], "uri": ["https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups"]}, {"label": ["22"], "mixed-citation": [" World Bank Group. FY22 List of Fragile and Conflict-Affected Situations. "], "uri": ["https://www.worldbank.org/en/topic/fragilityconflictviolence/brief/harmonized-list-of-fragile-situations"]}, {"label": ["23"], "mixed-citation": [" World Health Organization (WHO). ICD-11 for Mortality and Morbidity Statistics. Geneva: WHO; 2020. "]}, {"label": ["24"], "mixed-citation": [" United Nations. Global Indicator Framework for the Sustainable Development Goals and Targets of the 2030 Agenda for Sustainable Development. New York, NY: United Nations; 2020. "]}, {"label": ["26"], "mixed-citation": [" World Health Organization (WHO). Survive and Thrive: Transforming Care for Every Small and Sick Newborn. Geneva: WHO; 2019. "]}, {"label": ["27"], "mixed-citation": [" World Health Organization (WHO), UNICEF. Every Newborn Progress Report 2018. WHO, UNICEF; 2018. "]}, {"label": ["28"], "mixed-citation": [" World Health Organization (WHO), UNICEF. Reaching the Every Newborn National 2020 Milestones: Country Progress, Plans and Moving Forward. Geneva: WHO, UNICEF; 2017. "]}, {"label": ["29"], "mixed-citation": [" World Health Organization (WHO). Every Newborn Action Plan. "], "uri": ["https://www.who.int/initiatives/every-newborn-action-plan"]}, {"label": ["30"], "mixed-citation": [" World Health Organization (WHO), UNICEF. Ending Preventable Newborn Deaths and Stillbirths by 2030: Moving Faster Towards High Quality Universal Health Coverage in 2020-2025. Geneva: WHO, UNICEF; 2020. "]}, {"label": ["31"], "mixed-citation": [" UNICEF. Under-Five Mortality. "], "uri": ["https://data.unicef.org/topic/child-survival/under-five-mortality/"]}, {"label": ["43"], "mixed-citation": [" World Health Organization (WHO). Quality of Care in Fragile, Conflict-Affected and Vulnerable Settings: Taking Action. Geneva: WHO; 2021. "]}, {"label": ["45"], "person-group": ["\n"], "surname": ["Kabongo", "Gass", "Kivondo", "Kara", "Semrau", "Hirschhorn"], "given-names": ["L", "J", "B", "N", "K", "LR"], "article-title": ["Implementing the WHO Safe Childbirth Checklist: lessons learnt on a quality improvement initiative to improve mother and newborn care at Gobabis District Hospital, Namibia"], "source": ["BMJ Open Qual"], "year": ["2017"], "volume": ["6"], "issue": ["2"], "fpage": ["e000145"], "pub-id": ["10.1136/bmjoq-2017-000145"]}, {"label": ["47"], "mixed-citation": [" Schmets G, Kadandale S, Porignon D, Rajan D. Strategizing National Health in the 21st Century: A Handbook. Geneva: WHO; 2016. "]}, {"label": ["51"], "mixed-citation": [" World Health Organization (WHO). Global 100 Core Health Indicators (Plus Health-Related SDGs). Geneva: WHO; 2018. "]}, {"label": ["53"], "person-group": ["\n"], "surname": ["Gurung", "Litorp", "Berkelhamer"], "given-names": ["R", "H", "S"], "article-title": ["The burden of misclassification of antepartum stillbirth in Nepal"], "source": ["BMJ Glob Health"], "year": ["2019"], "volume": ["4"], "issue": ["6"], "fpage": ["e001936"], "pub-id": ["10.1136/bmjgh-2019-001936"]}, {"label": ["54"], "person-group": ["\n"], "surname": ["Kc", "Berkelhamer", "Gurung"], "given-names": ["A", "S", "R"], "article-title": ["The burden of and factors associated with misclassification of intrapartum stillbirth: evidence from a large scale multicentric observational study"], "source": ["Acta ObstetGynecol Scand"], "year": ["2020"], "volume": ["99"], "issue": ["3"], "fpage": ["303"], "lpage": ["311"], "pub-id": ["10.1111/aogs.13746"]}, {"label": ["58"], "person-group": ["\n"], "surname": ["Mony", "Varghese", "Thomas"], "given-names": ["PK", "B", "T"], "article-title": ["Estimation of perinatal mortality rate for institutional births in Rajasthan state, India, using capture-recapture technique"], "source": ["BMJ Open"], "year": ["2015"], "volume": ["5"], "issue": ["3"], "fpage": ["e005966"], "pub-id": ["10.1136/bmjopen-2014-005966"]}, {"label": ["63"], "mixed-citation": [" World Health Organization (WHO). Making Every Baby Count: Audit and Review of Stillbirths and Neonatal Deaths. Geneva: WHO; 2016. "]}, {"label": ["65"], "mixed-citation": [" Nkurunziza T. MPDSR Implementation in the WHO African Region. Paper presented at: Maternal and Perinatal Death Surveillance and Response. WHO/UNFPA/UNICEF Joint Workshop. South Africa: WHO, AFRO; 2018. "]}, {"label": ["66"], "mixed-citation": [" Shittu O, Kinney M. Assessment of Maternal and Perinatal Death Surveillance and Response Implementation in Nigeria. Healthy Newborn Network; 2017. "]}, {"label": ["72"], "mixed-citation": [" UNICEF. Stillbirth Definition and Data Quality Assessment for Health Management Information Systems (HMIS). New York: UNICEF; 2022. "]}]	{ "acronym": [], "definition": [] }	72	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 15; 12:7391	oa_package/91/96/PMC10590256.tar.gz
PMC10590471	0	[ "<title>Background</title>", "<p> Sanctions are interruptions of a country’s communications, diplomatic, and/or economic relations and are considered to be a positive tool to facilitate the resolution of conflict in a less violent manner. However, economic sanctions that affect trade and finance can cause severe economic destabilization with grave impacts on the livelihoods and well-being of populations in affected countries.<sup>##UREF##0##1##</sup> Economic sanctions are imposed by governments or the United Nations Security Council against individuals, companies, or countries. Iran and Iraq have experienced targeted economic sanctions (excluding food and medicines) by both the United Nations Security Council and the United States; whereas sanctions on Cuba by the United States (Unilateral) are comprehensive (including food, medicines, and medical equipment) and have extraterritorial components which effectively make it difficult for other countries to trade with Cuba. However, there is ample evidence of the adverse effects of any kind of economic sanctions on the welfare, health, and food security of civilians.<sup>##REF##24236359##2##</sup> It may appear as trade sanctions in the form of embargoes, seizures and/or boycotts, and interruption of financial and investment flows vis-à-vis a specific country. Recently, new forms of coercion have been emerging through asset freezing, asset control, and travel bans to influence persons who are perceived to have political influence.<sup>##UREF##1##3##</sup></p>", "<p> Many of the sanctions imposed on countries around the world are aimed at weakening their economies, resulting in increased poverty, reduced food security, and public welfare. Although sanction objectives are rarely met, these sanctions nevertheless lead to a humanitarian disaster.<sup>##REF##25988101##4##,##UREF##2##5##</sup> Sanctions can influence all dimensions of food security: Availability would be limited by preventing civilians from acquiring related essentials such as farm implements, fertilizers, transportation equipment, spare parts, pharmaceuticals, or chemicals for sanitation. The Weakening of critical infrastructure including roads, ports, power plants, transformer stations, hospitals, factories, warehouses, and water and sanitation plants will disrupt the process, distribution, and access to food and may lead to the spread of diseases that make it difficult to absorb nutrients (utilization). A collapse in the education system, on the other hand, can worsen unemployment for years to come, in turn having an impact on access to adequate food.<sup>##UREF##2##5##</sup></p>", "<p> This systematic review was conducted to identify the impact of economic sanctions on household food and nutrition security and policies to cope with them in exposed countries in the framework of sustainable food and nutrition security system. The practical aim was to provide solutions to prevent food insecurity in vulnerable households in the face of new sanctions against Iran.</p>" ]	[ "<title>Materials and Methods</title>", "<p> The experiences of all exposed countries to economic sanctions and the experience of Iran with the previous round of sanctions, in particular from the escalation of sanctions in 2011 to the time of the Joint Comprehensive Plan of Action in 2015, were systematically reviewed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020 were used to identify, select, appraise, synthesize, and report studies in the present systematic review to prepare a transparent, complete, and accurate account of why the review was conducted, how it was done and what the results were.<sup>##REF##33781348##6##</sup> The study was registered in PROSPERO with the Number CRD42020191028.</p>", "<title> Literature Search</title>", "<p> Electronic databases (Embase, PubMed, Scopus, Science Direct, Web of Science, JSTOR, and Google Scholar) in addition to Persian ones (SID, Magiran, IranDoc, and Noor) have been searched for all related documents published until March 1, 2022. There was no time limit for the start date of the search. Keywords relevant to sanction (economic sanction, embargo, or monetary sanction) and food and nutrition (food, nutrition, nutrient, “food secur,” and “food insecur”) were used. Moreover, some reference lists of identified studies, related projects, congresses abstract, dissertations, and relevant reviews were searched as gray literature to find more likely all eligible studies. According to the nature of the research topic, some sources eg, reports, preprints, working papers, and statements, produced by government departments and agencies, civil society or non-governmental organizations especially organizations providing humanitarian aid, academic centers and departments, private companies, and consultants were searched, too. There was no limitation on the time of papers. The search strategy of the review is presented in ##SUPPL##0##Supplementary file 1##.</p>", "<title> Article Screening, Inclusion, and Exclusion Criteria </title>", "<p> Initial screening was performed using the title and abstract and then, full texts were downloaded if needed. After searching for related articles, they were selected and reviewed by the project executives to remove irrelevant items. All relevant results were extracted from cross-sectional, retrospective, surveys, cohort, before-after, interventional, and qualitative studies. There was no limitation for the target groups in terms of age and gender and language of published studies. Book chapters and available conference proceedings were also considered for more access to relevant data. Exclusion criteria were: lack of data related to food insecurity in countries subject to sanction and very low quality of the article. Duplicate citations and non-accessible old publications were excluded, too.</p>", "<title> Data Extraction and Quality Assessment </title>", "<p> Two reviewers (FM-N and DG) conducted systematic processes of literature searches, quality assessment, and data extraction of eligible papers independently and potential conflicts were resolved through discussion. In cases of disagreement, help was sought from a third person (AH-R). Data extracted from the selected studies included author’s name(s), year of publication, imposed countries, methodological characteristics (study design, sample size, and sampling method), sanction type and duration, the impact of sanctions on different dimensions of food security including availability, access, utilization, stability, policies, and programs to cope with them. Some related factors to the success of the programs and policies such as context and process were reviewed, too.</p>", "<p> The quality of included studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal checklists for prevalence studies, quasi-experimental (non-randomized experimental) studies, and qualitative evidence. Each study can receive a high (H), medium (M), or low (L) quality rating.<sup>##UREF##3##7##</sup></p>", "<title> Statistical Analysis</title>", "<p> The main strategy in the analysis was data synthesis. The included studies found in each country were more than 4 studies; however, a meta-analysis of findings was not possible because of their heterogeneity in terms of the context of the society, studied dimensions of food security, policies to cope, and quality of the study. Therefore, the results were presented as a combination of qualitative and quantitative synthesis. In other words, the findings on the effects of the embargo on the food security of the countries and the strategies used to cope with them were reported from both quantitative and qualitative studies.</p>" ]	[ "<title>Results</title>", "<p> A total of 1428 studies were identified through a search of databases and gray literature on the subject of food security in sanctions. After excluding 861 duplicate and unrelated papers, we found 240 studies that assessed the status of food security in countries exposed to sanctions. After the full-text review, 204 were completely excluded because of duplication of data, not having required data, and the very low quality of the article. Of the remaining 36 publications in the review, most papers (n = 36) belonged to Iran (n = 8), followed by Cuba (n = 8), Russia (n = 7), Iraq (n = 7), and Haiti (n = 6), respectively. Figure S1 (##SUPPL##1##Supplementary file 2##) shows the process of searching for and selecting appropriate articles in this systematic review.</p>", "<p> Most of the studies were based on the existing routine data gathered in the imposed countries. Only three studies reported findings from interviews with experts and informants (1 in Iraq and 2 in Cuba) and another one in Iraq conducted document analysis. Review findings on the impact of economic sanctions on food and nutrition security and coping strategies against sanctions based on the imposed countries are presented as follows in ##TAB##0##Tables 1##-##TAB##4##5##.</p>", "<title> Haiti</title>", "<p> The embargo on Haitian exports was instituted by the Organization of American States in 1991 and partially lifted by the United States in February 1992.<sup>##REF##8086913##8##</sup> Initial sanctions froze the Haiti government’s assets in the United States and subsequent sanctions included more bans on imports and exports (excluding humanitarian goods). Sanctions were only lifted in 1994 after a re-establishment of the elected government.<sup>##UREF##0##1##</sup></p>", "<p> In Haiti, the price of basic foodstuffs rose fivefold from 1991 to 1993, unemployment increased quickly, and the export of mangoes decreased, on which many poor people depended. The national currency depreciated sharply and inflation hit hard. The estimated rate of low birth weight increased from 10% to 15% of infants. In addition, 7.8% of children under the age of five suffer from acute malnutrition compared to 3.4% in 1990. One of the important factors in increasing malnutrition was the absence of the mother at home due to economic activity. This has led to less attention being paid to breastfeeding, weaning foods for young children, and caring for sick children. During the sanctions, non-governmental organizations and governments performed key tasks outside government structures to prevent the legitimacy of the military regime. Many good employees left the government at that time and never returned. This has left Haiti with a weak infrastructure.<sup>##UREF##0##1##</sup></p>", "<title> Iraq</title>", "<p> Sanctions on all items imported into Iraq except drugs began on August 6, 1990. Following the Gulf War in January and February 1991, sanctions were reaffirmed by the United Nations, and Iraq was allowed to import food in addition to medicine. Humanitarian organizations imported only 5% of the medicines and foodstuffs they deemed necessary for Iraq because their demands were not met by hostile governments. During these years, access to food to buy in the country has decreased and the power of poverty and reduced nutrition has increased and children under 2 years old are most affected. Due to the destruction of many infrastructures and the unemployment of a large number of people, despite the lifting of sanctions, many of them still depend on imports and rations produced by the government to make a living.<sup>##UREF##2##5##</sup></p>", "<title> Russia</title>", "<p> At the beginning of 2014, Russia was embargoed and had to retaliate and did not allow imports of meat and dairy products, vegetables, fruits, and fish from the United States, Canada, Australia, Norway, and the European Union states. Despite the increase in the growth of domestic production of agricultural products, its effect on food availability was offset by a decrease in imports following the introduction of general and specific commodity sanctions. The price of red meat and milk for consumers increased due to reduced economic access, and consequently, food insecurity increased from 2013 to 2015. To counter the effects of sanctions on the nutritional status of the Russian people, the Russian Food Security Doctrine was established as a general framework for agricultural policy in which minimum targets for the domestic production of products such as potatoes, dairy products, cereals, and meat were established.<sup>##UREF##15##25##</sup> The impact of Russian sanctions and stop trading on the economy, finance, and food availability of other countries has also been reported in some articles<sup>##UREF##27##44##,##UREF##28##45##</sup> which were not considered as the aim of the present review and so they were excluded.</p>", "<title> Cuba</title>", "<p> The tightening of the US economic embargo in 1992 may have an unintended but profound effect on the health and nutrition of vulnerable populations in Cuba.<sup>##REF##10644277##46##</sup> The high prevalence of optic neuropathy from 1991 to mid-1993 in Cuba, has been attributed to an interaction of some toxins, in combination with nutritional deficiency, too.<sup>##REF##7936221##47##, ####REF##7872589##48##, ##REF##9648115##49##, ##REF##8629731##50##, ##REF##8108040##51####8108040##51##</sup></p>", "<p> Cuba’s focus on high-quality training, universal access to care, heightened vigilance for breakdowns in the social safety net, and judicious use of scarce goods shows, once again, that remarkably good health outcomes are possible if the few medical resources are put to the best use.<sup>##REF##9065219##28##,##REF##8942780##52##</sup></p>", "<title> Iran</title>", "<p> Major sanctions against Iran were formed after the Islamic Revolution of 1957, after the occupation of the US Embassy in Tehran, and intensified following the challenge to Iran’s nuclear program. Iran’s nuclear program has faced various sanctions since 1996; but despite the diversity and multiplicity of sanctions, for reasons such as the gradual and permanent nature of sanctions, the existence of oil revenues, adoption of import substitution strategy, global competition, lack of full compliance of independent emerging economies with sanctions, and foreign banking, their effects have diminished.<sup>##UREF##24##41##</sup></p>", "<p> Few studies wad studied the impact of previous rounds of sanctions on the nutritional status of Iranians. A systematic review of Kokabisaghi showed that the sanctions on Iran have lowered the ability of Iranians to access the necessities of a standard life such as nutritious food and healthcare as a result of the devaluation of the national currency, increased inflation, and unemployment. These adverse effects are more severe in poor people, patients, women, and children.<sup>##REF##29764102##39##</sup></p>", "<p> The main strategies in the agricultural sector to counter sanctions are to meet the country’s food needs, support domestic production and reduce dependence, especially in the cereal, seed, livestock, and poultry industries using research and new technologies (Unpublished data).</p>", "<title> Other Countries</title>", "<p> Sanctions, as a tool of coercive foreign policy, have been imposed on several other nations, such as North Korea, Libya, Venezuela, Sudan, Sierra Leone, Burundi, and Malawi, the apartheid government of South Africa, and former Yugoslavia, over the past few decades. However, no study was found on the impact of sanctions on food and nutrition security that was eligible for inclusion in the current systematic review. Effects of the economic sanctions on food and nutrition security and strategies to cope with them based on the review findings were summarized in Figure.</p>" ]	[ "<title>Discussion</title>", "<p> The history of sanctions returns to the First World War, in which Germany was subject to a shipping embargo by the Allied forces. As a result of the increased risk of deprivation, German children suffered severe malnutrition, and due to the blockade working-class children suffered the most.<sup>##UREF##29##53##, ####UREF##30##54##, ##UREF##31##55####31##55##</sup> So, sanctions have been interpreted as a weapon ever since. The US government tried to prohibit the sale of grain to the Soviet Union before 1971 and to embargo all grain sales to the Soviets in 1999.<sup>##UREF##32##56##,##UREF##33##57##</sup> More recently, the United Nations and the United States have, however, not planned for any economic sanctions on Ethiopia and Eritrea, which could compel both countries to de-escalate, because these sanctions would hurt the people of both countries which are highly dependent on food aides from international organizations.<sup>##UREF##34##58##,##UREF##35##59##</sup></p>", "<p> Targeted regimes and their populations may experience multiple political consequences, such as weakening some regimes and strengthening others. Economic sanctions may also influence conflicts and security in targeted states. The intensity of such impacts varies even for targets, often depending on the internal dynamics of the targeted states and their relations with other countries. Sanction threats, types of sanctions, and their senders are important for the domestic politics of targets, and threats of especially multilateral sanctions increase political activity in targeted states due to their signaling effect of outside support to opposition.<sup>##UREF##36##60##, ####REF##28289471##61##, ##UREF##37##62####37##62##</sup></p>", "<p> A review by Gutmann et al found that UN sanctions reduce life expectancy by 1.2–1.4 years and US sanctions by 0.4–0.5 years. Increased child mortality and deaths from cholera, along with declining public health expenditures, have been the main reason for the decline in life expectancy. Women are heavily affected by sanctions, too. There are concerns in the world about the undue effects of economic sanctions on human rights, especially children. Economic sanctions against countries are inconsistent with the United Nations Convention on the Rights of the Child, which deals with children’s rights to access healthcare, social welfare, and education.<sup>##UREF##38##63##</sup> Qualitative research based on two countries’ case studies found that sanctions negatively affect the availability of food and clean water. These findings are corroborant with quantitative ones.<sup>##REF##24236359##2##,##REF##9065219##28##</sup> Qualitative information is essential for developing useful causal models. Key informants from the social programs or data collection agencies already have a detailed understanding of which variables are related and the nature of their influence on each other.<sup>##UREF##39##64##</sup></p>", "<p> There is a growing policy consensus that economic sanctions are powerful tools to cope with major foreign policy crises. However, the real effectiveness of sanctions, particularly targeted sanctions and the circumstances in which policy change induce in sanctioned countries are in question.<sup>##UREF##40##65##</sup> However, studies in different countries exposed to sanctions indicate deteriorating food security and nutritional status of the people particularly poor and vulnerable groups. These effects are mainly mediated by the increase in unemployment and food prices, decrease in food imports and purchasing power, and ultimately poverty increase.<sup>##REF##29764102##39##</sup> The impact of sanctions on poverty (<italic toggle=\"yes\">a</italic>) increases with the severity of sanctions, (<italic toggle=\"yes\">b</italic>) is larger for multilateral sanctions than for unilateral sanctions imposed by the United States, and (<italic toggle=\"yes\">c</italic>) becomes longer lasting as the poverty gap widens 3.8 percentage points in sanctioned countries compared to the control group in the first 21 years of an embargo. A slowdown in exports and imports, as well as a reduction in foreign aid, are other pathways through which US sanctions negatively affect the target’s poverty level.<sup>##UREF##41##66##</sup></p>", "<p> Analysis of household expenditure data showed that — despite efforts of the agricultural sector — production, supply, and purchasing of milk and dairy products, red meats, and fish have decreased in both Iranian urban and rural households, especially after the cash transfer program, began the sanctions and inflation. However, the consumption of bread as the main staple food and oil remained almost unchanged.<sup>##UREF##42##67##</sup> World Food Program<sup>##UREF##43##68##</sup> also reported the marked deterioration of the macroeconomic performance of Iran following the subsidy reform in 2010 and the intensification of sanctions in 2012. Real gross domestic product (GDP) fell by 5.8% in the year 2012/2013 and inflation increased by 41.2%. Soaring food prices and subsidy cuts have directly affected the food security situation among the poor and vulnerable population. Higher infant and under 5-year’s mortality, energy, and protein deficiency, and poverty rate are also reported.</p>", "<p> Due to the role of a healthy diet (high amounts of fruits and vegetables, whole grains, legumes, low-fat milk and dairy products, and seafood) in preventing non-communicable diseases, reducing milk and dairy consumption, fish, and legumes, in the long run, can lead to increased burden of non-communicable diseases such as cardiovascular disease, hypertension, diabetes, and osteoporosis in populations under sanctions.<sup>##REF##30301145##69##, ####UREF##44##70##, ##REF##31200446##71####31200446##71##</sup></p>", "<p> Food aid can be considered as one of the strategies to reduce the effects of the embargo on the food security of embargoed countries. Despite the arguments made against the politicization of aid, mostly bilateral and multilateral aid remains tied to the political goals of rich countries. Such a link can be fragile (for example, aid is paid only if certain economic policies or political systems are adopted).<sup>##REF##12573389##11##,##UREF##45##72##</sup> On the other hand, the impact of sanctions on humanitarian action is closely related to the spread of counter-terrorism measures more broadly, which negatively affects the ability of humanitarian actors to operate. A restrictive environment for humanitarian actors, and their compounding effect leads to some challenges such as costs and delays caused by exemption procedures, restrictions on importing goods, restrictive clauses in donor agreements, fines, and prosecution.<sup>##UREF##46##73##,##UREF##47##74##</sup></p>", "<p> In Haiti, relying on international aid to maintain food security was not enough; In Iraq, the main strategy was to ration and deliver the minimum required food to all households based on the oil versus food program<sup>##UREF##0##1##</sup>; In Cuba, reinforcement of the health services system and preventing mothers and children mortality led to the death of the elderly and men<sup>##REF##9065219##28##</sup>; In Russia, self-reliance was possible due to climatic conditions. Iran tried a combination of coping strategies aiming to maintain a minimum of food required for the lower deciles was applied.</p>", "<title> Limitations</title>", "<p> Most of the studies were based on the existing routine data gathered in the imposed countries<sup>##UREF##6##16##,##UREF##7##17##</sup> and the use of both qualitative and quantitative literature is a positive attribute of this Review. The JBI Reviewer’s Manual guides to authors for the conduct and preparation of many kinds of systematic reviews and evidence syntheses. Therefore, considering the diversity of the types of studies reviewed and that the JBI Reviewer’s Manual included guidelines for almost all types of studies, we used JBI systematic reviews of mixed methods guidelines to quality assess the included studies. However, the JBI checklist is complex and detailed and its use for policy review is difficult which led to the assignment of low quality to many studies included in the review. The systematic review took longer than expected, because of the dispersion of studies and the COVID-19 pandemic made communication and sharing opinions difficult among the research team. Access to some scientific resources was limited, which makes it difficult to ensure access to all sources for a systematic review.</p>", "<p> Since at the time of this review, much time has passed since the embargo in the countries and the studies carried out on its effects (10 years or more), likely the conditions described in most of the sanctioned countries, especially for vulnerable groups have gotten worse. Furthermore, a meta-analysis does not capture much of the gray literature that captures the social context or narratives of the affected population. It is a flaw in any meta-analysis that it does not fully capture what’s going on.</p>" ]	[ "<title>Conclusion</title>", "<p> Ample evidence was found about the adverse effects of any kind of economic sanctions on the welfare, health, and food security of civilians in embargoed countries, which are mainly mediated by the increase in unemployment and food prices, decrease in food imports and, purchasing power. Because the increasing rate of poverty caused by sanctions affects particularly the most disadvantaged and vulnerable groups, planning to improve food security and provide support packages for these groups (eg, women and children in low-income households) seems essential.</p>", "<p> The most important strategies to improve food security in countries under economic sanctions can be summarized in four categories: the humanitarian assistance provided by the international community (Haiti), equity, and priority for vulnerable groups mainly by expanding the healthcare system (Cuba), adopting food ration system in the oil-for-food program and fixing the price of food baskets (Iraq), and supporting production, processing, and distributing food to consumers (import substitution and self-sufficiency in Russia), support domestic production and reducing dependency especially in staple cereals, seeds, livestock and, poultry industry using new research and technologies, direct and indirect support and compensation packages for vulnerable households (the approach of resistance economy in Iran).</p>", "<p> The effectiveness of sanctions is determined only by their political outcome, and the suffering of the people of these countries due to malnutrition in addition to their social and biological consequences is ignored.</p>" ]	[ "<p>\n<bold>Background:</bold> This review was conducted to identify the impact of economic sanctions on household food and nutrition security and policies to cope with them in countries exposed to sanctions.\n</p>", "<p><bold>Methods:</bold> The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020 were used to identify, select, appraise, and synthesize studies. Electronic databases in addition to Persian ones have been systematically searched for all related documents published until March 2022. Exclusion criteria were: lack of data related to food insecurity in countries subject to sanction and very low quality of the article. The quality of included studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal checklists. The results were presented as qualitative and quantitative syntheses.\n</p>", "<p><bold>Results:</bold> Of 1428 identified studies, 36 publications remained in the review, which belong to Iran (n=8), Cuba (n=8), Russia (n=7), Iraq (n=7), and Haiti (n=6), respectively. Declining gross domestic product (GDP), devaluation of the national currency, and the quality of food, increase in inflation, unemployment, and consumer prices, infant and under 5 years mortality, energy, and protein deficiency, and the poverty rate were reported as sanction consequences. The most important strategies to improve food security were the humanitarian assistance provided by the international community (Haiti), equity and priority for vulnerable groups mainly by expanding the healthcare system (Cuba), adopting a food ration system in the oil-for-food program, and fixing the price of food baskets (Iraq), import substitution and self-sufficiency (Russia), support domestic production, direct and indirect support and compensation packages for vulnerable households (the approach of resistance economy in Iran).\n</p>", "<p><bold>Conclusion:</bold> Due to the heterogeneity of studies, meta-analysis was not possible. Since inadequate physical and economic food access caused by sanctions affects especially disadvantaged and vulnerable groups, planning to improve food security and providing support packages for these groups seems necessary.</p>", "<p>\n<bold>Citation:</bold> Mohammadi-Nasrabadi F, Ghodsi D, Haghighian-Roudsari A, et al. Economic sanctions affecting household food and nutrition security and policies to cope with them: a systematic review. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7362. doi:10.34172/ijhpm.2023.7362</p>" ]	[ "<title>Acknowledgements</title>", "<p> This systematic review was conducted in the National Nutrition and Food Technology Research Institute (NNFTRI) of Iran in the framework of the research project entitled “Study of economic sanctions affecting household food and nutrition security, policies to cope with them and offer a supportive package in Iran” (Prospero Registration No. CRD42020191028). The authors thank the research deputy of NNFTRI and all researchers who made this review possible through their valuable studies.</p>", "<title>Ethical issues</title>", "<p> This study was approved by Ethics Committee of National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences (IR.SBMU.NNFTRI.REC.1398.053).</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This study was funded by the NNFTRI of Iran (Grant No. 99-18177).</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nEffects of the Economic Sanctions on Food and Nutrition Security and Strategies to Cope With Them Based on the Review Findings. Abbreviation: GDP, gross domestic product.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Impact of Economic Sanctions on Food and Nutrition Security and Policies to Cope With Them in Haiti Based on Included Studies in the Review\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Author, Date</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Sanction Type/Years</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Study Design</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Population, Sampling, Sample Size</bold>\n</th><th colspan=\"4\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Impact of Sanctions on Food Security</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Strategies to Cope</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Quality of the Study</bold>\n</th></tr><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Availability</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Access</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Utilization</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Stability</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Chelala, 1994<sup>##REF##8086913##8##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">United Nations sanctions</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Results from 3 national surveys</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Haitian population</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The embargo on fuel has limited most people's access to healthcare - No fuel to provide proper services to vulnerable populations in the remote regions.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Infant mortality has greatly increased.<break/>60% of children aged below 5 are estimated to be malnourished, and 3% of them have severe malnutrition.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Organize humanitarian aid under a single leadership.<break/>No improvements will be sustainable unless the political crisis would be over.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mulder-Sibanda, 1998<sup>##REF##9883076##9##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">International sanctions which became extremely stringent in 1993-1994</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Examination of the nutritional status </td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Haitian children</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Decline in GDP.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9% increase in mortality among young children corresponding to the trends in malnutrition. The prevalence of wasting almost doubled. Physical access to health services worsened. </td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Garfield, 1999<sup>##UREF##0##1##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Trade, except humanitarian goods/1991-1994 by the US and the OAS</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Data available from the Haiti population</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Agricultural production declined 20%, GNP declined by 30%. </td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The price of staple foods increased fivefold; Industry employment declined 8%; The value of the national currency plummeted and hyperinflation occurred.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Increase in low birth weight, underweight, acute and chronic malnutrition in children and adults, infant mortality.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The export of mangoes, on which many poor depended, was halted.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Humanitarian assistance by the United Nations (mainly the US); feeding programs, immunization supplies, and a humanitarian fuel program.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Gibbons and Garfield, 1999<sup>##REF##10511830##10##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic sanctions</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review data </td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">National surveillance systems, service statistics from humanitarian organizations, and special studies on employment, income, nutrition, and mortality</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Per capita gross national product declined by $ 120, or 30%.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The price of rice increased 137% and the price of corn increased 184%. Declining incomes forced people to reduce household expenditures and the quality of food were declined.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The mortality of children 1-4 years of age rose from 56 per 1000 to 61 per 1000 (measles epidemic) and infant mortality declined by 38%.<break/>Low birth weight increased from 10% to 15% due to maternal malnutrition.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Prevention of the export of $15 million of coffee and cocoa, $12 million of mangoes, and $14 million of essential oils, while it accelerated deforestation and erosion.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The international community provided Haiti with humanitarian assistance totaling an estimated $250 million, or $35 per capita.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Farmer et al, 2003<sup>##REF##12573389##11##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic sanctions and embargoes</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review existing data</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A population-based sample.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Crops were not planted because many parents, especially fathers, were in hiding.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A rise in the number of trauma cases attributable in large part to road accidents (patients have to travel long distances to receive care).</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A reduction in the availability of potable water (from 53% to 35%); Child mortality doubled; measles outbreak as a consequence of deterioration of the public health infrastructure and shortages of food, medicine, and other supplies; 22% of child deaths were associated with severe malnutrition or kwashiorkor.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The USA, other “donor nations,” and multilateral organizations promised US$ 500 million over 2-3 years in development aid to rebuild Haiti’s battered health, education, and sanitation infrastructure.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Reid et al, 2007<sup>##REF##17844931##12##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">International embargo/1991-1994</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Data systematically collected from 1989 to 1996</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Longitudinal anthropometric records on 1593 children, 24 months old or younger.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The incidence of childhood mortality and severe malnutrition were higher during the period of the embargo than in the periods before and after the embargo.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Impact of Economic Sanctions on Food and Nutrition Security and Policies to Cope With Them in Iraq Based on Included Studies in the Review\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Author, Date</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Sanction Type/Years</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Study Design</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Population, Sampling, Sample Size</bold>\n</th><th colspan=\"4\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Impact of Sanctions on Food Security</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Strategies to Cope</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Quality of the Study</bold>\n</th></tr><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Availability</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Access</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Utilization</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Stability</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Drèze and Gazdar, 1992<sup>##UREF##4##13##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Embargo on all imports to and exports except for medical purposes, and, in humanitarian circumstances, foodstuffs/1990, following the invasion of Kuwait</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Quantitative and qualitative </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Data was collected through household surveys, and a large number of interviews with household members, factory managers, United Nations personnel, relief workers, government official, etc.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Iraq’s public distribution system is remarkably comprehensive, equitable, efficient, and reliable.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The level of employment has more or less stagnated, money wages have also roughly stagnated, and prices have increased very sharply leading to short-term local shortages and speculation, quantity constraints on the supply of imported goods due to sanctions, and depreciation of the unofficial exchange rate of the Iraqi dinar.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To store adequate amounts of food (either imported from abroad or procured within the country), distribute “ration cards” to the population, and supply the agents. Food is supplied to the agents every month according to the number of “coupons” which they can produce.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Garfield, 1999<sup>##UREF##5##14##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The economic sanctions on all items except medicines/1990</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review the information from 22 field studies</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Iraqi children under five years of age.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A rapid decline in per capita product.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A rapid decline in the GDP and its most important component, export earnings from the petroleum sector led to a rapid rise in inflation and food prices for goods not purchased via ration.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Most Iraqi children survive under the social, economic, and political crises of the 1990s in Iraq but experience profound limitations on their health and wellbeing. Access to piped water is high but its quality has declined.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Implementing the oil for food program.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Garfield, 1999<sup>##UREF##0##1##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">All items imported to Iraq, except Medicines/1990-1999</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\"> Iraqi population.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Grain and meat production fell.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Purchasing power and educational achievement receded.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The energy, water, medical, and transportation infrastructure declined; Diarrhea and war-related mortality rose.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Popal, 2000<sup>##REF##11794085##15##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NR</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Health research</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">All Iraqi population.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3120 kcal energy vs. 1093 kcal (65.0% decrease); 62.5 g vs. 20.9 g Protein (64.7% decrease).</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Widespread unemployment and shortage of hard currency led to the significant erosion of purchasing power of most families.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The failure in the importation of high quantities of medical supplies led to a neutral impact on the health services. Increasing all forms of malnutrition in children, unsafe drinking water, polluted environment + poor sewage.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Oil-for-food program led to improvements in the availability of food, drug, medical supplies, the memorandum of understanding between the United Nations and Iraq, the distribution of governmental food rations.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Koc et al, 2007<sup>##UREF##2##5##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Breakdown of food distribution led to countrywide food shortage, widespread malnourishment, and pre-famine conditions in some areas.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Food accessibility decreases through overcrowding in urban areas, where growing poverty exacerbates the situation.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Malnourishment compounded with poor water quality, sanitation led to an increase of children under 5 mortality rate- anemia, vitamin A and iodine deficiency. </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Introduction of a food rationing system by the United Nations for all Iraqi residents in August 1990 to provide the essential staples.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Saleh, 2015<sup>##UREF##6##16##,##UREF##7##17##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Comprehensive</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Existing macro-economic data</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">All Iraqi population.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The calories provided per person decreased from 3200 to 2450 calories/day.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Deteriorating purchasing power of individuals.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Adopting food ration system in the oil-for-food program; Fixing the price of food baskets.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Woertz, 2019<sup>##UREF##8##18##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">UN/1991-2003<break/>Oil-for-Food Program (1996)</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Document analysis</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Iraqi archival resources and newspapers.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Electric cuts interrupted irrigation pumps and diversion of water supplies to farmers. Reduced incentives increasingly weighed on agriculture. Input price inflation and the declining terms of trade of agriculture.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Prioritization of agricultural self-sufficiency especially cereal production to break the embargo used food rationing to avert famine, and instrumentalized food trade to reward cronies and punish opponents; Public distribution system that procures and allocates food at subsidized controlled prices.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Impact of Economic Sanctions on Food and Nutrition Security and Policies to Cope With Them in Russia Based on Included Studies in the Review\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Author, Date</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Sanction Type/Years</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Study Design</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Population, Sampling, Sample Size</bold>\n</th><th colspan=\"4\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Impact of Sanctions on Food Security</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Strategies to Cope</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Quality of the Study</bold>\n</th></tr><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Availability</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Access</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Utilization</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Stability</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Kulikov et al, 2019<sup>##UREF##9##19##,##UREF##10##20##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Sanctions and the counter-embargo/2014 </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Monographic, statistical and economic methods</td><td style=\"text-align:center;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Existing data</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Decrease in imports, reduction of investments in agricultural development.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Reduce access to vegetables, fruits, the cattle meat, and dairy products.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Low consumption of milk, vegetables, and fruits; High consumption of bread, potatoes, and sugar.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Threaten the loss of food independence, adverse climatic changes. </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Growth in agricultural and food production, Import substitution Improvement of state support, the concentration of production in agricultural organizations and farmer households, development of related industries, organization of agricultural products storage, processing in the places of production, the creation of consumer cooperatives.</td><td style=\"text-align:center;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Volchkova and Kuznetsova, 2019<sup>##UREF##11##21##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Sectoral sanctions/2014</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Results of the consequences of counter-sanctions</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Existing data</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Success of import substitution (tomatoes, pork, poultry and beef), failure of import substitution (apples, cheese, fish, condensed milk, and processed meat), very expensive import substitution (sour milk, milk and butter).</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Decrease in prices and a significant increase in consumption (poultry, pork, tomatoes).</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Increase in food expenditure. </td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Support domestic producers via trade restrictions (import substitution).</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Olgarenko et al, 2019<sup>##UREF##12##22##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Food threats/2014</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Calculation of the import substitution’s composite index</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Federal districts</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Inability to use scientific and technical achievements to improve the efficiency and competitiveness of their products to modernize the production.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Poor social infrastructure, Financial and economic threats.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Low productivity.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Import substitution of food for the Russian Federation in the context of the country's food security, socio-economic development, self-sufficiency in food by the regions. </td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Boldyreva and Rudash, 2019<sup>##UREF##13##23##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic sanctions/2014</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Market-oriented economy</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Existing data</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The ability of the agricultural sector to ensure food processing of agricultural raw materials, and the population required for the full life of food products.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Complete self-sufficiency (cereals, vegetable oil, eggs, sugar), reaching soon complete self-sufficiency (meat of pigs and poultry, field vegetables), self-sufficiency in the long term (cattle meat, milk, vegetables of the protected ground).</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The customs policy of the state includes export subsidies, tariff, and non-tariff measures to protect the domestic food market from imports.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Voronin et al, 2018<sup>##UREF##14##24##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Trade restrictions/2014</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic forecasting</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Existing data</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Negative impact on the economy of the agrarian sector, slowing down the rate of economic growth, international trade turnover decreased.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The number of population with incomes below the subsistence minimum increased, the poverty level exceeded several points, a rise in the price of many food products.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A decrease in the level and quality of life of the population.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The development of agriculture, provides the population with staple foodstuffs in accordance with rational norms and medical indicators and with minimal imports of agricultural products.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Zhiryaeva, 2017<sup>##UREF##15##25##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Foodstuff imported/2014</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Existing data</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Russian citizens</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Growth in agricultural production, decline in imports.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Consumer prices rose due to reduced economic availability of meat and milk.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Import substitution necessarily led to not competitive production and a decline in the quality of food.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Support producers, import-substitution, development of the selection and genetic engineering, development of the wholesale and distribution centers, development of a financial credit system, protect consumers.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Wengle, 2015<sup>##UREF##16##26##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Food embargo/2014 </td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A significant devaluation of the ruble; the ability of Russian companies to substitute their products for imported food.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A rise in food inflation; a drop in the real income of consumers; a jump in the number of people living in poverty; the purchase of cheaper products by consumers. </td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The Russian strategy for achieving food self-sufficiency: (1) increase domestic production by super farms; (2) reduce food imports through the use of tariffs and non-tariff barriers.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T4\"><label>Table 4</label><caption><title>Impact of Economic Sanctions on Food and Nutrition Security and Policies to Cope With Them in Cuba Based on Included Studies in the Review\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Author, Date</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Sanction Type/Years</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Study Design</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Population, Sampling, Sample Size</bold>\n</th><th colspan=\"4\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Impact of Sanctions on Food Security</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Strategies to Cope</bold>\n</th><th rowspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Quality of the Study</bold>\n</th></tr><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Availability</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Access</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Utilization</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Stability</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Kuntz, 1994<sup>##REF##8150565##27##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Trade — mostly in food and medicines — by US companies/1992</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Investigate the current health situation in the country</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The American Public Health Association members.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A 'tax' of 30% on all imports which must be purchased from markets.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The dramatic increase in the price of staple goods.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The percentage of low weight births rose 23%, mortality among Cuban women rose rapidly, women with inadequate weight gains during pregnancy or with anemia rose rapidly.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The general standard of living in Cuba and the quality of health services have declined dramatically.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Extraordinary efforts to provide extra food rations to pregnant women and retool birthing procedures.</td><td style=\"text-align:center;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Garfield and Santana, 1997<sup>##REF##9065219##28##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">All US subsidiary trade, including trade in food and medicines/1989, Tightening in 1992</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Existing data and interviews</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Data from surveillance systems for nutrition, supplemented with utilization data from the national health system and interviews with health leaders.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">60% decline in Cuba's GDP, Importation of foodstuffs declined by about 50%.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Per capita protein and calorie availability declined by 25% and 18%, respectively, the high proportion of calories from refined sugar, which increased from 18% to 26%.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Under-nutrition is the major risk factor associated with an epidemic of optic neuropathy, the massive decline in available resources, a deteriorating public health infrastructure, and rising incidence rates for infectious diseases and low birth weight.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Health goods can no longer best retched to meet the needs of the entire population. Preferential access to essential goods for women and children has resulted in the creation of new vulnerable groups (adult men and the elderly).</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Only about 1200 calories are available from low-cost rationed distribution.<break/>The entire population has been provided with monthly vitamin supplements.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Chaplowe, 1998<sup>##UREF##17##29##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The tightening of the US economic embargo in 1992</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Questionnaire surveys, in addition to formal and informal interviews</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Gardeners, the community members, officials, and workers from the MINAGRI, members of non-governmental organizations, Cuban Institute of Geography and faculty from the Department of Geography at the University of Havana.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The decline in food production and imports.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Shortage of petroleum needed to transport, refrigerate and store.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The government added over 200 consumer goods to the list of rationed items and reduced the quotas of two-thirds of all rationed items. Decentralizing food production and distribution (Home gardens).</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Garfield, 1999<sup>##UREF##0##1##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Trade, 1992</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Available data from Cuba’s population.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Importation of foodstuffs declined by about 50%, milk production declined by 55%, average calorie availability (1992-1996): 3100 to 1865 kcal.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Poor nutrition and deteriorating sanitary conditions.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The dual policies of equity and priority for vulnerable groups.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Warwick, 1999<sup>##UREF##18##30##,##UREF##19##31##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Tightened existing trade embargo prevents any American from selling food or medicine to Cuba/1992</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Stifle the regrowth of the Cuban economy, by deterring foreign investment.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Reducing transportation, refrigeration, and storage costs by relocating agricultural production.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Urban agriculture, organic foods.</td><td style=\"text-align:center;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Low</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Pérez R, <break/>2009<sup>##UREF##20##32##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NR</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Policy and Practice</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NR</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Per capita daily energy intake decreased to 1863 kcal. </td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The FAO price index rose 28%.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Micronutrient deficiencies were associated with a neuropathy epidemic.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Many food staples have been sold in limited quantities to all Cuban families at subsidized prices. Land use and marketing policies are aimed at correcting insufficient, overpriced, and inconsistent supplies of fruits and vegetables and at increasing domestically-produced foodstuffs to substitute for costly imports.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Low</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Rosset et al, 2011<sup>##REF##21284238##33##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The US trade embargo</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Evaluation study</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Food production initially collapsed due to the loss of imported fertilizer, pesticides, tractors, parts, petroleum.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Food production initially collapsed (-5.1%) due to the loss of imported fertilizer, pesticides, tractors, parts, petroleum.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The ANAP used to build a grassroots agroecology movement, farming practices evolved over time and contributed to significantly increased relative and absolute production.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Drain and Barry, 2015<sup>##REF##20430999##34##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">USA Tightening the embargo/1992<break/>Ending restrictions on selling food/2000</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NR</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Food shortages.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A national epidemic of optic and peripheral neuropathy, which started was associated with malnutrition. Cuba has the highest average life expectancy, and the lowest infant and child mortality among Latin American and Caribbean countries.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Emphasis on disease prevention and primary healthcare.<break/>By educating their population about disease prevention and health promotion, the Cubans rely less on medical supplies to maintain a healthy population.<break/>A healthcare infrastructure to support primary-care medicine.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T5\"><label>Table 5</label><caption><title>Impact of Economic Sanctions on Food and Nutrition Security and Policies to Cope With Them in Iran Based on Included Studies in the Review\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Author, Date</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Sanction Type/Years</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Study Design</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Population, Sampling, Sample Size</bold>\n</th><th colspan=\"4\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Impact of Sanctions on Food Security</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Strategies to Cope</bold>\n</th><th rowspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Quality of the Study</bold>\n</th></tr><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Availability</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Access</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Utilization</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Stability</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Hejazi and Emamgholipour, 2022<sup>##REF##33160296##35##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Imposition of US sanctions against Iran in 2018</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">ITS analysis</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The average retail price of food products in Iran.</td><td style=\"border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The percentage of urban and rural households in Iran that were prone to food insecurity increased from 8.84% and 25.17% to 11.2% and 29.2%, respectively, from 2017 to 2019. </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The annual average cost of a healthy diet for a sample Iranian family of 3.3, based on the current prices is 341 866 008 IRR (US$ 2849) which is 3.6 times greater than the average amount of Iranian families spent on food last year (94 505 000 IRR or US$ 788).</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A significant increase in the prices of all food groups occurred in 2018. The highest inflation rate was observed in the vegetable, meat, and fruit groups.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Creating efficient food assistance programs by the government and the international community, founding food banks with the assistance of charities and non-governmental organizations, and participation of individuals in nutritional education programs and learning how to plan a cheap and balanced diet.</td><td style=\"text-align:center;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Rustamovich, 2020<sup>##UREF##21##36##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Increased economic sanctions in 2012</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">In 2014, Iran’s GDP fell significantly from $ 6376 to $ 5293; as the result of sanctions affecting the energy, banking, and financial sectors, since.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Inflation in Iran increased from 10.7% in 2009/2010 to 39.266% in 2013/2014, resulting in more people living below the poverty line.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High levels of unemployment.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Low</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Aloosh et al, 2019<sup>##REF##30771721##37##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic sanction/2012-2015</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Narrative review</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Data from the World Bank and the Central Bank of Iran.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">11.8% reduction in GDP growth in 2012 compared to 2011 and 14.1% increase in GDP growth in 2016 (from -1.6% to 12.5%); 40% inflation; 200% depreciation of Iranian currency; The Gini coefficient has increased from 37% to 41%.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1. More than 40% of Iran's 82 million population are living below the poverty line. 2. Unemployment increase from 10.4% in 2013 to 13.1% in 2017.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1. Active labor market programs; 2. Family support programs; 3. Provision of quality and equitable access to primary care and medications for vulnerable populations; 4. Debt relief programs.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Heidary, 2018<sup>##UREF##22##38##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">US, Security Council and European countries sanctions/2002-2017</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Longitudinal prospective study</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Urban and rural households of Iran.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Calorie supply has increased from 3094 in 2010 to 3172 in 2017. The total food security score in 2010 and 2017 was 86% and 85% in the urban and 78% and 83% in the rural areas, respectively.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">At least 10%-30% of urban households and 10%-20% of rural households received less than 2300 calories.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Cash transfer to reduce household inequality; Offer direct and indirect supportive packages for households; Supporting domestic production.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Kokabisaghi, 2018<sup>##REF##29764102##39##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic sanction/2012-2017</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Systematic review</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">55 papers.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">GDP per capita decreased by 35%; GDP per capita PPP decreased by more than 10% and the value of the national currency declined by 80%. </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The consumer price index increased from 100 to 178; The inflation rate increased from 20% to 38%; Minimum wage decreased from US$ 275.4 to US$ 155; Unemployment rate decreased from 10.5 to 11.3; About 11% of Iranians were living below the absolute poverty line and 30% under the relative poverty line in 2016.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:center;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">High</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Deputy Minister of Social Welfare, Ministry of Cooperatives, Labor and Social Welfare, 2018<sup>##UREF##23##40##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic sanctions and the US withdrawal from the UN Security Council/ from 2011 to 2018</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">6% increase in the poverty rate from 2011 to 2013; 10% increase in the poverty rate in rural areas and close to 3% in urban areas.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7% reduction in per capita expenditures of Iranian households from 2011 to 2013; Percentage of households with food poverty from 5.35 in 2011 to 9.08 in 2016; Increasing the number of households suffering from food, energy, or protein deficiency.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Minimum income guarantee program (to individuals who earn less than 50% of the approved minimum salary); Predicting the pensions of households covered by support institutions with a ratio of the minimum wage; Development of public employment; Integration of the social protection system.</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Toghyani and Derakhshan, 2015<sup>##UREF##24##41##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic sanctions/ 1978 to 2013</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Time series data.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">In long term, weak and strong sanctions had no significant impact on economic growth, but moderate sanctions with coefficient 0.024 have had a Negative impact on economic growth.</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">- Managing public opinion and insisting more on the principles and maintaining the independence of the country<break/>- Activating the domestic production capacity, strategic trade policy and seriously pursuing the approach of resistance economy<break/>- Active policy-making and diversification of the drawer exchange system<break/>- Identifying and planning to support the vulnerable groups.</td><td style=\"text-align:center;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr><tr><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Ziaei et al, 2013<sup>##UREF##25##42##,##UREF##26##43##</sup></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Economic sanction</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Cross-sectional</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">267 Rural households of Gorgan selected by stratified random sampling.<break/></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Income, employment of household head, chronic illness of one of the household members, education level of household head and spouse, household size, and access to credit had a significant effect on the nonfood coping strategy.</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The mean of the coping strategy index was 15.52.<break/><break/></td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Most households use a coping strategy of \"using less preferred and cheaper food.\"</td><td style=\"text-align:center;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medium</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Search Strategy.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 2 contains Figure S1.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: GDP, gross domestic product; GNP, gross national product; OAS, Organization of American States.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: GDP, gross domestic product; UN, United Nations; NR, not reported.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: GDP, gross domestic product; ANAP, National Association of Small Farmers; FAO, Food and Agriculture Organization; MINAGRI, Ministry of Agriculture; NR, not reported.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: GDP, gross domestic product; PPP, purchasing power parity; ITS, Interrupted time series.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7362-g001\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7362-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7362-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" Garfield R. The Impact of Economic Sanctions on Health and Well-being. London, United Kingdom: Relief and Rehabilitation Network (RRN), Overseas Development Institute; 1999. "]}, {"label": ["3"], "mixed-citation": [" Fernandezi Palacios J, Gharib Abadi K, Escamillo J. Unilateral Coercive Measures (UCMs) and Their Impacts. Venezuela: Foreign Affairs of the Bolivarian Republic of Venezuela; 2018. "]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Koc", "Jernigan", "Das"], "given-names": ["M", "C", "R"], "article-title": ["Food security and food sovereignty in Iraq: the impact of war and sanctions on the civilian population"], "source": ["Food Cult Soc"], "year": ["2007"], "volume": ["10"], "issue": ["2"], "fpage": ["317"], "lpage": ["348"], "pub-id": ["10.2752/155280107x211467"]}, {"label": ["7"], "mixed-citation": [" Aromataris E, Munn Z. Joanna Briggs Institute Reviewers\u2019 Manual. The Joanna Briggs Institute; 2017. "]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Dr\u00e8ze", "Gazdar"], "given-names": ["J", "H"], "article-title": ["Hunger and poverty in Iraq, 1991"], "source": ["World Dev"], "year": ["1992"], "volume": ["20"], "issue": ["7"], "fpage": ["921"], "lpage": ["945"], "pub-id": ["10.1016/0305-750x(92)90121-b"]}, {"label": ["14"], "mixed-citation": [" Gar\ufb01eld R. Morbidity and Mortality Among Iraqi Children from 1990 Through 1998: Assessing the Impact of the Gulf War and Economic Sanctions. New York, USA: Columbia University; 1999. "]}, {"label": ["16"], "person-group": ["\n"], "surname": ["Saleh"], "given-names": ["MM"], "article-title": ["Towards facing global famine: modeling food distribution according to Iraqi case"], "source": ["Eur Sci J"], "year": ["2015"], "volume": ["1"], "fpage": ["660"], "lpage": ["666"]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Saleh"], "given-names": ["MM"], "article-title": ["Food ration system prevented eminent famine in Iraq during 1990-2003 sanction"], "source": ["Br J Humanit Soc Sci"], "year": ["2015"], "volume": ["13"], "issue": ["2"], "fpage": ["19"], "lpage": ["24"]}, {"label": ["18"], "person-group": ["\n"], "surname": ["Woertz"], "given-names": ["E"], "article-title": ["Iraq under UN embargo, 1990-2003: food security, agriculture, and regime survival"], "source": ["Middle East J"], "year": ["2019"], "volume": ["73"], "issue": ["1"], "fpage": ["92"], "lpage": ["111"], "pub-id": ["10.3751/73.1.15"]}, {"label": ["19"], "person-group": ["\n"], "surname": ["Krivko", "Smutka", "Strielkowski"], "given-names": ["M", "L", "W"], "article-title": ["Food security and the trade via lenses of sanctions"], "source": ["J Secur Sustain Issues"], "year": ["2019"], "volume": ["8"], "issue": ["4"], "fpage": ["815"], "lpage": ["826"], "pub-id": ["10.9770/jssi.2019.8.4(22)"]}, {"label": ["20"], "person-group": ["\n"], "surname": ["Kulikov", "Minakov"], "given-names": ["IM", "IA"], "article-title": ["Food security: problems and prospects in Russia"], "source": ["Scientific Papers Series Management, Economic Engineering in Agriculture and Rural Development"], "year": ["2019"], "volume": ["19"], "issue": ["4"], "fpage": ["141"], "lpage": ["148"]}, {"label": ["21"], "person-group": ["\n"], "surname": ["Volchkova", "Kuznetsova"], "given-names": ["N", "P"], "article-title": ["How much do counter-sanctions cost: well-being analysis"], "source": ["Journal of the New Economic Association"], "year": ["2019"], "volume": ["43"], "issue": ["3"], "fpage": ["173"], "lpage": ["183"], "pub-id": ["10.31737/2221-2264-2019-43-3-9"]}, {"label": ["22"], "person-group": ["\n"], "surname": ["Olgarenko", "Ugryumova", "Kapustina", "Zamahovsky"], "given-names": ["GV", "AA", "TA", "MP"], "article-title": ["Problems and prospects of food security in the regions of the Russian Federation"], "source": ["IOP Conf Ser Earth Environ Sci"], "year": ["2019"], "volume": ["317"], "issue": ["1"], "fpage": ["012012"], "pub-id": ["10.1088/1755-1315/317/1/012012"]}, {"label": ["23"], "person-group": ["\n"], "surname": ["Boldyreva", "Rudash"], "given-names": ["IA", "JV"], "article-title": ["Customs tools to ensure food security in Russia"], "source": ["IOP Conf Ser Earth Environ Sci"], "year": ["2019"], "volume": ["272"], "issue": ["3"], "fpage": ["032127"], "pub-id": ["10.1088/1755-1315/272/3/032127"]}, {"label": ["24"], "person-group": ["\n"], "surname": ["Voronin", "Potekhin", "Chupina"], "given-names": ["B", "N", "I"], "article-title": ["Consequences of economic sanctions for food security of Russia"], "source": ["J Environ Manag Tour"], "year": ["2018"], "volume": ["9"], "issue": ["32"], "fpage": ["1799"], "lpage": ["1804"], "pub-id": ["10.14505/jemt.v9.8(32).20"]}, {"label": ["25"], "person-group": ["\n"], "surname": ["Zhiryaeva"], "given-names": ["EV"], "article-title": ["Food caught in the sanctions war: is food security a casualty?"], "source": ["Administrative Consulting"], "year": ["2017"], "volume": ["9"], "issue": ["9"], "fpage": ["447"], "lpage": ["133"], "pub-id": ["10.22394/1726-1139-2017-9-117-133"]}, {"label": ["26"], "person-group": ["\n"], "surname": ["Wengle"], "given-names": ["S"], "article-title": ["The domestic effects of the Russian food embargo"], "source": ["Demokratizatsiya"], "year": ["2016"], "volume": ["24"], "issue": ["3"], "fpage": ["281"], "lpage": ["289"]}, {"label": ["29"], "person-group": ["\n"], "surname": ["Chaplowe"], "given-names": ["SG"], "article-title": ["Havana\u2019s popular gardens: sustainable prospects for urban agriculture"], "source": ["Environmentalist"], "year": ["1998"], "volume": ["18"], "issue": ["1"], "fpage": ["47"], "lpage": ["57"], "pub-id": ["10.1023/a:1006582201985"]}, {"label": ["30"], "person-group": ["\n"], "surname": ["Warwick"], "given-names": ["H"], "article-title": ["Cuba\u2019s organic revolution"], "source": ["Ecologist"], "year": ["1999"], "volume": ["29"], "issue": ["8"], "fpage": ["457"], "lpage": ["460"]}, {"label": ["31"], "person-group": ["\n"], "surname": ["Pe\u00f1a-D\u00edaz"], "given-names": ["J"], "article-title": ["Cuba\u2019s urban landscape needs a second round of innovation for health"], "source": ["MEDICC Rev"], "year": ["2015"], "volume": ["17"], "issue": ["3"], "fpage": ["48"], "pub-id": ["10.37757/mr2015.v17.n3.10"]}, {"label": ["32"], "person-group": ["\n"], "surname": ["P\u00e9rez"], "given-names": ["R"], "article-title": ["The public health sector and nutrition in Cuba"], "source": ["MEDICC Rev"], "year": ["2009"], "volume": ["11"], "issue": ["4"], "fpage": ["6"], "lpage": ["8"]}, {"label": ["36"], "person-group": ["\n"], "surname": ["Rustamovich"], "given-names": ["KM"], "article-title": ["The impact of economic sanctions on well-being of vulnerable populations of target countries"], "source": ["Int J Econ Finance Sustain Dev"], "year": ["2019"], "volume": ["1"], "issue": ["1"], "fpage": ["17"], "lpage": ["20"]}, {"label": ["38"], "person-group": ["\n"], "surname": ["Heidary"], "given-names": ["K"], "article-title": ["Evaluation the impact of US sanctions on food security in Iranian households (Persian)"], "source": ["Social Security Journal"], "year": ["2018"], "volume": ["14"], "issue": ["3"], "fpage": ["35"], "lpage": ["52"]}, {"label": ["40"], "person-group": ["\n"], "surname": ["Deputy Minister of Social", "Ministry of", "Labour and Social"], "given-names": ["Welfare", "Cooperatives", "Welfare"], "article-title": ["Welfare programs to mitigate the effects of sanction (Persian)"], "source": ["Social Security Journal"], "year": ["2018"], "volume": ["14"], "issue": ["3"], "fpage": ["15"], "lpage": ["34"]}, {"label": ["41"], "person-group": ["\n"], "surname": ["Toghyani", "Derakhshan"], "given-names": ["M", "M"], "article-title": ["Analysis of the factors of impact of economic sanctions on Iran and solutions to cope with it (Persian)"], "source": ["Rahbord"], "year": ["2015"], "volume": ["23"], "issue": ["4"], "fpage": ["115"], "lpage": ["146"]}, {"label": ["42"], "mixed-citation": [" Ziaei SM, Shirani Bidabadi F, Eshraghi F, Keramatzadeh A. Application of nonfood coping strategies in assessing in food security in rural areas of Gorgan. Agricultural Economics Research 2013;5(3):83-97. [Persian]. "]}, {"label": ["43"], "mixed-citation": [" Ziaei SM, Shirani Bidabadi F, Eshraghi F, Keramatzadeh A. Study of Food Security Situation in Rural Areas of Gorgan County in Economic Sanction Condition. International E-Conference on Economy Under Sanctions; 2013; Babolsar, Iran, The University of Mazandaran. "]}, {"label": ["44"], "mixed-citation": [" Korhonen I, Simola H, Solanko L. Sanctions, Counter-Sanctions and Russia: Effects on Economy, Trade and Finance. Helsinki, Finland: Bank of Finland Institute for Economies in Transition (BOFIT); 2018. "]}, {"label": ["45"], "person-group": ["\n"], "surname": ["Fedoseeva", "Herrmann"], "given-names": ["S", "R"], "article-title": ["The price of sanctions: an empirical analysis of German export losses due to the Russian agricultural ban"], "source": ["Can J Agric Econ"], "year": ["2019"], "volume": ["67"], "issue": ["4"], "fpage": ["417"], "lpage": ["431"], "pub-id": ["10.1111/cjag.12194"]}, {"label": ["53"], "person-group": ["\n"], "surname": ["Cox"], "given-names": ["ME"], "article-title": ["Hunger games: or how the allied blockade in the First World War deprived German children of nutrition, and allied food aid subsequently saved them"], "source": ["Econ Hist Rev"], "year": ["2015"], "volume": ["68"], "issue": ["2"], "fpage": ["600"], "lpage": ["631"], "pub-id": ["10.1111/ehr.12070"]}, {"label": ["54"], "person-group": ["\n"], "surname": ["Mah\u00e9"], "given-names": ["LP"], "article-title": ["Is the issue of European self-sufficiency in vegetal proteins definitely obsolete?"], "source": ["Ol Corps Gras Lipides"], "year": ["2005"], "volume": ["12"], "issue": ["3"], "fpage": ["196"], "lpage": ["202"], "pub-id": ["10.1051/ocl.2005.0196"]}, {"label": ["55"], "person-group": ["\n"], "surname": ["Schmidt"], "given-names": ["T"], "article-title": ["Weapons embargo and war trade during the middle ages"], "source": ["Vierteljahrschr Soz Wirtschaftsgesch"], "year": ["2006"], "volume": ["93"], "issue": ["1"], "fpage": ["23"], "lpage": ["33"]}, {"label": ["56"], "person-group": ["\n"], "surname": ["Okaiyeto"], "given-names": ["PO"], "article-title": ["Embargoes and corporate goals"], "source": ["Food Policy"], "year": ["1983"], "volume": ["8"], "issue": ["2"], "fpage": ["154"], "pub-id": ["10.1016/0306-9192(83)90007-6"]}, {"label": ["57"], "person-group": ["\n"], "surname": ["Lindell"], "given-names": ["E"], "article-title": ["US\u2014Soviet grain embargoes: regulating the MNCs"], "source": ["Food Policy"], "year": ["1982"], "volume": ["7"], "issue": ["3"], "fpage": ["240"], "lpage": ["246"], "pub-id": ["10.1016/0306-9192(82)90061-6"]}, {"label": ["58"], "person-group": ["\n"], "surname": ["Cella"], "given-names": ["J"], "article-title": ["Line in the sand: the Ethio-Eritrean border"], "source": ["Harvard Int Rev"], "year": ["2005"], "volume": ["27"], "issue": ["2"], "fpage": ["6"], "lpage": ["7"]}, {"label": ["59"], "person-group": ["\n"], "surname": ["Bereketeab"], "given-names": ["R"], "article-title": ["The morality of the UN Security Council sanctions against Eritrea: defensibility, political objectives, and consequences"], "source": ["Afr Stud Rev"], "year": ["2013"], "volume": ["56"], "issue": ["2"], "fpage": ["145"], "lpage": ["161"], "pub-id": ["10.1017/asr.2013.46"]}, {"label": ["60"], "person-group": ["\n"], "surname": ["Madani"], "given-names": ["K"], "article-title": ["Have international sanctions impacted Iran\u2019s environment?"], "source": ["World"], "year": ["2021"], "volume": ["2"], "issue": ["2"], "fpage": ["231"], "lpage": ["252"], "pub-id": ["10.3390/world2020015"]}, {"label": ["62"], "person-group": ["\n"], "surname": ["\u00d6zdamar", "Shahin"], "given-names": ["\u00d6", "E"], "article-title": ["Consequences of economic sanctions: the state of the art and paths forward"], "source": ["Int Stud Rev"], "year": ["2021"], "volume": ["23"], "issue": ["4"], "fpage": ["1646"], "lpage": ["1671"], "pub-id": ["10.1093/isr/viab029"]}, {"label": ["63"], "person-group": ["\n"], "surname": ["Gutmann", "Neuenkirch", "Neumeier"], "given-names": ["J", "M", "F"], "article-title": ["Sanctioned to death? The impact of economic sanctions on life expectancy and its gender gap"], "source": ["J Dev Stud"], "year": ["2021"], "volume": ["57"], "issue": ["1"], "fpage": ["139"], "lpage": ["162"], "pub-id": ["10.1080/00220388.2020.1746277"]}, {"label": ["64"], "mixed-citation": [" Bessler M, Garfield R, Mc Hugh G. Sanctions Assessment Handbook: Assessing the Humanitarian Implications of Sanctions. New York: United Nations, Inter-Agency Standing Committee (IASC); 2004. "]}, {"label": ["65"], "person-group": ["\n"], "surname": ["Peksen"], "given-names": ["D"], "article-title": ["When do imposed economic sanctions work? A critical review of the sanctions effectiveness literature"], "source": ["Def Peace Econ"], "year": ["2019"], "volume": ["30"], "issue": ["6"], "fpage": ["635"], "lpage": ["647"], "pub-id": ["10.1080/10242694.2019.1625250"]}, {"label": ["66"], "person-group": ["\n"], "surname": ["Neuenkirch", "Neumeier"], "given-names": ["M", "F"], "article-title": ["The impact of US sanctions on poverty"], "source": ["J Dev Econ"], "year": ["2016"], "volume": ["121"], "fpage": ["110"], "lpage": ["119"], "pub-id": ["10.1016/j.jdeveco.2016.03.005"]}, {"label": ["67"], "mixed-citation": [" Mohammadi-Nasrabadi F, Ghodsi D. Final Report of \u201cAssessment and Analysis of Food Market in the Recent Decade in Iran (from 2006 to 2016).\u201d Tehran, Iran: National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences; 2019. "]}, {"label": ["68"], "mixed-citation": [" World Food Program. Food and Nutrition Security in Iran. Tehran, Iran, WFP Iran Country Office; 2016. "]}, {"label": ["70"], "person-group": ["\n"], "surname": ["Mirmiran", "Fallah Ghohroudy", "Hosseinpour Niazi", "Ahmadi", "Nayeri", "Azizi"], "given-names": ["P", "A", "S", "B", "F", "F"], "article-title": ["Dietary patterns and non communicable disease among Iranian women: a systematic review"], "source": ["Womens Health Bull"], "year": ["2014"], "volume": ["1"], "issue": ["3"], "fpage": ["e21358"], "pub-id": ["10.17795/whb-21358"]}, {"label": ["72"], "mixed-citation": [" Kim JY, Millen JV, Irwin A, Gershman J. Dying for Growth: Global Inequality and the Health of the Poor. Monroe, Maine: Common Courage Press; 2000. "]}, {"label": ["73"], "mixed-citation": [" Debarre A. Safeguarding Humanitarian Action in Sanctions Regimes. New York: International Peace Institute; 2019. "]}, {"label": ["74"], "mixed-citation": [" Huv\u00e9 S, Brubaker R, Day A, Hud\u00e1kov\u00e1 Z. Enforcing UN Sanctions and Protecting Humanitarian Action: Towards a Coherent and Consistent Approach. New York: United Nations University; 2022. "]}]	{ "acronym": [], "definition": [] }	74	CC BY	no	2024-01-13 00:02:15	Int J Health Policy Manag. 2023 Aug 5; 12:7362	oa_package/86/b4/PMC10590471.tar.gz
PMC10592353	38211305	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"westjmsurg139198-0067\" id=\"sp1\" content-type=\"scanned-page\" xlink:role=\"69\" position=\"float\"/>", "<graphic xlink:href=\"westjmsurg139198-0068\" id=\"sp2\" content-type=\"scanned-page\" xlink:role=\"70\" position=\"float\"/>", "<graphic xlink:href=\"westjmsurg139198-0069\" id=\"sp3\" content-type=\"scanned-page\" xlink:role=\"71\" position=\"float\"/>", "<graphic xlink:href=\"westjmsurg139198-0070\" id=\"sp4\" content-type=\"scanned-page\" xlink:role=\"72\" position=\"float\"/>", "<graphic xlink:href=\"westjmsurg139198-0071\" id=\"sp5\" content-type=\"scanned-page\" xlink:role=\"73\" position=\"float\"/>", "<graphic xlink:href=\"westjmsurg139198-0072\" id=\"sp6\" content-type=\"scanned-page\" xlink:role=\"74\" position=\"float\"/>" ]	[]	[]	{ "acronym": [], "definition": [] }	0	CC0	no	2024-01-13 00:02:15	West J Med Surg. 1855 Jan; 3(1):69-74	oa_package/c1/e1/PMC10592353.tar.gz
PMC10631038	37940953	[ "<title>Introduction</title>", "<p id=\"Par14\">Fluid administration in the operating room is a cornerstone of perioperative hemodynamic optimization [##UREF##0##1##–##UREF##1##4##], and its titration is obtained by adopting the fluid challenge (FC) to assess preload dependency and avoid fluid overload. In patients under mechanical ventilation, dynamic indices such as stroke volume variation (SVV) and pulse pressure variation (PPV) reliably predict the effect of FC because the fixed and repetitive inspiratory and expiratory pressure changes affect right ventricle’s preload, afterload and, hence, stroke volume (SV).</p>", "<p id=\"Par15\">In the last decade, different aspects of the use of PPV and SVV in the operating room have been further investigated, providing clinically relevant implications. First of all, PPV and SVV reliability is affected by specific validity criteria including a tidal volume (Vt) > 8 ml/kg, a normal right ventricle’s function, the absence of heart arrythmias, an heart rate/respiratory rate ratio > 3.6 and an unimpaired respiratory mechanics [##REF##25658489##5##–##REF##15754196##7##], becoming clinically useful only below or above a grey zone of uncertainty [##REF##21705869##8##]. The majority of these criteria are usually respected in the operating room, with the exception of a protective Vt, which seems to be associated with better outcomes [##UREF##2##9##] and is now suggested as standard ventilation in the operating room [##REF##25978325##10##]. This is clinically meaningful, since reducing the average Vt adopted in the operating room, also the threshold adopted in the past to stratify fluid responders and non-responders (i.e. 13% [##REF##30300177##11##]) may be changed.</p>", "<p id=\"Par16\">On the contrary, in the operating room other factors associated to the type of surgery may impact a lot on PPV and SVV reliability, such as the type of anesthesia adopted, the position of the patient, the use of laparoscopy (LPS) and the opening of the abdomen or the chest.</p>", "<p id=\"Par17\">As second, the impact of different determinants of the FC itself (i.e. the volume, the rate, the type of fluid used and the threshold to define fluid responsiveness [##REF##34709017##12##–##REF##34895718##14##]), have been further investigated and, as consequence, the value of PPV and SVV in studies adopting different types of FC may be inconsistent.</p>", "<p id=\"Par18\">We, therefore, conducted a comprehensive systematic review and metanalysis with the primary aim of investigating the performance of PPV and SVV in different surgical setting, stratifying the patients according to chest/abdomen opening, intraoperative position, and the use of LPS.</p>", "<p id=\"Par19\">Secondarily, we assessed the impact of other potential factors influencing the reliability of these indices in predicting fluid responsiveness in mechanically ventilated patients in the different surgical settings, specifically FC characteristics, the modality of ventilation and the type of anestestia.</p>" ]	[ "<title>Material and methods</title>", "<p id=\"Par20\">We adhered to the <italic>Preferred Reporting Items for Systematic Reviews and Meta-Analysis – Protocols</italic> (PRISMA-P) guidelines [##REF##19622551##15##] (Additional file ##SUPPL##0##1##: Table S1). The protocol of this study was prospectively registered with the <italic>International Prospective Register of Systematic Reviews</italic> (PROSPERO) (CRD42022379120).</p>", "<title>Data sources and search strategy</title>", "<p id=\"Par21\">A systematic literature search was performed including PUBMED® and EMBASE® and the Cochrane Controlled Clinical trials register databases, by using the following terms: 'pulse pressure variation' OR 'stroke volume variation' OR 'fluid responsiveness' AND (surgery) OR (surgical patients) (Additional file ##SUPPL##0##1##: Table S2).</p>", "<p id=\"Par22\">Articles written in English, enrolling at least 10 adult, mechanically ventilated patients undergoing elective surgery and published from 1st January 2000 until 1st March 2023 in indexed scientific journals were considered. Editorials, commentaries, letters to editor, opinion articles, reviews, and meeting abstracts were excluded. References of selected papers, review articles, commentaries, and editorials on this topic were also reviewed to identify other studies of interest missed during the primary search. When multiple publications of the same research group/center described potentially overlapping cohorts, the most recent publications were selected.</p>", "<p id=\"Par23\">We included only those studies clearly stating the threshold for defining fluid responsiveness as SV (or its surrogates) increase above a predefined limit. Articles including data collected in the postoperative period were excluded, while data recorded in the post-operative ICU just after the end of the surgery were included. Finally, we excluded studies performed during liver transplantation, in pediatric population and during pregnancy/labor.</p>", "<title>Data abstraction</title>", "<p id=\"Par24\">Three couples of examiners independently performed the evaluation of titles and abstracts. The articles were then subdivided into three subgroups: “included” and “excluded” (if the two examiners agreed with the selection) or “uncertain” (in case of disagreement). In the case of “uncertain” classification, discrepancies were resolved by further examination performed by two expert authors (A.M. and M.Ce.). We used a standardized electronic spreadsheet (Microsoft Excel, V 14.4.1; Microsoft, Redmond, WA) to extract data from all included studies, recording: trial characteristics (<italic>i.e.</italic> number of centers, country), patient population (<italic>i.e.</italic> demographics, type of surgery, baseline illness severity scores), intraoperative monitoring and interventions (<italic>i.e.</italic> mechanical ventilation characteristics, monitoring technology used, FC characteristics).</p>", "<title>Risk of bias assessment in the included studies</title>", "<title>Assessment of risk of bias in the included studies</title>", "<p id=\"Par25\">The QUADAS-2 scale was used to assess the risk of bias of the included studies [##REF##22007046##16##]. Two expert authors (A.M. and M.Ce.) independently examined the studies using predefined criteria, which are reported in the Additional file ##SUPPL##0##1##: Table S4:</p>", "<p id=\"Par26\">For each criterion, the risk of bias was judged as high (3 points), unclear (2 points) or low (1 point). If the answers to all signaling questions for a domain were “yes,” then risk of bias was judged as “low”. If any signaling question was answered “no,” the potential risk of bias was defined as indicted in Additional file ##SUPPL##0##1##: Table S4. The sum of these points was used to calculate the global risk of bias. Studies were included in the highest risk of bias group if the sum of the points obtained by the risk of bias and applicability judgment assessment, was higher than the median value for all the studies [##REF##31358025##17##].</p>", "<title>Statistical analysis</title>", "<p id=\"Par27\">Descriptive analysis was carried out: the statistical unit of observation for all the selected variables was the single study and not the patient. Quantitative variables were summarized with means (standard deviations, SD) or medians (inter-quartile ranges, IQR) according to their distribution.</p>", "<p id=\"Par28\">Patients were stratified in five main groups, according to the surgical characteristics at inclusion: (1) Patients enrolled with closed abdomen and chest; (2) Patients enrolled with closed abdomen and open chest (including sternotomy and thoracotomy); (3) Patients enrolled with open abdomen and closed chest; (4) LPS; (5) Prone position.</p>", "<p id=\"Par29\">We adopted a metanalysis pooling of aggregate data with random effects models using the common-effect inverse variance model. The area under the curve (AUC) of pooled receiving operating characteristics (ROC) curves was reported with 95% confidence intervals (95%CI). In-between study heterogeneity was assessed with the I<sup>2</sup> statistic. According to Higgins et al., I<sup>2</sup> values around 25%, 50%, and 75% represented no, low, moderate, and high heterogeneity [##REF##12111919##18##]. Unless stated otherwise, we considered the number of the FC performed equal to the number of patients included in the study. In the studies comparing two different surgical settings in the same population (i.e., open chest/closed chest, supine/prone etc.) data of the two subgroups of patients were separately analyzed for the purpose of the ROC curve analysis. Missing data in AUC reporting was considered an exclusion criterion from metanalysis.</p>", "<p id=\"Par30\">For each of these five subgroups we performed a meta-regression considering the following independent variables: 1) Tidal volume (Vt) ≥ 8 ml/kg; 2) Positive end-expiratory pressure (PEEP) level (<italic>i.e.,</italic> PEEP = 0 cmH<sub>2</sub>O; PEEP = 0–5 cmH<sub>2</sub>O; PEEP > 5 cmH<sub>2</sub>O); 3) total intravenous anesthesia (TIVA); 4) FC using colloids vs crystalloids; 5) volume of FC administration > 4 ml/kg; 6) rate of FC administration > 15 min).</p>", "<p id=\"Par31\">In case of mixed populations (i.e. receving TIVA anesthesia/alogenates or undergoing LPS /laparotomy), the subgroup including at least 75% of the population was used for the final classification of the study.</p>", "<p id=\"Par32\">The statistical analysis was performed using the software STATA® version 17 (StataCorp, College Station, TX, USA) and Medcalc (Software 8.1.1.0; Mariakerke, Belgium). For all comparisons, we considered significant <italic>p</italic> values < 0.05.</p>" ]	[ "<title>Results</title>", "<p id=\"Par33\">The electronic search identified 3,300 potentially relevant titles and 59 full-text manuscripts were finally selected. A detailed description of the selection process is provided in Fig. ##FIG##0##1##. Overall, the included studies enrolled 2,947 patients with a median age of 61 (55–65), and 59% (46–71) were males. The median number of patients enrolled per study was 40 (26–52), overall receiving 3,870 FCs with a median number of FCs administered of 40 (25–53) for each study and a median of fluid responders of 55% (46–63), ranging from 26.9 [##REF##32863016##19##] to 91.4% [##REF##31278544##20##], and colloids have been used in 41 studies (68.3%) (Table ##TAB##0##1##).</p>", "<p id=\"Par34\">Preoperative comorbidities were reported for 2280 patients (76.1%), with cancer diagnoses being the most represented (32.7%). Surgery type was reported for 2932 patients (99.5%), with neurosurgical operations (26.4%) being the most prevalent (Additional file ##SUPPL##0##1##: Table S3). Seven studies (11.6%) enrolled only patients undergoing LPS, in 25 (42.4%) the patients received halogenate/opiate anesthesia, while in 23 (39.0%) TIVA and in the remaining 11 studies (18.6%) the type of anesthesia was mixed or unspecified.</p>", "<p id=\"Par35\">Overall, the median (IQR) QUADAS-2 score of the included studies was 9 (7 -10) and 18 studies (30.5%) were classified in the subgroup with the highest risk of bias (Additional file ##SUPPL##0##1##: Table S5).</p>", "<title>Overall pooled AUC of PPV and SVV in the included studies</title>", "<p id=\"Par36\">The pooled AUC for the PPV obtained from 52 studies was 0.77 (0.73–0.80), with a mean threshold of 10.8 (10.6–11.0) (<italic>I</italic><sup>2</sup> = 92.2%) (Additional file ##SUPPL##0##1##: Table S6).</p>", "<p id=\"Par37\">The pooled AUC for the SVV obtained from 36 studies was 0.76 (0.72–0.80), with a mean threshold of 12.1 (11.6–12.7) (<italic>I</italic><sup>2</sup> = 88.3%) (Additional file ##SUPPL##0##1##: Table S7).</p>", "<p id=\"Par38\">Overall, 19 studies (32.2%) reported the grey zone of PPV or SVV, with a median of 56% (40–62) and 57% (46–83) of patients included in this range of uncertainty, respectively.</p>", "<title>Pooled AUC and grey zone in the different PPV subgroups</title>", "<p id=\"Par39\">\n<list list-type=\"order\"><list-item><p id=\"Par40\">In the studies enrolling patients with closed chest and abdomen, the pooled AUC for PPV was 0.79 (95%CI 0.73–0.84) for a threshold of 10.9% (10.5–11.2) and a <italic>I</italic><sup>2</sup> of 92.7%. (Additional file ##SUPPL##0##1##: Figure S1); 7 studies [##REF##31094781##21##–##REF##28742783##27##] reported a median of 61.8% of patients (52–75) included in the grey zone of PPV, with a median low value of 6% (5–8) and a high value of 12% (11–17).</p></list-item><list-item><p id=\"Par41\">In the studies enrolling patients with closed chest and open abdomen, the pooled AUC for PPV was 0.79 (95%CI 0.71–0.88) for a threshold of 11.5% (11.3–11.6) and a <italic>I</italic><sup>2</sup> of 88.2%. (Additional file ##SUPPL##0##1##: Figure S2); 6 studies [##REF##21705869##8##, ##REF##23171725##25##, ##REF##31021879##26##, ##REF##27428237##28##–##REF##31846441##32##] reported a median of 43.5% (36–50) included in the grey zone of PPV, with a median low value of 7% (5–10) and a high value of 14% (12–25).</p></list-item><list-item><p id=\"Par42\">In the studies enrolling patients with closed abdomen and open chest, the pooled AUC for PPV was 0.69 (95%CI 0.59–0.78) for a threshold of 6.9% (6.7–7.11) and a <italic>I</italic><sup>2</sup> of 68.8%. (Additional file ##SUPPL##0##1##: Figure S3); 1 study [##REF##33687175##33##] reported 86.0% of patients included in the grey zone of PPV, with a low value of 5% and a high value of 19%.</p></list-item><list-item><p id=\"Par43\">Studies including patients undergoing LPS showed a pooled PPV AUC of 0.74 (95%CI 0.64–0.83), with a pooled threshold of 11.3% (10.6 – 11.9) and a I<sup>2</sup> of 60.7%. (Additional file ##SUPPL##0##1##: Figure S4); 1 study [##REF##31390982##34##] reported 26% of patients included in the grey zone of PPV, and 2 studies [##REF##31390982##34##, ##REF##29149433##35##] a median low value of 6% (6–7) and a high value of 15% (9–21).</p></list-item><list-item><p id=\"Par44\">In studies including patients in prone position, the pooled PPV AUC was 0.78 (95%CI 0.69–0.88), with a pooled threshold of 11.2% (10.9–11.5) and a <italic>I</italic><sup>2</sup> of 84.9%. (Additional file ##SUPPL##0##1##: Figure S5); 2 studies [##REF##30013353##36##, ##REF##32028416##37##] reported a median of 60.0% (58–62) included in the grey zone of PPV, with a median low value of 6% (5–6) and a high value of 11% (10–11),</p></list-item></list></p>", "<title>Pooled AUC and grey zone in the different SVV subgroups</title>", "<p id=\"Par45\">\n<list list-type=\"order\"><list-item><p id=\"Par46\">In the studies enrolling patients with closed chest and abdomen, the pooled AUC for SVV was 0.76 (95%CI 0.69–0.82) for a threshold of 10.7% (10.4–10.9) and a <italic>I</italic><sup>2</sup> of 78.4%. (Additional file ##SUPPL##0##1##: Figure S6); 1 study [##REF##31021879##26##] reported 88.5% of patients included in the grey zone of SVV, while 2 studies [##REF##33399372##30##, ##REF##29679768##31##] reported a median low value of 5% (3–7) and a high value of 15% (13–16).</p></list-item><list-item><p id=\"Par47\">In the studies enrolling patients with closed chest and open abdomen, the pooled AUC for SVV was 0.79 (95%CI 0.70–0.88) for a threshold of 10.1% (9.8–10.5) and a <italic>I</italic><sup>2</sup> of 86.2%. (Additional file ##SUPPL##0##1##: Figure S7); 3 studies [##REF##27428237##28##, ##REF##33399372##30##, ##REF##29679768##31##] reported a median of 46.0% (33.0–57.0) included in the grey zone of SVV, with a median low value of 5% (4–6) and a high value of 12% (11–15).</p></list-item><list-item><p id=\"Par48\">In the studies enrolling patients with closed abdomen and open chest, the pooled AUC for SVV was 0.72 (95%CI 0.57–0.87) for a threshold of 10.0% (9.8–10.2) and a <italic>I</italic><sup>2</sup> of 85.7%. (Additional file ##SUPPL##0##1##: Figure S8); 1 study [##REF##33687175##33##] reported 93.0% of patients included in the grey zone of SVV, with a low value of 5% and a high value of 18%.</p></list-item><list-item><p id=\"Par49\">Studies including patients undergoing LPS showed a pooled SVV AUC of 0.78 (95%CI 0.69–0.87), with a pooled threshold of 10.8% (10.4–11.3) and a <italic>I</italic><sup>2</sup> of 64.4%. (Additional file ##SUPPL##0##1##: Figure S9); 1 study [##REF##31390982##34##] reported 55.0% of patients included in the grey zone of SVV, while 3 studies [##REF##31390982##34##, ##REF##29149433##35##, ##REF##24366723##38##] reported a median low value of 7% (3–13) and a high value of 13% (6–15).</p></list-item><list-item><p id=\"Par50\">In studies including patients in prone position, the pooled SVV AUC was 0.73 (95%CI 0.64–0.83), with a pooled threshold of 10.2% (9.9–10.4) and a <italic>I</italic><sup>2</sup> of 74.9%. (Additional file ##SUPPL##0##1##: Figure S10); 1 study [##REF##32028416##37##] reported 66% of patients included in the grey zone of SVV, with a median low value of 6% and a high value of 14%.</p></list-item></list></p>", "<p id=\"Par51\">Data about pooled ROC and grey zones of the considered subgroups for PPV and SVV are summarized in the Table ##TAB##1##2##.</p>", "<title>Metaregression</title>", "<p id=\"Par52\">As shown in Table ##TAB##2##3##, the pooled AUC for PPV was positively affected by the by Vt ≥ 8 ml/kg (<italic>p</italic> < 0.001) and by the use of colloids for the FC (p < 0.001) in the group of studies with closed chest and abdomen; the Vt ≥ 8 ml/kg (p < 0.001) was also associated to increased AUC in studies enrolling prone patients. The AUCs of these subgroups are reported in the Table ##TAB##3##4##. The was no effect of any of the considered variables on the AUC of SVV.</p>" ]	[ "<title>Discussion</title>", "<p id=\"Par53\">This systematic review and metanalysis evaluated the PPV and SVV performance in different surgical settings, updating previous papers and focusing on the role of potential factors that may be associated with better performance of the indices for predicting fluid responsiveness. Our data may be summarized as follows: (1) the overall performance of PPV and SVV in operating room in predicting fluid responsiveness is moderate, ranging close to an AUC of 0.80 only in non-LPS surgery, with closed chest, suggesting caution in the interpretation of this indices; (2) overall, the best threshold of PPV is 11%, while for the SVV is 10%. However, the minority of the studies reporting the grey zone showed that the majority of patients are patients included in this range of uncertainty, respectively; (3) a high Vt and the choice of colloids, may impact positively on PPV performance, especially among patients with closed chest and abdomen, or in prone position.</p>", "<p id=\"Par54\">PPV and SVV have been widely investigated as indices to guide fluid administration, but also as targets of a goal-directed therapy [##REF##28640019##22##]. In the operating room, most of the validity criteria affecting PPV and SVV reliability (such as low tidal volume, heart rate/respiratory rate ratio < 3.6, presence of spontaneous breathing activity, low respiratory compliance, right ventricle dysfunction) occur less frequently compared to critically ill patients. This would, in principle, improve their performance as tests for fluid responsiveness. The role of Vt has also been extensively investigated. In 2009 Marik et al. reported on an AUC of 0.93 (95% CI, 0.92–0.94) for the PPV in a small subgroup of surgical studies adopting a mean Vt > 8 ml/kg [##REF##19602972##39##]. In 2011 Zhang et al. reported an AUC of 0.94 (95% CI, 0.907–0.945) for the SVV in 8 surgical studies [##REF##21892779##40##], decreasing to 0.84 by excluding only one study on 20 patients [##REF##20035228##41##]. Similarly, Messina et al. in 2018 reported an AUC of 0.86 for PPV (10 studies) and of 0.87 for SVV (16 studies) in surgical trials with a mean Vt of 8 ml/kg [##REF##30300177##11##]. The metaregression showed that the only AUCs of the PPV in the subgroups of patients with closed chest and abdomen or in prone position were positively affected by the intraoperative use of a Vt ≥ 8 ml/kg. Although the use of an intraoperative lung-protective ventilation strategy is associated with a better outcome [##UREF##2##9##] and is now suggested as standard practice in the operating room [##REF##25978325##10##], this limits the assessment of fluid responsiveness in surgical patients by means of dynamic indices and, not surprisingly, pooling data from recent studies show an overall worse performance of PPV, as compared to the past.</p>", "<p id=\"Par55\">Accordingly to the reduced Vt, also the thresholds of PPV and SVV should be reconsidered. Our results suggest a best pooled threshold for PPV (11%) and SVV (10%) both lower than 13% proposed in the past [##REF##21705869##8##]. However, these thresholds derived from ROC curve analysis may be scarcely useful in clinical practice, since it often falls within the grey zone of uncertainty. Considering the different subgroups, our results show that the range of PPV and SVV values included between the lowest 5–7% and the highest of 12–19%, should be considered with caution, suggesting the use of other functional hemodynamic tests in surgical patients for enhancing the reliability of these dynamic indices [##REF##31358025##17##].</p>", "<p id=\"Par56\">The metaregression showed that the AUC of the PPV in the subgroups of patients with closed chest and abdomen was improved by the use of colloids (<italic>p</italic> < 0.001) and, potentially, by a FC volume > 4 ml/kg (borderline effect; <italic>p</italic> = 0.05). For the SVV, these two variables showed also borderline effects (<italic>p</italic> = 0.06 and <italic>p</italic> = 0.08, respectively). Recently, it has been demonstrated that at least 4 ml/kg should be infused to effectively challenge cardiac preload [##REF##34895718##14##, ##REF##26683506##42##]. Accordingly, reducing FC volume would impact on the identification of fluid responders and, in turn, on AUC magnitude. Colloids are still adopted in the operating room, and their different persistence in the intravascular space may affect fluid responsiveness especially when the time of evaluation of FC is prolonged above 10 min (when the effect of a crystalloid FC fades[##REF##34494204##13##]).</p>", "<title>Strenghts and limitations</title>", "<p id=\"Par57\">To the best of our knowledge, this is the most updated and largest metanalysis on PPV and SVV use in the operating room. Our approach considered the physiologic characteristics of the surgical patients and not the specific type of surgery. This implies that the results may be applied to different settings (i.e. the subgroup with closed chest and abdomen may include neurosurgery, vascular non-abdominal surgery and otolaryngology surgery). Moreover, the meta-regression analysis enhanced specific variables potentially affecting PPV and SVV reliability.</p>", "<p id=\"Par58\">Regarding the limitations, despite the minority of the studies (30.5%) were classified in the subgroup with the highest risk of bias, the QUADAS-2 score, however, as any other bias score, would not perfectly fit to the design of the included studies, and it has been adapted by the authors in some domain, considering clinical of physiological variables potentially affecting FC outcome and, hence, ROC curve analysis.</p>", "<p id=\"Par59\">Moreover, the heterogeneity of the AUCs obtained from of the analyzing data ranged from 43.5 to 88.2%, implying a significant variability in the population enrolled and data presentation. Again, this is, unfortunately, a quite common problem in the field of hemodynamic for either critically ill and surgical patients as previously shown in other papers [##REF##31358025##17##, ##REF##35729632##43##]. Overall, data obtained from the meta-regression should be considered with caution, due to the small number of studies included in some subgroup.</p>", "<p id=\"Par60\">This is not a meta-analysis based on individual data and the assessment of fluid responsiveness has been evaluated by different hemodynamic tools, including echocardiography, calibrated and uncalibrated machines.</p>", "<p id=\"Par61\">The authors state some discrepancies between the final literature search, focused on PPV and SVV use in studies assessing the performance of these variables in predicting fluid responsiveness, and the original PROSPERO registration, which includes also randomized-controlled studies adopting PVV and SVV in the context of perioperative hemodynamic optimization. After an initial screening, it was clear that these studies should have been not included in the literature search, and the string has been modified, accordingly.</p>" ]	[ "<title>Conclusions</title>", "<p id=\"Par62\">The overall performance of PPV and SVV in operating room in predicting fluid responsiveness is moderate, ranging close to an AUC of 0.80 only for some subgroups of surgical patients, with a best threshold of 11% and 10%, respectively. Considering the different subgroups, the grey zone of these dynamic indices (from 5 to 7% and to 12 to 19%) is wide and should be carefully considered during the assessment of fluid responsiveness. A high Vt and the choice of colloids for the FC, may impact positively on the performance of the dynamic indices, especially among patients with closed chest and abdomen, or in prone position.</p>" ]	[ "<title>Background</title>", "<p id=\"Par1\">Pulse pressure and stroke volume variation (PPV and SVV) have been widely used in surgical patients as predictors of fluid challenge (FC) response. Several factors may affect the reliability of these indices in predicting fluid responsiveness, such as the position of the patient, the use of laparoscopy and the opening of the abdomen or the chest, combined FC characteristics, the tidal volume (Vt) and the type of anesthesia.</p>", "<title>Methods</title>", "<p id=\"Par2\">Systematic review and metanalysis of PPV and SVV use in surgical adult patients. The QUADAS-2 scale was used to assess the risk of bias of included studies. We adopted a metanalysis pooling of aggregate data from 5 subgroups of studies with random effects models using the common-effect inverse variance model. The area under the curve (AUC) of pooled receiving operating characteristics (ROC) curves was reported. A metaregression was performed using FC type, volume, and rate as independent variables.</p>", "<title>Results</title>", "<p id=\"Par3\">We selected 59 studies enrolling 2,947 patients, with a median of fluid responders of 55% (46–63). The pooled AUC for the PPV was 0.77 (0.73–0.80), with a mean threshold of 10.8 (10.6–11.0). The pooled AUC for the SVV was 0.76 (0.72–0.80), with a mean threshold of 12.1 (11.6–12.7); 19 studies (32.2%) reported the grey zone of PPV or SVV, with a median of 56% (40–62) and 57% (46–83) of patients included, respectively. In the different subgroups, the AUC and the best thresholds ranged from 0.69 and 0.81 and from 6.9 to 11.5% for the PPV, and from 0.73 to 0.79 and 9.9 to 10.8% for the SVV. A high Vt and the choice of colloids positively impacted on PPV performance, especially among patients with closed chest and abdomen, or in prone position.</p>", "<title>Conclusion</title>", "<p id=\"Par4\">The overall performance of PPV and SVV in operating room in predicting fluid responsiveness is moderate, ranging close to an AUC of 0.80 only some subgroups of surgical patients. The grey zone of these dynamic indices is wide and should be carefully considered during the assessment of fluid responsiveness. A high Vt and the choice of colloids for the FC are factors potentially influencing PPV reliability.</p>", "<p id=\"Par5\"><bold>Trial Registration:</bold> PROSPERO (CRD42022379120), December 2022. <ext-link ext-link-type=\"uri\" xlink:href=\"https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=379120\">https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=379120</ext-link></p>", "<title>Supplementary Information</title>", "<p>The online version contains supplementary material available at 10.1186/s13054-023-04706-0.</p>", "<title>Keywords</title>" ]	[ "<title>Supplementary Information</title>", "<p>\n</p>" ]	[ "<title>Acknowledgements</title>", "<p>Not applicable.</p>", "<title>Author contributions</title>", "<p>AM and MCe conceived and designed the study; AM and EM performed the data analysis; MCa, LC, GL, DB, GMM and AB performed data extraction and helped in data analysis; LF, MA and MSC helped in drafting the article and revising it critically for important intellectual content. All the authors approved the final version to be published and agreed to be accountable for all aspects of the work thereby ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.</p>", "<title>Funding</title>", "<p>This work was partially supported by “Ricerca Corrente” funding from Italian Ministry of Health to IRCCS Humanitas Research Hospital.</p>", "<title>Availability of data and materials</title>", "<p>The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.</p>", "<title>Declarations</title>", "<title>Ethical approval and consent to participate</title>", "<p id=\"Par63\">Not applicable.</p>", "<title>Consent for publication</title>", "<p id=\"Par64\">Not applicable.</p>", "<title>Competing interests</title>", "<p id=\"Par65\">Prof. Michelle Chew is a Critical Care journal editor and received travel reimbursements and speaker fees from Edwards Lifesciences and from AOP Health. Dr. Messina received travel expenses and registration for meetings, congresses, and courses and lecture fees from Vygon, Phlips, Edwards; Prof. Cecconi is a consultant for Edwards Lifesciences.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><p>Flow of the studies</p></caption></fig>" ]	[ "<table-wrap id=\"Tab1\"><label>Table 1</label><caption><p>Fluid challenge characteristics and hemodynamic monitoring in the included studies</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\">Authors</th><th align=\"left\">Year</th><th align=\"left\"><italic>n</italic></th><th align=\"left\">FCs</th><th align=\"left\">Volume infused (ml)</th><th align=\"left\">Infusion time (min)</th><th align=\"left\">Fluid type</th><th align=\"left\">Monitoring devices</th><th align=\"left\">Reference Variable</th><th align=\"left\">Responders (%)</th><th align=\"left\">Authors</th><th align=\"left\">Year</th><th align=\"left\"><italic>n</italic></th><th align=\"left\">FCs</th><th align=\"left\">Volume infused (ml)</th><th align=\"left\">Infusion time (min)</th><th align=\"left\">Fluid type</th><th align=\"left\">Monitoring devices</th><th align=\"left\">Reference Variable</th><th align=\"left\">Responders (%)</th></tr></thead><tbody><tr><td align=\"left\">Hofer C.K., et al. [##REF##16100177##44##]</td><td align=\"left\">2005</td><td align=\"left\">40</td><td align=\"left\">40</td><td align=\"left\">10 ml/kg</td><td align=\"left\">20</td><td align=\"left\">HES 6%</td><td align=\"left\">PiCCOplus</td><td align=\"left\">SV ≥ 10%</td><td char=\".\" align=\"char\">60.0</td><td align=\"left\">De Broca B., et al. [##REF##27428237##28##]</td><td align=\"left\">2016</td><td align=\"left\">60</td><td align=\"left\">60</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">CardioQ</td><td align=\"left\">SV ≥ 15%</td><td align=\"left\">62.0</td></tr><tr><td align=\"left\">Preisman S., et al. [##REF##16286349##45##]</td><td align=\"left\">2005</td><td align=\"left\">18</td><td align=\"left\">70</td><td align=\"left\">250</td><td align=\"left\">5–7</td><td align=\"left\">Colloids</td><td align=\"left\">PiCCO</td><td align=\"left\">VTI ≥ 15%</td><td char=\".\" align=\"char\">46.0</td><td align=\"left\"><p>Biais M.,</p><p>et al. [##REF##28640019##22##]</p></td><td align=\"left\">2017</td><td align=\"left\">44</td><td align=\"left\">88</td><td align=\"left\">250</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">ProAQT</td><td align=\"left\">SV ≥ 10%</td><td align=\"left\">31.8</td></tr><tr><td align=\"left\">Cannesson M., et al. [##REF##17525584##46##]</td><td align=\"left\">2007</td><td align=\"left\">25</td><td align=\"left\">25</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">PAC</td><td align=\"left\">CI ≥ 15%</td><td char=\".\" align=\"char\">60.0</td><td align=\"left\"><p>Biais M.,</p><p>et al. [##REF##27922547##23##]</p></td><td align=\"left\">2017</td><td align=\"left\">28</td><td align=\"left\">28</td><td align=\"left\">250</td><td align=\"left\"> > 10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">ProAQT</td><td align=\"left\">SV ≥ 10%</td><td align=\"left\">57.1</td></tr><tr><td align=\"left\"><p>Lee J.-H.,</p><p>et al. [##REF##17621598##47##]</p></td><td align=\"left\">2007</td><td align=\"left\">20</td><td align=\"left\">20</td><td align=\"left\">7 ml/kg</td><td align=\"left\">1mL/kg/min</td><td align=\"left\">HES 6%</td><td align=\"left\">TEE</td><td align=\"left\">SVI ≥ 15%</td><td char=\".\" align=\"char\">55.0</td><td align=\"left\"><p>Biais M.,</p><p>et al. [##REF##28742783##27##]</p></td><td align=\"left\">2017</td><td align=\"left\">41</td><td align=\"left\">41</td><td align=\"left\">250</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">ProAQT</td><td align=\"left\">SV ≥ 10%</td><td align=\"left\">51.2</td></tr><tr><td align=\"left\">Cannesson M., et al. [##REF##18349192##48##]</td><td align=\"left\">2008</td><td align=\"left\">25</td><td align=\"left\">25</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">PAC</td><td align=\"left\">CI ≥ 15%</td><td char=\".\" align=\"char\">68.0</td><td align=\"left\">Messina A., et al. [##REF##28722695##49##]</td><td align=\"left\">2017</td><td align=\"left\">46</td><td align=\"left\">46</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">MostCare</td><td align=\"left\">CI > 15%</td><td align=\"left\">41.3</td></tr><tr><td align=\"left\">Cannesson M., et al. [##REF##18522935##50##]</td><td align=\"left\">2008</td><td align=\"left\">25</td><td align=\"left\">25</td><td align=\"left\">500</td><td align=\"left\"> > 10</td><td align=\"left\">HES 6%</td><td align=\"left\">PAC</td><td align=\"left\">CI ≥ 15%</td><td char=\".\" align=\"char\">64.0</td><td align=\"left\"><p>Min J.J.,</p><p>et al. [##REF##28207430##51##]</p></td><td align=\"left\">2017</td><td align=\"left\">49</td><td align=\"left\">49</td><td align=\"left\">6mL/kg</td><td align=\"left\">≤10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">PAC</td><td align=\"left\">NA</td><td align=\"left\">42.0</td></tr><tr><td align=\"left\">Cannesson M., et al. [##REF##19151280##52##]</td><td align=\"left\">2009</td><td align=\"left\">25</td><td align=\"left\">25</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">Mixed</td><td align=\"left\">CI ≥ 15%</td><td char=\".\" align=\"char\">68.0</td><td align=\"left\"><p>Jeong D.M.,</p><p>et al. [##REF##28504996##53##]</p></td><td align=\"left\">2017</td><td align=\"left\">79</td><td align=\"left\">79</td><td align=\"left\">7mL/kg</td><td align=\"left\">30</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SVI ≥ 10%</td><td align=\"left\">37.0</td></tr><tr><td align=\"left\">Derichard A., et al. [##REF##19797246##54##]</td><td align=\"left\">2009</td><td align=\"left\">11</td><td align=\"left\">56</td><td align=\"left\">200–500</td><td align=\"left\">8–15</td><td align=\"left\">Colloids</td><td align=\"left\">Mixed</td><td align=\"left\">CI ≥ 15%</td><td char=\".\" align=\"char\">57.1</td><td align=\"left\"><p>Min J.J.,</p><p>et al. [##REF##26964992##55##]</p></td><td align=\"left\">2017</td><td align=\"left\">40</td><td align=\"left\">40</td><td align=\"left\">6mL/kg</td><td align=\"left\">≤10</td><td align=\"left\">HES 6%</td><td align=\"left\">NICOM</td><td align=\"left\">CI ≥ 12%</td><td align=\"left\">47.5</td></tr><tr><td align=\"left\">De Waal E., et al. [##REF##19114886##56##]</td><td align=\"left\">2009</td><td align=\"left\">22</td><td align=\"left\">22</td><td align=\"left\">10 ml/kg</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">PICCO2</td><td align=\"left\">SVI ≥ 12%</td><td char=\".\" align=\"char\">83.3</td><td align=\"left\"><p>Zlicar M.,</p><p>et al. [##REF##29149433##35##]</p></td><td align=\"left\">2018</td><td align=\"left\">56</td><td align=\"left\">56</td><td align=\"left\">3mL/kg</td><td align=\"left\"> > 5</td><td align=\"left\">HES 6%</td><td align=\"left\">LiDCO</td><td align=\"left\">nSI ≥ 10%</td><td align=\"left\">73.0</td></tr><tr><td align=\"left\"><p>Biais M.,</p><p>et al. [##REF##20190260##57##]</p></td><td align=\"left\">2010</td><td align=\"left\">27</td><td align=\"left\">54</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo System</td><td align=\"left\">SVI ≥ 10%</td><td char=\".\" align=\"char\">63.0</td><td align=\"left\">Kim D.-H., et al. [##REF##30013353##36##]</td><td align=\"left\">2018</td><td align=\"left\">53</td><td align=\"left\">53</td><td align=\"left\">6ml/kg</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">CardioQ</td><td align=\"left\">SVI ≥ 15%</td><td align=\"left\">75.0</td></tr><tr><td align=\"left\">Suheiro K., et al. [##REF##20638869##58##]</td><td align=\"left\">2010</td><td align=\"left\">30</td><td align=\"left\">30</td><td align=\"left\">500</td><td align=\"left\">30</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SVI ≥ 25%</td><td char=\".\" align=\"char\">50.0</td><td align=\"left\"><p>Weil G.,</p><p>et al. [##REF##29679768##31##]</p></td><td align=\"left\">2019</td><td align=\"left\">49</td><td align=\"left\">115</td><td align=\"left\">250</td><td align=\"left\">5</td><td align=\"left\">HES 6%</td><td align=\"left\">Mixed</td><td align=\"left\">SVOD ≥ 15%</td><td align=\"left\">62.6</td></tr><tr><td align=\"left\">Cannesson M.,et al. [##REF##21705869##8##]</td><td align=\"left\">2011</td><td align=\"left\">413</td><td align=\"left\">413</td><td align=\"left\">500</td><td align=\"left\">10–20</td><td align=\"left\">Colloids</td><td align=\"left\">Mixed</td><td align=\"left\">CO ≥ 15%</td><td char=\".\" align=\"char\">51.0</td><td align=\"left\">Joosten A., et al. [##REF##31094781##21##]</td><td align=\"left\">2019</td><td align=\"left\">57</td><td align=\"left\">57</td><td align=\"left\">5mL/kg</td><td align=\"left\">10</td><td align=\"left\">Other colloid</td><td align=\"left\">Mixed</td><td align=\"left\">COTD ≥ 10%</td><td align=\"left\">46.0</td></tr><tr><td align=\"left\"><p>Lee J.-H.,</p><p>et al. [##REF##21088596##59##]</p></td><td align=\"left\">2011</td><td align=\"left\">49</td><td align=\"left\">49</td><td align=\"left\">7 ml/kg</td><td align=\"left\">7mL/kg/min</td><td align=\"left\">HES 6%</td><td align=\"left\">TEE</td><td align=\"left\">CI > 15%</td><td char=\".\" align=\"char\">72.0</td><td align=\"left\"><p>Jun J.-H.,</p><p>et al. [##REF##31390982##34##]</p></td><td align=\"left\">2019</td><td align=\"left\">38</td><td align=\"left\">38</td><td align=\"left\">6mL/kg</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">CardioQ</td><td align=\"left\">SVI ≥ 10%</td><td align=\"left\">63</td></tr><tr><td align=\"left\"><p>Høiseth, L.,</p><p>et al. [##REF##22092127##60##]</p></td><td align=\"left\">2011</td><td align=\"left\">25</td><td align=\"left\">34</td><td align=\"left\">250</td><td align=\"left\">2–2.5</td><td align=\"left\">HES 6%</td><td align=\"left\">Mixed</td><td align=\"left\">SV ≥ 15%</td><td char=\".\" align=\"char\">64.7</td><td align=\"left\">Messina A., et al. [##REF##31021879##26##]</td><td align=\"left\">2019</td><td align=\"left\">40</td><td align=\"left\">40</td><td align=\"left\">250</td><td align=\"left\">10</td><td align=\"left\">Ringer’s Lactate</td><td align=\"left\">MostCare</td><td align=\"left\">SVI > 10%</td><td align=\"left\">52.5</td></tr><tr><td align=\"left\"><p>Biais M.,</p><p>et al. [##REF##21642606##61##]</p></td><td align=\"left\">2011</td><td align=\"left\">35</td><td align=\"left\">35</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SV ≥ 15%</td><td char=\".\" align=\"char\">57.1</td><td align=\"left\"><p>Ali A.,</p><p>et al. [##REF##30117033##62##]</p></td><td align=\"left\">2019</td><td align=\"left\">88</td><td align=\"left\">88</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SVI ≥ 15%</td><td align=\"left\">44.0</td></tr><tr><td align=\"left\">Suheiro K., et al.[##REF##21744128##63##]</td><td align=\"left\">2011</td><td align=\"left\">73</td><td align=\"left\">73</td><td align=\"left\">500</td><td align=\"left\">30</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">CI ≥ 15%</td><td char=\".\" align=\"char\">64.0</td><td align=\"left\">Vistisen S.T., et al. [##REF##30414054##64##]</td><td align=\"left\">2019</td><td align=\"left\">61</td><td align=\"left\">122</td><td align=\"left\">5mL/kg</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SV > 10%</td><td align=\"left\">56.7</td></tr><tr><td align=\"left\"><p>Høiseth, L.,</p><p>et al. [##REF##22288953##65##]</p></td><td align=\"left\">2012</td><td align=\"left\">20</td><td align=\"left\">22</td><td align=\"left\">250</td><td align=\"left\">2–2.5</td><td align=\"left\">HES 6%</td><td align=\"left\">Mixed</td><td align=\"left\">SVOD ≥ 15%</td><td char=\".\" align=\"char\">31.8</td><td align=\"left\"><p>Ali A.,</p><p>et al. [##REF##31213047##66##]</p></td><td align=\"left\">2019</td><td align=\"left\">48</td><td align=\"left\">48</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SVI ≥ 15%</td><td align=\"left\">44.0</td></tr><tr><td align=\"left\"><p>Kim S.Y.,</p><p>et al. [##REF##24101958##67##]</p></td><td align=\"left\">2013</td><td align=\"left\"/><td align=\"left\">66</td><td align=\"left\">500</td><td align=\"left\">15–20</td><td align=\"left\">HES 6%</td><td align=\"left\">Mixed</td><td align=\"left\">SVI ≥ 12%</td><td char=\".\" align=\"char\">63.6</td><td align=\"left\"><p>Ali A.,</p><p>et al. [##REF##30994311##68##]</p></td><td align=\"left\">2019</td><td align=\"left\">33</td><td align=\"left\">66</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SVI ≥ 15%</td><td align=\"left\">45.0</td></tr><tr><td align=\"left\"><p>Seo H.,</p><p>et al. [##REF##26469925##69##]</p></td><td align=\"left\">2015</td><td align=\"left\">39</td><td align=\"left\">39</td><td align=\"left\">500</td><td align=\"left\">20</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">MAP ≥ \\ 15%</td><td char=\".\" align=\"char\">44.0</td><td align=\"left\">Kimura A., et al. [##REF##33687175##33##]</td><td align=\"left\">2021</td><td align=\"left\">30</td><td align=\"left\">30</td><td align=\"left\">250</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SV/MAP ≥ 10%</td><td align=\"left\">57.0</td></tr><tr><td align=\"left\"><p>Berger K.,</p><p>et al. [##REF##25263024##70##]</p></td><td align=\"left\">2015</td><td align=\"left\">52</td><td align=\"left\">52</td><td align=\"left\">250</td><td align=\"left\">30</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SVI ≥ 20</td><td char=\".\" align=\"char\">42.3</td><td align=\"left\">Watanabe R., et al. [##REF##34856928##71##]</td><td align=\"left\">2021</td><td align=\"left\">30</td><td align=\"left\">30</td><td align=\"left\">250</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SVI ≥ 15%</td><td align=\"left\">43.3</td></tr><tr><td align=\"left\"><p>Tusman G.,</p><p>et al. [##REF##26505574##72##]</p></td><td align=\"left\">2016</td><td align=\"left\">52</td><td align=\"left\">52</td><td align=\"left\">500</td><td align=\"left\">10</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">PiCCO</td><td align=\"left\">CI ≥ 15%</td><td char=\".\" align=\"char\">40.0</td><td align=\"left\">Kimura A., et al. [##REF##34191254##29##]</td><td align=\"left\">2022</td><td align=\"left\">30</td><td align=\"left\">30</td><td align=\"left\">250</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">SV > 10%</td><td align=\"left\">67.0</td></tr><tr><td align=\"left\">Montenij L.J., et al. [##REF##26227160##73##]</td><td align=\"left\">2016</td><td align=\"left\">22</td><td align=\"left\">22</td><td align=\"left\">7mL/kg</td><td align=\"left\">15</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">Vigileo/Flotrac</td><td align=\"left\">CO ≥ 15%</td><td char=\".\" align=\"char\">40.9</td><td align=\"left\"><p>Flick M.,</p><p>et al. [##REF##35233702##74##]</p></td><td align=\"left\">2022</td><td align=\"left\">33</td><td align=\"left\">33</td><td align=\"left\">500</td><td align=\"left\">NA</td><td align=\"left\">Saline 0.9%</td><td align=\"left\">PAC</td><td align=\"left\">CI > 15%</td><td align=\"left\">39.0</td></tr><tr><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td char=\".\" align=\"char\"/><td align=\"left\">Shen J., et al. [[##REF##36123625##24##]</td><td align=\"left\">2022</td><td align=\"left\">80</td><td align=\"left\">80</td><td align=\"left\">6mL/kg</td><td align=\"left\">10</td><td align=\"left\">HES 6%</td><td align=\"left\">TTE</td><td align=\"left\">SVI ≥ 15%</td><td align=\"left\">55.0</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab2\"><label>Table 2</label><caption><p>Summary of pooled AUCs and grey zones of PPV and SVV in the considered subgroups</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\" rowspan=\"2\">Subgroup</th><th align=\"left\" colspan=\"4\">PPV</th><th align=\"left\" colspan=\"4\">SVV</th></tr><tr><th align=\"left\">Pooled AUC</th><th align=\"left\">Threshold (%)</th><th align=\"left\">Grey zone L</th><th align=\"left\">Grey zone H</th><th align=\"left\">Pooled AUC</th><th align=\"left\">Threshold</th><th align=\"left\">Grey zone L</th><th align=\"left\">Grey zone H</th></tr></thead><tbody><tr><td align=\"left\">Closed Chest and Abdomen</td><td char=\".\" align=\"char\">0.79</td><td char=\".\" align=\"char\">10.9</td><td align=\"left\">6</td><td align=\"left\">12</td><td char=\".\" align=\"char\">0.75</td><td char=\".\" align=\"char\">10.7</td><td align=\"left\">5</td><td align=\"left\">15</td></tr><tr><td align=\"left\">Closed Chest and = pen Abdomen</td><td char=\".\" align=\"char\">0.79</td><td char=\".\" align=\"char\">11.5</td><td align=\"left\">7</td><td align=\"left\">14</td><td char=\".\" align=\"char\">0.79</td><td char=\".\" align=\"char\">10.1</td><td align=\"left\">5</td><td align=\"left\">12</td></tr><tr><td align=\"left\">Open Chest and Closed Abdomen</td><td char=\".\" align=\"char\">0.69</td><td char=\".\" align=\"char\">6.9</td><td align=\"left\">5</td><td align=\"left\">19</td><td char=\".\" align=\"char\">0.72</td><td char=\".\" align=\"char\">10.0</td><td align=\"left\">5</td><td align=\"left\">18</td></tr><tr><td align=\"left\">LPS</td><td char=\".\" align=\"char\">0.74</td><td char=\".\" align=\"char\">11.3</td><td align=\"left\">6</td><td align=\"left\">15</td><td char=\".\" align=\"char\">0.78</td><td char=\".\" align=\"char\">10.8</td><td align=\"left\">7</td><td align=\"left\">13</td></tr><tr><td align=\"left\">Prone</td><td char=\".\" align=\"char\">0.78</td><td char=\".\" align=\"char\">11.2</td><td align=\"left\">6</td><td align=\"left\">11</td><td char=\".\" align=\"char\">0.73</td><td char=\".\" align=\"char\">10.2</td><td align=\"left\">6</td><td align=\"left\">14</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab3\"><label>Table 3</label><caption><p>Metaregression of PPV and SVV ROC curves in the considered subgroups of studies</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\">PPV</th><th align=\"left\">Closed Abdomen<break/>Closed Chest<break/>(<italic>N</italic> = 20)</th><th align=\"left\">Open Abdomen<break/>Closed Chest<break/>(<italic>N</italic> = 8)</th><th align=\"left\">Closed Abdomen<break/>Open Chest<break/>(<italic>N</italic> = 9)</th><th align=\"left\">Prone<break/>(<italic>N</italic> = 9)</th><th align=\"left\">Laparoscopy<break/>(<italic>N</italic> = 6)</th></tr></thead><tbody><tr><td align=\"left\"><italic>PEEP (cmH</italic><sub><italic>2</italic></sub><italic>O)</italic></td><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/></tr><tr><td align=\"left\"><italic>0</italic></td><td align=\"left\">Ref</td><td align=\"left\">Ref</td><td align=\"left\">Ref</td><td align=\"left\">Ref</td><td align=\"left\">Ref</td></tr><tr><td align=\"left\"><italic>0–5</italic></td><td align=\"left\">− 0.08 (<italic>p</italic> = 0.39)</td><td align=\"left\">− 0.15 (<italic>p</italic> = 0.35)</td><td align=\"left\">0.05 (<italic>p</italic> = 0.69)</td><td align=\"left\">− 0.09 (<italic>p</italic> = 0.38)</td><td align=\"left\">− 0.16 (<italic>p</italic> = 0.31)</td></tr><tr><td align=\"left\"> > <italic>5</italic></td><td align=\"left\">− 0.20 (<italic>p</italic> = 0.09)</td><td align=\"left\">− 0.24 (<italic>p</italic> = 0.19)</td><td align=\"left\">NA</td><td align=\"left\">NA</td><td align=\"left\">− 0.20 (<italic>p</italic> = 0.34)</td></tr><tr><td align=\"left\"><italic>VT</italic> > <italic>8 </italic>ml/Kg</td><td align=\"left\"><bold>0.20 (</bold><bold><italic>p</italic></bold><bold> < 0.001)</bold></td><td align=\"left\">0.02 (<italic>p</italic> = 0.86)</td><td align=\"left\">0.07 (<italic>p</italic> = 0.55)</td><td align=\"left\"><bold>0.22 (</bold><bold><italic>p</italic></bold><bold> = 0.03)</bold></td><td align=\"left\">− 0.14 (<italic>p</italic> = 0.31)</td></tr><tr><td align=\"left\"><italic>TIVA</italic></td><td align=\"left\">0.00 (<italic>p</italic> = 0.97)</td><td align=\"left\">0.14 (<italic>p</italic> = 0.26)</td><td align=\"left\">NA</td><td align=\"left\">0.06 (<italic>p</italic> = 0.61)</td><td align=\"left\">− 0.07 (<italic>p</italic> = 0.65)</td></tr><tr><td align=\"left\"><italic>COLLOIDS</italic></td><td align=\"left\"><bold>0.18 (</bold><bold><italic>p</italic></bold><bold> < 0.001)</bold></td><td align=\"left\">− 0.03 (<italic>p</italic> = 0.76)</td><td align=\"left\">− 0.06 (<italic>p</italic> = 0.70)</td><td align=\"left\">0.11 (<italic>p</italic> = 0.31)</td><td align=\"left\">0.03 (<italic>p</italic> = 0.86)</td></tr><tr><td align=\"left\"><italic>Volume</italic> > <italic>4 </italic>ml/kg</td><td align=\"left\">0.11 (<italic>p</italic> = 0.05)</td><td align=\"left\">0.13 (<italic>p</italic> = 0.22)</td><td align=\"left\">NA</td><td align=\"left\">0.17 (<italic>p</italic> = 0.32)</td><td align=\"left\">0.17 (<italic>p</italic> = 0.14)</td></tr><tr><td align=\"left\"><italic>Rate ≥ 15 </italic>Min</td><td align=\"left\">0.02 (<italic>p</italic> = 0.89)</td><td align=\"left\">NA</td><td align=\"left\">− 0.07 (<italic>p</italic> = 0.58)</td><td align=\"left\">− 0.08 (<italic>p</italic> = 0.63)</td><td align=\"left\">− 0.07 (<italic>p</italic> = 0.65)</td></tr></tbody></table><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\">SVV</th><th align=\"left\">Closed abdomen<break/>Closed chest<break/>(<italic>N</italic> = 9)</th><th align=\"left\">Open abdomen<break/>Closed chest<break/>(<italic>N</italic> = 8)</th><th align=\"left\">Closed abdomen<break/>Open chest<break/>(<italic>N</italic> = 6)</th><th align=\"left\">Prone<break/>(<italic>N</italic> = 7)</th><th align=\"left\">Laparoscopy<break/>(<italic>N</italic> = 6)</th></tr></thead><tbody><tr><td align=\"left\"><italic>PEEP (cmH</italic><sub><italic>2</italic></sub><italic>O)</italic></td><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/><td align=\"left\"/></tr><tr><td align=\"left\"><italic>0</italic></td><td align=\"left\">Ref</td><td align=\"left\">Ref</td><td align=\"left\">Ref</td><td align=\"left\">Ref</td><td align=\"left\">Ref</td></tr><tr><td align=\"left\"><italic>0–5</italic></td><td align=\"left\">− 0.06 (<italic>p</italic> = 0.56)</td><td align=\"left\">− 0.09 (<italic>p</italic> = 0.38)</td><td align=\"left\">0.25 (<italic>p</italic> = 0.29)</td><td align=\"left\">− 0.03 (<italic>p</italic> = 0.78)</td><td align=\"left\">0.02 (<italic>p</italic> = 0.87)</td></tr><tr><td align=\"left\"> > <italic>5</italic></td><td align=\"left\">− 0.17 (<italic>p</italic> = 0.18)</td><td align=\"left\">− 0.10 (<italic>p</italic> = 0.51)</td><td align=\"left\">NA</td><td align=\"left\">NA</td><td align=\"left\">− 0.22 (<italic>p</italic> = 0.22)</td></tr><tr><td align=\"left\"><italic>VT</italic> > <italic>8 </italic>ml/Kg</td><td align=\"left\">0.07 (<italic>p</italic> = 0.34)</td><td align=\"left\">0.10 (<italic>p</italic> = 0.34)</td><td align=\"left\">0.22 (<italic>p</italic> = 0.19)</td><td align=\"left\">0.17 (<italic>p</italic> = 0.07))</td><td align=\"left\">0.02 (<italic>p</italic> = 0.91)</td></tr><tr><td align=\"left\"><italic>TIVA</italic></td><td align=\"left\">− 0.00 (<italic>p</italic> = 0.95)</td><td align=\"left\">0.14 (<italic>p</italic> = 0.24)</td><td align=\"left\">− 0.25 (<italic>p</italic> = 0.29)</td><td align=\"left\">0.14 (<italic>p</italic> = 0.15)</td><td align=\"left\">− 0.23 (<italic>p</italic> = 0.09)</td></tr><tr><td align=\"left\"><italic>COLLOIDS</italic></td><td align=\"left\">0.12 (<italic>p</italic> = 0.06)</td><td align=\"left\">− 0.01 (<italic>p</italic> = 0.91)</td><td align=\"left\">NA</td><td align=\"left\">0.13 (<italic>p</italic> = 0.21)</td><td align=\"left\">− 0.17 (<italic>p</italic> = 0.07)</td></tr><tr><td align=\"left\"><italic>Volume</italic> > <italic>4 </italic>ml/kg</td><td align=\"left\">0.12 (<italic>p</italic> = 0.08)</td><td align=\"left\">0.04 (<italic>p</italic> = 0.65)</td><td align=\"left\">NA</td><td align=\"left\">0.11 (<italic>p</italic> = 0.33)</td><td align=\"left\">0.01 (<italic>p</italic> = 0.91)</td></tr><tr><td align=\"left\"><italic>Rate</italic> ≥ <italic>15 </italic>Min</td><td align=\"left\">0.02 (<italic>p</italic> = 0.82)</td><td align=\"left\">NA</td><td align=\"left\">− 0.22 (<italic>p</italic> = 0.19)</td><td align=\"left\">0.00 (<italic>p</italic> = 0.98)</td><td align=\"left\">− 0.23 (<italic>p</italic> = 0.09)</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab4\"><label>Table 4</label><caption><p>Difference in the AUCs of the subgroups positively affected by the variables analyzed in the metaregression</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\" colspan=\"4\">Closed Chest and Closed Abdomen</th><th align=\"left\" colspan=\"2\">Prone patients</th></tr><tr><th align=\"left\" colspan=\"2\">AUC of PPV</th><th align=\"left\" colspan=\"2\">AUC of PPV</th><th align=\"left\" colspan=\"2\">AUC of PPV</th></tr><tr><th align=\"left\">VT > 8 ml/Kg</th><th align=\"left\">VT ≤ 8 ml/Kg</th><th align=\"left\">Colloids YES</th><th align=\"left\">Colloids NO</th><th align=\"left\">VT > 8 ml/Kg</th><th align=\"left\">VT ≤ 8 ml/Kg</th></tr></thead><tbody><tr><td align=\"left\">0.88 (0.82–0.93)</td><td char=\"–\" align=\"char\">0.69 (0.65 – 0.74)</td><td align=\"left\">0.86 (0.80–0.92)</td><td char=\"–\" align=\"char\">0.70 (0.65 – 0.75)</td><td align=\"left\">0.85 (0.76–0.94)</td><td char=\"–\" align=\"char\">0.64 (0.54 – 0.74)</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[ "<supplementary-material content-type=\"local-data\" id=\"MOESM1\"></supplementary-material>" ]	[ "<table-wrap-foot><p>HES 6%, Hydroxyethylstarch 6%; OD, esophageal doppler; FloTrac/Vigileo/Vigilance/ ThermodilutionVIP + ™, Edwards Lifesciences Co., Irvine, Ca, USA; TTE, Transthoracic echocardiography, <italic>TEE</italic> Transesophageal echocardiography, Pulsioflex/ProAQT®, Maquet, Rastatt, Germany, <italic>PAC</italic> Pulmonary artery catheter; PiCCO/ProAQT/PICCO2, PULSION Medical Systems, MostCare, Pressure Recording Analytical Method, PRAM, Vytech Health®, Padova, Italy; CardioQ™, Deltex Medical Ltd., Chichester (esophageal doppler monitor), UK; NICOM, Non-Invasive Continuous Cardiac Output, Imedex, France; IntelliVue©, Phillips Medical Systems, MA, USA; LiDCO, LiDCO Group PLC, London, UK, <italic>CO</italic> Cardiac output, <italic>CI</italic> Cardiac index, <italic>SV</italic> Stroke volume, <italic>SVI</italic> Stroke volume index, <italic>VTI</italic> Velocity time integral, <italic>R</italic> Responders, <italic>Vol</italic> Volume, <italic>R</italic> Responders, <italic>Vol</italic> Volume, <italic>NA</italic> Not available, <italic>PAC</italic> Pulmonary arterial catheter</p></table-wrap-foot>", "<table-wrap-foot><p>Complete data analysis is reported in the Results section. <italic>AUC</italic> Area under receiver operator characteristic curve, <italic>PPV</italic> Pulse pressure variation, <italic>SVV</italic> Stroke volume variation <italic>L</italic> Low value of grey zone, <italic>H</italic> High value of grey zone, <italic>LPS</italic> Laparoscopy</p></table-wrap-foot>", "<table-wrap-foot><p>Bold variables indicates statistically significant values</p><p><italic>PPV</italic> Pulse pressure variation, <italic>SVV</italic> Stroke volume variation, <italic>ROC</italic> Receiver operator characteristic curve, <italic>PEEP</italic> Positive end-expiratory pressure, <italic>VT</italic> Tidal volume, <italic>TIVA</italic> Total intravenous anesthesia, <italic>NA</italic> Non-applicable for collinearity; ref, reference, ml/Kg Milliliters per kilogram, <italic>min</italic> Minutes. Data are expressed as coefficient of metaregression (<italic>p</italic> value); ref, reference</p></table-wrap-foot>", "<table-wrap-foot><p><italic>PPV</italic> Pulse pressure variation, <italic>SVV</italic> Stroke volume variation, <italic>AUC</italic> Area under receiver operator characteristic curve, <italic>PEEP</italic> Positive end-expiratory pressure, <italic>VT</italic> Tidal volume, <italic>TIVA</italic> Total intravenous anesthesia, <italic>NA</italic> Non-applicable for collinearity, <italic>ref</italic> Reference, ml/Kg Milliliters per kilogram, <italic>min</italic> Minutes</p><p>Data are expressed as coefficient of metaregression (p value); ref, reference</p></table-wrap-foot>", "<fn-group><fn><p><bold>Publisher's Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"13054_2023_4706_Fig1_HTML\" id=\"MO1\"/>" ]	[ "<media xlink:href=\"13054_2023_4706_MOESM1_ESM.docx\"><caption><p><bold>Additional file 1.</bold> Supplementray Tables and Figures.</p></caption></media>" ]	[{"label": ["1."], "surname": ["Thiele", "Raghunathan", "Brudney", "Lobo", "Martin", "Senagore", "Cannesson", "Gan", "Mythen", "Shaw", "Miller"], "given-names": ["RH", "K", "CS", "DN", "D", "A", "M", "TJ", "MM", "AD", "TE"], "article-title": ["Perioperative quality initiative IW: American society for enhanced recovery (aser) and perioperative quality initiative (poqi) joint consensus statement on perioperative fluid management within an enhanced recovery pathway for colorectal surgery"], "source": ["Perioper Med"], "year": ["2016"], "volume": ["5"], "fpage": ["24"], "pub-id": ["10.1186/s13741-016-0049-9"]}, {"label": ["4."], "surname": ["Navarro", "Bloomstone", "Auler", "Cannesson", "Rocca", "Gan", "Kinsky", "Magder", "Miller", "Mythen", "Perel", "Reuter", "Pinsky", "Kramer"], "given-names": ["LH", "JA", "JO", "M", "GD", "TJ", "M", "S", "TE", "M", "A", "DA", "MR", "GC"], "suffix": ["Jr"], "article-title": ["Perioperative fluid therapy: a statement from the international fluid optimization group"], "source": ["Perioper Med"], "year": ["2015"], "volume": ["4"], "fpage": ["3"], "pub-id": ["10.1186/s13741-015-0014-z"]}, {"label": ["9."], "surname": ["Futier", "Constantin", "Paugam-Burtz", "Pascal", "Eurin", "Neuschwander", "Marret", "Beaussier", "Gutton", "Lefrant", "Allaouchiche"], "given-names": ["E", "JM", "C", "J", "M", "A", "E", "M", "C", "JY", "B"], "article-title": ["A trial of intraoperative low-tidal-volume ventilation in abdominal surgery"], "source": ["N Eng J Med"], "year": ["2013"], "volume": ["369"], "issue": ["5"], "fpage": ["428"], "lpage": ["37"], "pub-id": ["10.1056/NEJMoa1301082"]}]	{ "acronym": [ "FC", "MV", "SVV", "PPV", "SV", "AUC", "LPS", "Vt" ], "definition": [ "Fluid challenge", "Mechanical ventilation", "Stroke volume variation", "Pulse pressure variation", "Stroke volume", "Area under the curve (AUC) of pooled receiving operating characteristics (ROC) curve", "Laparoscopy", "Tidal volume" ] }	74	CC BY	no	2024-01-13 23:36:47	Crit Care. 2023 Nov 8; 27:431	oa_package/5d/09/PMC10631038.tar.gz
PMC10640475	37393557	[ "<title>Introduction</title>", "<p id=\"Par3\">There is a wide consensus that life emerged and diversified relatively early in Earth’s history, as suggested by geochemical signatures, putative microfossils and biosedimentary structures from the early Archean [##UREF##0##1##]. Particularly, phototrophic non-lithifying microbial mats and stromatolites have been extensively documented in the Archean rock record, as shown in the fossil evidence from the Dresser formation (3.48 Ga) [##UREF##1##2##], the Buck Reef Chert (3.42 Ga) [##UREF##2##3##, ##UREF##3##4##], and the Moodies group (3.22 Ga) [##UREF##4##5##–##UREF##6##7##]. These microbial structures are also found in marginalized modern environments; they occur as benthic, stratified, and self-sustaining biological communities of thousands of phylogenetically diverse microorganisms embedded in a matrix of extracellular polymeric substances (EPS) [##UREF##7##8##, ##UREF##8##9##]. Given the morphological, chemical, and sedimentological similarities between modern and fossil microbial mats, it is straightforward to infer that these biological structures have been thriving on Earth for more than 3.5 Ga. As such, modern microbial mats are often considered analogs to benthic Precambrian communities in shallow-water environments, and therefore of paramount importance to better interpret the paleobiological record [##UREF##9##10##, ##UREF##10##11##].</p>", "<p id=\"Par4\">The undeniable success of microbial mats can only be understood in terms of ecological stability; namely, the community response to disturbances, which can be dissected into the degree to which a community is insensitive to perturbations (ecological resistance) and the rate at which a community restores to the pre-disturbed state (ecological resilience) [##UREF##11##12##, ##UREF##12##13##]. Environmental disturbances can be classified into pulses and presses if the perturbation is a discrete, short-term event, or a continuous, long-term transition, respectively [##UREF##11##12##, ##UREF##13##14##]. Microbial community stability is a topic of interest for a wide array of systems and disturbances, such as dry-rewetting events [##UREF##14##15##], differences in water level [##UREF##15##16##], temperature variations [##UREF##16##17##, ##UREF##17##18##], chemical stress [##UREF##18##19##], shifting redox patterns [##UREF##19##20##], and changes in salinity [##UREF##20##21##]. Previous studies have shown that microbial communities commonly display high functional redundancy owing to the spatial coexistence of taxonomically distinct microorganisms, most of which belong to the rare biosphere [##UREF##21##22##, ##UREF##22##23##], while perturbations commonly have a negative effect on the species richness along with changes in the ecological interactions [##UREF##23##24##–##UREF##26##27##]. Despite recent advances, the impact of disturbances on the microbial dynamics of lithifying and non-lithifying microbial mats remains unclear [##UREF##27##28##–##UREF##31##32##]. A better understanding of these dynamics would provide insights into the ecological stability of these structures since the Precambrian.</p>", "<p id=\"Par5\">The microbial mats in the Archean Domes system, in the Cuatro Ciénegas Basin (CCB), Mexico, endure extreme conditions. These conditions include extended droughts lasting approximately nine months each year, which could be classified as a press disturbance, as well as variations in salinity, pH, burial by precipitating salts, and shifts of trophic states. Additionally, daily temperature shifts amidst the desert and burial by sediments during heavy rainfall could be considered pulse perturbations. Thus, the Archean Domes system is best regarded as a multi-perturbation system. To gain insight into the underlying ecological processes and mechanisms that allow these microbial communities to flourish despite the seasonal disturbances that characterize this system, we employed a metagenomic approach to assess ecological stability and community dynamics over a four-year sampling period. We hypothesize that ecologically stable microbial mats would demonstrate no significant changes in community composition and functional profiles, whereas mats with high turnover rates would indicate limited resistance and resilience, potentially reducing the lifetime of the system. Our study aims to address several questions, including whether we can detect any differential responses between seasons, what is the contribution of the core community and rare biosphere to this system, and if we are able to observe any long-term genetic drift as a consequence of extreme environmental perturbations.</p>" ]	[ "<title>Materials and Methods</title>", "<title>Study site and Sample Collection</title>", "<p id=\"Par6\">In this work, we investigate the microbial system known as the Archean Domes, situated in the CCB, Mexico (Fig. ##FIG##0##1##). The Archean Domes (2649’41.7”N, 10201’28.7”W) is a seasonal, water-fluctuating pond in Rancho Pozas Azules from Pronatura Noreste located at the eastern side of the Cuatro Ciénegas Basin, Coahuila, México (Site overview in Fig. ##SUPPL##0##S1##: Supplementary material). This site was discovered in 2016, and was firstly described by [##UREF##32##33##] [unpublished], [##UREF##33##34##], and [##UREF##34##35##]. During the rainy season, mostly during the months of August to September, the pond fills with water up to 20 cm. Green mats emerge over the sediment surface (i.e., epibenthic microbial mats), building dome-like sedimentary structures up to 10-20 cm in diameter (Fig. ##FIG##0##1##b,c). Although unusual in morphology and size, similar structures have been previously reported in several hypersaline, intertidal and supratidal environments [##UREF##35##36##–##UREF##37##38##]. Descriptions of gas domes and other Microbially Induced Sedimentary Structures (MISS) from these non-lithifying microbial mats can be found in Fig. ##SUPPL##0##S2##: Supplementary material. From November to July, water evaporates and salt precipitation covers the pond completely, burying the microbial mats (Fig. ##FIG##0##1##a). Salinity is variable between the two seasonal states, transitioning from 52.5‰ (as measured in the rainy season of 2016) when filled with water to salt saturation during the dry season. From a recent sampling in September 2021, we observed that green mats and gas filled structures start to quickly develop after a day of rainfall (Fig ##SUPPL##0##S3##: Supplementary material). Inside the dome-like structures of the mats, variable concentrations of methane (2.619.6 g/L on the dry season of 2016, 102-402 g/L on the dry season of 2017) and carbon dioxide (1.081.40 mg/L on the dry season of 2017) were measured (Table ##SUPPL##0##S1##: Supplementary material). Chemical analyses for organic and inorganic nitrogen (ON/IN), phosphorus (OP/IP), and organic carbon (OC) were determined for the dry and rainy seasons of 2019 (Table ##SUPPL##0##S2##: Supplementary material); on average, molar ratios for the 2019 dry season are 2.37 for OC:ON, 152.72 for OC:OP, and 77.61 for ON:OP, while the 2019 wet season shows 1.56 for OC:ON, 16.98 for OC:OP, and 9.96 for ON:OP. During dry season, pH is 58.6, while on rainy season the pH rises to 8.29.5 with the dissolution of salts. Water/mat temperature is 31.534.5 when sampled (always during daylight). Sediment grain size at this site is dominated by sand (66.1%68.3%) followed by silt (23.4%24.0%) and clay (8.5%9.9%), which correspond to a sandy loam soil texture (Table ##SUPPL##0##S2##: Supplementary material). For details on equipment and physicochemical methods, confer the following section.</p>", "<p id=\"Par7\">We collected six samples of mats and associated sediment across a four-year period (See photo gallery for each sampling in Fig ##SUPPL##0##S3##: Supplementary material). During this time span, we got to collect three samples of each seasonal state: dry and rainy season. The mats from the dry season are from the sampling of April 2016, February 2017 and March 2019 (hereinafter denoted as Dry-2016, Dry-2017 and Dry-2019, respectively); mats from the rainy season are from the sampling of October 2016, October 2018 and September 2019 (hereinafter denoted as Wet-2016, Wet-2018 and Wet-2019, respectively). Rainy season samples come directly from developing domes, whereas dry season samples derive from regions where mats were visible to the naked eye. As the rainy season is heavily contingent on the cyclone dynamics of the Gulf of Mexico, samples were taken at different times, 1-2 weeks after a heavy rainfall to ensure a high level of water in the pond. To prevent contamination, samples were collected with gloves, sterile forceps and sterile conical tubes (50 mL). Samples were stored at 4 C and subsequently frozen in liquid nitrogen for preservation, prior to DNA extraction. Samples were collected under the collection permit SGPA/DGVS/03188/20 issued by Subsecretaría de Gestión para la Protección Ambiental, Dirección General de Vida Silvestre (<ext-link ext-link-type=\"uri\" xlink:href=\"https://www.gob.mx/semarnat\">https://www.gob.mx/semarnat</ext-link>). Weather parameters during sampling were taken from the National Meteorological Service, CONAGUA (<ext-link ext-link-type=\"uri\" xlink:href=\"https://smn.conagua.gob.mx/es/\">https://smn.conagua.gob.mx/es/</ext-link>), at the EMA station No. 15DBB372 in Cuatro Ciénegas (270’7.2”N, 1024’22.7”W). Weather data is provided in Fig. S4 and Table ##SUPPL##0##S3##: Supplementary material.</p>", "<title>Measurement of Physicochemical Parameters</title>", "<p id=\"Par8\">Water salinity, temperature, and pH were measured <italic>in situ</italic> using a Hydrolab MS5 Water multiparameter sonde (OTT Hydromet GmbH, Germany). Prior to chemical analyses, samples were air dried, sediments were sieved through a 2.0 mm sieve and subsequently ground in an agate mortar. The pH of the sediment was determined using a Thermo Scientific (Waltham, Massachusetts) H03062 digital pH meter [##UREF##38##39##]. Total organic carbon (TOC) and organic matter (OM) content were quantified using the Walkley-Black method [##UREF##39##40##]. The OM content was calculated with the conversion factor 1.298 (1/0.77) used for Mexican soils. Total nitrogen (TN) was determined with the micro-Kjeldahl method (salicylic acid-thiosulfate modification, [##UREF##40##41##]), while inorganic nitrogen (IN) was determined by direct-distillation of the sediment extract [##UREF##41##42##]. Organic nitrogen (ON) was estimated as TN minus IN. Total phosphorus (TP) and inorganic phosphorus (IP) fractions were extracted with bicarbonate [##UREF##42##43##]. Both P fractions were reduced with ascorbic acid and quantified by the molybdate colorimetric method [##UREF##43##44##]. The organic phosphorus (OP) fraction was estimated by the difference between TP and IP. Finally, the sediment texture was determined by the Bouyoucos hydrometer method [##UREF##44##45##].</p>", "<p id=\"Par9\">Dissolved CH and CO concentration inside the domes were determined with a discrete headspace. equilibration technique. Briefly, triplicate water samples were collected with 60 mL plastic syringes, ensuring the absence of air bubble. Then, 20 mL of water was gently evacuated and substituted with CH- and CO-free nitrogen (99.999 % N, Praxair, Mexico). The syringe content was vigorously shaken for equilibration, the liquid volume was evacuated, and 5 mL of subsample of the gas content of the syringe was injected into a continuous flow of nitrogen connected to an ultraportable greenhouse gas analyzer (UGGA, Los Gatos Research, CA, USA). The presence of CH and CO in the gas sample was detected as a peak response, that was integrated, after proper calibration with standard CH /CO samples. Lastly, dissolved CH and CO concentration were derived from the gas concentration using the Henry’s solubility constant of both gases [##UREF##45##46##].</p>", "<title>DNA Purification and Sequencing</title>", "<p id=\"Par10\">From each sample, only the mat layer (1 cm) was taken for DNA extraction. As the samples of the dry seasons contain a thick layer of salt, this layer had to be separated with a sterile scalpel to facilitate the extraction. We perform the extraction of total DNA from the six samples as reported in [##UREF##46##47##]. Purified DNA was sent to CINVESTAV-LANGEBIO (<ext-link ext-link-type=\"uri\" xlink:href=\"http://langebio.cinvestav.mx/labsergen/\">http://langebio.cinvestav.mx/labsergen/</ext-link>) for shotgun metagenomic sequencing. DNA libraries for Illumina paired-end sequencing were prepared using Ilumina TruSeq DNA Nano; no amplification steps were performed. Library quality control was performed with Aligent Bioanalyzer High Sensitivity DNA Analysis Chip. DNA from all samples was sequenced with Illumina MiSeq, 2 x 300 bp paired-end reads format. The total number of paired-end reads per metagenome range from 4.7 to 28.0 Gbp per library and orientation (forward and reverse). Number of raw reads and quality control metadata can be found in Table ##SUPPL##0##S4##: Supplementary material.</p>", "<title>Quality Control, Assembly and Annotation of Metagenomes</title>", "<p id=\"Par11\">We preprocessed the raw reads with Trimmomatic v0.38 [##UREF##47##48##] with a sliding window of 4 bp, a Phred quality score of 30, minimum length of 35, and an average mean quality of 28. For each metagenome, reads were assembled into contigs to facilitate gene prediction. Forward and reverse paired reads, and individual forward and reverse with no pair, were assembled using MEGAHIT v1.1.1 [##UREF##48##49##] with minimum contig length of 500, k-min of 27 and k-step of 10 as suggested for highly-diverse metagenomes [##UREF##49##50##, ##UREF##50##51##]. To control for sequencing depth bias, we used the minimum number of reads (1,288,875 reads) to sample the metagenomic datasets at random to normalize coverage for comparisons. Unassembled reads were collected with BBtools [##UREF##51##52##] and SAMtools v1.12 [##UREF##52##53##]. For assembled contigs, gene prediction and subsequent taxonomic annotation was done with CAT v5.2 [##UREF##53##54##]. CAT is a robust taxonomic annotator that integrates known software programs such as gene predictor Prodigal [##UREF##54##55##] and gene annotator DIAMOND [##UREF##55##56##] against the NCBI non-redundant database [##UREF##56##57##] to give a deep gene taxonomic annotation. Since taxonomic annotation with CAT revolves against all kinds of predicted genes, we also used six ribosomal protein families (PF00177, PF00298, PF00573, PF00237, PF00163 and PF00318) to validate CAT results. We downloaded ribosomal genes’ seeds from Pfam database [##UREF##57##58##]. HMM profiles were built with HMMER v3.3 [##UREF##58##59##], and hmmsearch was performed against all metagenomes (e-value 10). Ribosomal genes were annotated with DIAMOND, coupled with the NCBI non-redundant database. Additional information regarding quality control, metagenome assembly, processing of not assembled reads with MEGAHIT, and taxonomic annotation (CAT and ribosomal) can be found in Table ##SUPPL##0##S4##-##SUPPL##0##S8##: Supplementary material. Functional profiling for each sample was performed with SUPER-FOCUS [##UREF##59##60##] against the NCBI non-redundant database (<ext-link ext-link-type=\"uri\" xlink:href=\"https://www.ncbi.nlm.nih.gov/\">https://www.ncbi.nlm.nih.gov/</ext-link>). Additionally, we selected resistance genes based on GO classification [##UREF##60##61##, ##UREF##61##62##] and downloaded the amino acid sequences from UniProt database. Selected GO terms are shown in Table ##SUPPL##0##S9##: Supplementary material. Resistance query sequences were aligned with BLAST [##UREF##62##63##] against all metagenomes. Finally, we selected key energy metabolisms as in [##UREF##63##64##]. Protein families involved in each metabolic pathway were initially searched in UniProt [##UREF##64##65##] and KEGG [##UREF##65##66##] databases, and subsequently downloaded from Pfam</p>", "<title>Normalization, Statistical Analyses and Data Visualization</title>", "<p id=\"Par12\">We used R programming language [##UREF##66##67##] to run each statistical analysis, to normalize data, and to generate figures. We list the libraries used as follows: ggplot2 v3.3.5 [##UREF##67##68##] for sockplots and boxplots, edgeR v3.34.1 for data normalization [##UREF##68##69##], RAM v1.2.1.7 [##UREF##69##70##] for PCoA, PCA and CCA analyses, vegan v2.5-7 [##UREF##70##71##] for rarefaction curves and alpha-diversity metrics, UpSetR v1.4.0 [##UREF##71##72##] for upset plots, DESeq2 v1.32.0 [##UREF##72##73##] and EnhancedVolcano v1.10.0 [##UREF##73##74##] for differential expression analysis, patchwork v1.1.1 [##UREF##74##75##] and fmsb v0.7.1 [##UREF##75##76##] for radar charts, streamgraph v0.9.0 [##UREF##76##77##] for streamgraphs, easyalluvial v0.3.0 [##UREF##77##78##] and parcats v0.0.3 [##UREF##78##79##] for alluvial plots, NetCoMi v1.0.2 for network analyses [##UREF##79##80##], and umap v0.2.7.0 and dbscan v1.1-8 for clustering. Libraries BBmisc v1.11 [##UREF##80##81##], dplyr v1.07 [##UREF##81##82##], tidyr v1.1.4 [##UREF##82##83##] were used for data manipulation. Gene abundances were normalized with the Relative Log Expression (RLE) method. PCoA and NMDS analyses for taxonomic groups were calculated with a Bray-Curtis measure. Co-occurrence NetCoMi networks were grouped by seasons in order to minimize environmental indirect edges, a relevant effect reported elsewhere [##UREF##83##84##]. The networks were built using SparCC measure, Bayesian-multiplicative replacement for zero handling and association threshold of 0.5. Phylum-level networks were built with the top 120 phyla, while genus-level networks were built with all the 250 core genera. Groups of taxa and functions clustered with UMAP/HDBSCAN and k-means, respectively, are provided as supplementary.csv files.</p>" ]	[ "<title>Results and Discussion</title>", "<title>Functional Inference and Changes Through the Seasons</title>", "<p id=\"Par13\">Coding sequences were functionally classified. As expected, basic functions shared between all living beings are widely distributed among all samples, such as carbohydrate (14.5%), amino acid (11.9%), protein (8.9%), DNA (5.9%), RNA (5.0%), and fatty acids and lipids (3.1%) metabolisms; other processes regarding cofactor, vitamins, and pigments (10.7%), cell wall and capsule (4.2%), respiration (3.9%), and stress response (3.8%) are also among the top functions for all samples (Table ##SUPPL##0##S10##: Supplementary material). The fact that stress response genes appear in a relative high abundance is plausibly an adaptation to a community that is subject to ceaseless environmental pressures [##UREF##84##85##, ##UREF##85##86##], such as those found in the Archean Domes system. Differences in function abundance for every major process according to SUPER-FOCUS classification are depicted in Fig. ##FIG##1##2##a. Overall, samples appear to be similar among them, despite some functions with differential distribution among the samples, such as amino acid, fatty acids and lipids, central, secondary, nitrogen, potassium, and RNA metabolisms.</p>", "<p id=\"Par14\">We inspect in detail the functional role of stress response genes present at the Archean Domes. Using the GO classification, we identify resistance genes related to pH (both, alkaline and acidic genes as well as not specified, general pH control genes) salt, dormancy, and endosporulation conditions. Alkaline and salt resistance genes were the most abundant, with a mean proportion of 56.5% and 31.5%, respectively (Fig. ##SUPPL##0##S5##: Supplementary material). This behavior is expected, since salt and pH fluctuate considerably between seasons, and might exert a selection pressure on the organisms thriving on this site.</p>", "<p id=\"Par15\">Pfam protein groups were used to infer energy metabolisms and nutrient cycling within the mat samples (Fig. ##FIG##1##2##b). Based on normalized abundance, Wood-Ljungdahl pathway rules carbon metabolism among the mat, followed by the Calvin cycle. These results are consistent with other microbial mats previously described, where Wood-Ljungdahl dominance is regarded as a result of energy limitation, since this mechanism of carbon fixation is inefficient compared to other pathways [##UREF##63##64##, ##UREF##86##87##, ##UREF##87##88##]. Anoxygenic photosynthesis genes dominate over those specific to oxygenic photosynthesis, while sulfur oxidation and nitrogen fixation are potentially the main processes for sulfur and nitrogen metabolisms. Dissimilatory sulfate reduction is portrayed as a process with low gene abundances in the Archean Domes, despite the highly abundant sulfate reducing bacteria previously described; as such, metabolism inference based on gene abundances should be taken cautiously. Further reconstruction of full pathways would provide more accuracy in the relative abundances.</p>", "<p id=\"Par16\">Ecological resilience is not straightforward to assess in this system, as press disturbances are continuous and seasonal. Rather, inferences on ecological resilience could be evaluated under the assumption of many stable states in which a community may thrive. PCoA plots could be visualized as stability landscapes, where each snapshot of the community’s composition/function could be envisioned as a ball and where the different alternative stable states represent basins in the stability landscape. If resistance and resilience is high, a disturbance would not modify the current stable state of the community. On the contrary, if overall stability is low, and the disturbance powerful enough, the community will leave its current stable state to fall into an alternative stable state [for an in-depth review on the stability landscape, cf. ##UREF##11##12##, ##UREF##88##89##]. Looking at the PCoA plot with a Bray-Curtis measure for functions (Fig. ##FIG##2##3##a) we could see that seasonal “valleys” of alternative equilibria are formed, and that these equilibrium states are arranged into seasonal groups, although ordination is sparse. Further robust sampling will support the predictability of this clustering method.</p>", "<p id=\"Par17\">We modify a differential expression analysis to adapt it to our metagenomic using the classification defined by SUPER-FOCUS. Although none of the metabolic subsystems had a significant difference between seasons (<italic>p</italic> > 0.5), there were some processes that had a higher or lower abundance as seen by their fold change (Log Fold Change , Fig. ##SUPPL##0##S6##: Supplementary material). In the dry season, there were three slightly more abundant functions: the pentose phosphate pathway of plants, the alpha-acetolactate operon, and the biotin biosynthesis. From the pentose phosphate pathway, we had the glucose 6 phosphate dehydrogenase, the key enzyme of the Oxidative Pentose Phosphate Pathway (OPPP), which is related to the response of short- or long-term exposure to drought stress in plants [##UREF##89##90##]. The alpha-acetolactate operon has been described as a component in the mixed acid fermentation, done by some bacteria such as <italic>Bacillus subtilis</italic>, to produce acetoin in the absence of nitrate [##UREF##90##91##]; this could be associated to a shortage of nutrients in the dry season. Lastly, biotin biosynthesis is an important process, since biotin is a key cofactor in the fatty acids and amino acid metabolisms, as well as in the replenishment of the tricarboxylic acid cycle [##UREF##91##92##] which could be a relevant resistance process at low water activity. For the rainy season, some functions with a higher fold change were: the acyl homoserine lactone (AHL) inducer, which is involved in primary quorum sensing signals by Gram-negative bacteria [##UREF##92##93##]; the phage carbon metabolism auxiliary metabolic genes (AMGs), which consist of phage strategies for resource management during host infection [##UREF##93##94##, ##UREF##94##95##]; some archaeal hydrogenases involved in carbon fixation [##UREF##95##96##]; prenylated indole alkaloids production from actinomycetes, which have multiple biological functions such as antifungal and antibacterial activity [##UREF##96##97##]; and lastly, chlorophyll degradation related genes. Some of these functions could be directly associated with the presence of the green, cyanobacterial built, layer seen in the rainy seasons, such as in the phage-cyanobacterial AMGs [##UREF##93##94##], the quorum sensing for biofilm formation [##UREF##97##98##], and the chlorophyll degradation.</p>", "<p id=\"Par18\">Moreover, we were interested in how functions have changed over time and if there is a group of functions that leads global patterns in the community. According to k-means and hierarchical clustering, two main groups of functions were predicted. PCA analysis showed how these functions are projected, where high abundant functions are sparsely distributed in the plot, and most functions with low abundance functions were tightly clustered together (Fig. ##FIG##2##3##b). Each function’s class is provided as a supplementary.csv file. Comparing function abundance across samples suggest that functions are more similar between adjacent samples (Fig. ##FIG##2##3##c), despite the high similarity in function abundance for each sample. In consequence, the correlation cloud appears to be scattering when samples are more distant in time. For instance, sample Dry-2016 showed higher correlation with sample Wet-2016 than with the last sample from 2019 (Wet-2019). While major functions appear to be constant over time, this result suggests that overall functions are changing in abundance, perhaps slightly, between samples, and that cumulative changes in abundance for the final sample differ drastically from the initial function state. Further sampling may reinforce this hypothesis.</p>", "<p id=\"Par19\">Since functions are mostly preserved (in abundance) through the seasons, the microbial community might harbor a high degree of functionally redundant taxa [##UREF##23##24##]. This grants the community a robust capability to withstand taxonomic replacement, a phenomenon detected at the Archean Domes system which is the outcome of a non-resistant community in terms of phylogenetic composition (see the following section).</p>", "<title>Taxonomical Characterization, Compositional Dynamics, and Seasonal Comparison</title>", "<p id=\"Par20\">We built rarefaction curves to evaluate diversity coverage for all samples. For genera richness, each sample reaches saturation and comparisons between them is suitable (Fig. ##SUPPL##0##S7##: Supplementary material). Open read-frames were predicted for reads, and further annotated for taxonomic classification with CAT and ribosomal protein families. With CAT, we detected 162 phyla, 2250 genera (across all samples), and more than 8,000 phylotypes per sample (Table ##SUPPL##0##S7##: Supplementary material). Nevertheless, only 30-58% of the total predicted genes for each sample were classified, suggesting a considerable amount of potential novel taxonomic groups, which comprise the so called microbial dark matter; these potentially uncultured organisms are by no means irrelevant, as they have shown to be of importance in other hypersaline microbial mats [##UREF##98##99##]. From the 2250 total genera found in the system, only between 16-19 for each sample belong to the abundant genera, that is, with an abundance >1%. In contrast, between 426-619 genera have abundances <0.1%, and belong to the so called rare biosphere. Rare taxa account for the 11.218.9% of the whole community, whereas abundant taxa comprises the 43.367.6% (Table S11 and Fig. ##SUPPL##0##S8##: Supplementary material). Therefore, although taxa that are abundant only consists of a few genera, these taxa often build most of the microbial community biomass. Moderately abundant taxa (>0.1% and <1%) sits between the abundant and rare, with a relative abundance of 19.637.7% in the samples studied.</p>", "<p id=\"Par21\">Regarding the taxonomic composition, overall, mean abundances per domain show consistent results between CAT and ribosomal gene annotation. For CAT taxonomic assignment we got mean abundances of: 85.24% for Bacteria, 14.43% for Archaea, and 0.3% for Eukaryota (Table ##SUPPL##0##S7##: Supplementary material); whereas ribosomal gene annotation showed: 86.56% for Bacteria, 13.35% for Archaea, and 0.08% for Eukaryota (Table ##SUPPL##0##S8##: Supplementary material). At the phylum level, samples consistently displayed Proteobacteria (23.51%), Euryarchaeota (11.42%), Bacteroidetes (10.26%), Firmicutes (4.35%), Cyanobacteria (3.30%), Spirochaetes (2.84%), Planctomycetes (1.99%) and Chloroflexi (1.42%) as the most abundant phyla (Fig. ##FIG##3##4##). The taxonomic annotation with ribosomal genes is also consistent with the phyla relative abundances of CAT annotation (taxonomic profile based on ribosomal proteins is shown in Fig. ##SUPPL##0##S9##: Supplementary material).</p>", "<p id=\"Par22\">At the genus level, we find <italic>Coleofasciculus</italic> as the most abundant Cyanobacteria between all samples, which is widely known as a key mat-forming genus in sandy environments [##UREF##8##9##, ##UREF##10##11##, ##UREF##99##100##, ##UREF##100##101##]. Other cyanobacterial genera such as <italic>Leptolyngbya</italic>, <italic>Halothece</italic>, and <italic>Phormidium</italic> are also abundant between samples, and have also been previously reported in microbial mats [##UREF##99##100##, ##UREF##101##102##, ##UREF##102##103##]. Anaerobic, halophilic, sulfate-reducing members of the Deltaproteobacteria such as <italic>Desulfonatronovibrio</italic>, <italic>Desulfonatronospira</italic>, and <italic>Desulfovermiculus</italic> [##UREF##103##104##] also appear in abundance in the Archean Domes samples. Other relevant and abundant taxonomic genera present in the samples include <italic>Halorubrum</italic> (Euryarchaeota), <italic>Halanaerobium</italic> (Firmicutes), <italic>Spirocheta</italic> (Spirochetes), <italic>Chitinispirillum</italic> (Fibrobacteres), and <italic>Tangfeifania</italic> (Bacteroidetes).</p>", "<p id=\"Par23\">Figure ##FIG##4##5##a show the community composition changes through the years. One of the most noticeable changes through the years was a rise of Archaea (from 1-4% to 33%) in the samples of 2019 (Tables ##SUPPL##0##S5## and ##SUPPL##0##S6##: Supplementary material). Consequently, Bacteria reduced their abundance up to 65%, a third less from previous years. Viruses followed the same tendency as the Archaea during 2019, in a subtle rise of abundance (0.080.2% to 0.4%), while Eukaryota had an apparent seasonal pattern in the first two years (2016–2018), continuing with a steady state in 2019. Since the increased abundance of Archaea was considerable, the compositional dynamics between 2016-2018 is not readily noticeable. Considering only the abundance shifts between 2016-2018, all domains presented a plausible seasonal pattern: archaea, eukaryotes and viruses rose proportionally in the rainy season compared to the dry one. To explore which organisms may drive these seasonal patterns, we examined phyla changes in abundance through time. Interactive streamgraphs for phyla shifts are provided as.html supplementary files. Phyla with prominent shifts were Spirochaetes, Proteobacteria, Cyanobacteria, Cloroflexi, Bacteroidetes, and the Euryarchaeota. Euryarchaeota became one of the main groups in the communities of 2019 (from 2% to 28%), and the phylum responsible for the overall increase in Archaea. In contrast, Cyanobacteria, Chloroflexi and Bacteroidetes showed a diminished abundance during that same year. Spirochaetes had increased in abundance in October 2016 to end in a constant frequency in the following samples. From this initial domain and phyla description, we could infer that the community’s composition is heavily affected by each seasonal-and overall, temporal-shift(s), pointing towards a sensitive, non-resistant, microbial community [##UREF##104##105##].</p>", "<p id=\"Par24\">At the genus level, the taxonomic replacement is even more noticeable (Fig. ##FIG##4##5##b). For each sample, we could observe two main phenomena: i) some genera are present in every sample (core genera), while ii) most genera are new additions or become undetected between each sample. As a matter of fact, taxonomic replacement becomes increasingly complex with each new sample, which reflects how the community has changed since the first sampling in April 2016. We were interested to evaluate which taxa are key in driving the community to new compositional states, based on the differential abundances between samples. Coupling UMAP (Uniform Manifold Approximation and Projection), a nonlinear dimensionality reduction method, with HDBSCAN (Hierarchical Density-Based Spatial Clustering of Applications with Noise), a clustering algorithm, we find groups that might be leading the community dynamics (Fig. ##FIG##4##5##c). First, the main cluster contains most of the genera, with the inclusion of all the abundant taxa (1734 genera in class 4). In contrast, four small groups with fewer genera in each one (22, 116, 200, and 182 genera in classes 0,1,2, and 3, respectively. Group composition is supplied as a supplementary.csv file); these groups are made up entirely of genera belonging to the rare biosphere, and shifts in their abundance seem to be major ecological drivers in the system. This result could further support the relevance of the rare biosphere in biogeochemical processes and microbial community assembly, particularly, under fluctuating conditions as those met in the Archean Domes system [for reviews on rare biosphere, see ##UREF##21##22##, ##UREF##105##106##].</p>", "<p id=\"Par25\">On account of the morphological changes of the pond in response to environmental perturbations, we conduct statistical analyses to evaluate if samples have higher resemblance to those collected in the same seasonal state. Alpha diversity indexes were calculated for each sample (Table S12 and Fig. ##SUPPL##0##S10##: Supplementary material), and no statistical significance was found between seasonal states (Wilcoxon Rank Sum test: Chao1 <italic>p</italic>=0.4, Shannon <italic>p</italic>=1, Inverse Simpson <italic>p</italic>=0.8); nonetheless, the Archean Domes have a high alpha diversity for both seasonal states as seen in Chao (143-271), Shannon (2.53.1) and inverse Simpson (4.68.3) indexes, and overall, the microbial system during the 2016-2019 dry seasons is less diverse. This fact is remarkable, as ecological resistance has been classically associated with the species/genera richness, where an increase or decrease in biodiversity could point to a decrease in compositional stability [##UREF##106##107##].</p>", "<p id=\"Par26\">Principal coordinates analysis (PCoA) and non-metric multidimensional scaling (NMDS) at the genus, order, and phylum level showed no seasonal aggregation of samples (Fig. ##SUPPL##0##S11##: Supplementary material); rather, three temporally-related groups seem to have formed: one with both 2016 samples, a second group with the 2017-2018 samples, and a last one more closely arranged which comprises the samples from 2019. This last cluster is expected, as taxonomic profiles from the dry and rainy seasons of 2019 showed noticeable similar compositions (Fig. ##FIG##3##4##) as noted previously (i.e., an increase in the Archaea relative abundances). Interpreting the resulting PCoA plot for taxonomic composition as a stability landscape (as mentioned above), it seems that the community transitioned towards different compositional states from 2016 until 2018, but in the 2019 samples the community remained in the same compositional equilibrium state. Aditionally, canonical correspondence analyses (CCA) were performed at the genus and phylum level along with the environmental variables provided by the EMA meteorological station (Fig. ##SUPPL##0##S12##: Supplementary material). From these analyses, apparently, 2017-2018 samples were driven by precipitation, whereas 2019 samples were driven by wind speed and humidity. These associations should be regarded with care due to the low sample number.</p>", "<p id=\"Par27\">Co-occurrence networks were built for each seasonal state to inspect general properties at the phylum level (Table S13 and Fig. ##SUPPL##0##S13##: Supplementary material). Both seasons show mainly two clusters, which might be interpreted as groups of highly interacting organisms or functional guilds with niche overlapping to some degree [##UREF##83##84##]. During the rainy season, several phyla from both groups transition to build a third cluster; hence, it is possible that these fluctuating environmental conditions directly influence differential interactions between phyla or niche overlaps, plausible consequences of phenotypic plasticity [##UREF##107##108##–##UREF##109##110##]. The phylum-level networks showed a positive edge percentage of 49.02% and 48.77% during the dry and rainy seasons, respectively; this network metric has been used to evaluate resilience and resistance in microbial co-occurrence networks: high positive/negative ratios, such as those found in these networks, have been interpreted to increase the community stability by avoiding feedback loops in taxa with overlapping niches [##UREF##25##26##]. High modularity has also been considered as a measure of community stability, diminishing the propagation of perturbations through the network [##UREF##25##26##, ##UREF##110##111##]. Modules in these networks might reliably represent functional guilds or niche overlapping [##UREF##25##26##, ##UREF##83##84##], and the Archean Domes microbial mats seem to change in modularity between the dry season (0.01) and rainy season (0.07) states. Lower modularity during the dry season might reflect the exposure and vulnerability of the system relative to when the mats are wet. We restrain to make inferences on specific biological interactions, as the small sample size might induce spurious correlations in the microbial networks.</p>", "<title>The Core Community</title>", "<p id=\"Par28\">Taxonomic composition and functions changed through time to some extent, as described in the previous sections. Still, there is a core community shared between all samples and seasons. The (global) core community consists of 250 genera out of the 967 total genera detected across the samples; just about 26% of the total diversity found in the Archean Domes (Fig. ##FIG##5##6##a). Conversely, the core community accounts for much of the genera relative abundance, ranging from 75.6%, 77.5% and 78.7% in samples Dry-2019, Wet-2019 and Wet-2016, respectively, to 80.8%, 81.4% and 92.9% in samples Dry-2017, Wet-2018 and Dry-2016, accordingly (Fig. ##SUPPL##0##S14##: Supplementary material). These genera can be portrayed as microbes with high physiological plasticity, able to cope with both environmental conditions (dry and rainy seasonal states) [##UREF##19##20##]. Seasonal cores were identified, that is, genera that only appeared in rainy or in dry season exclusively. Unlike the core community, seasonal cores were particularly small, with just 1 and 10 genera for dry and rainy seasons, accordingly (Fig. ##FIG##5##6##a). Every genus in the seasonal cores have a low abundance (<0.01%), and belong to the rare biosphere during each season. The organisms found only in rainy samples comprise several Alphaproteobacteria (<italic>Croceicoccus</italic>, <italic>Shimia</italic>, <italic>Rhodoplanes</italic>, and <italic>Polymorphum</italic>), Gammaproteobacteria (<italic>Teredinibacter</italic> and <italic>Allochromatium</italic>), Bacteroidetes (<italic>Ohtaekwangia</italic>), Cyanobacteria (<italic>Geminocystis</italic>), one Euryarchaeota (<italic>Methanosalsum</italic>) and a novel genus of Planctomycetes (Candidatus <italic>Jettenia</italic>) previously described in an anammox bioreactor [##UREF##111##112##]. Among these genera present only in rainy season, it is noticeable the presence of the phototrophs <italic>Allochromatium</italic> (purple sulfur bacteria), <italic>Rhodoplanes</italic> (photoheterotroph) and <italic>Geminocystis</italic> (oxygenic phototroph) [##UREF##112##113##, ##UREF##113##114##]. Recently, a <italic>Croceicoccus</italic> species has been found to be capable to produce AHL [##UREF##114##115##], which could be consistent with the slight increase in the AHL inducer genes during the rainy season. <italic>Teredinibacter</italic> have nitrogen fixation capabilities [##UREF##115##116##], while <italic>Methanosalum</italic> is a methylotrophic methanogen [##UREF##116##117##], which might aid in nutrient cycling during the rainy season. In contrast, the dry season core only contained the <italic>Maledivibacter</italic> genus, a member of the Clostridiales, Firmicutes. This genus produces hydrogen sulfide and ammonia under obligately halophilic conditions [##UREF##117##118##]. In fact, all the genera found in the seasonal cores are halophilic to some extent.</p>", "<p id=\"Par29\">We further analyzed the taxonomical structure and functions of the global core community. Most of the 250 core genera belong to the Proteobacteria (102), Bacteroidetes (43), Firmicutes (28), Euryarchaeota (12), Actinobacteria (11), and Cyanobacteria (10) (Fig. ##SUPPL##0##S15##: Supplementary material). Although these genera appear in every sample, their relative abundances fluctuate drastically between samples (Fig. ##SUPPL##0##S16##: Supplementary material). For instance, <italic>Coleofasciculus</italic> transitioned from being one of the genera with the highest abundance (10.2%) in 2017 to belong to the rare biosphere during the dry and rainy season of 2019 (0.06% and 0.05%, respectively). This change in abundance could be responsible for the reduced dome size and abundance in later samplings (cf. Figure ##SUPPL##0##S2##: Supplementary material), as EPS production has significant relevance in containing gases, inhibiting gas exchange between water, microbial mats, and the atmosphere [##UREF##10##11##]. Remarkably, most of the genera belonging to the core are part of the rare biosphere as well; likewise, every abundant genus belong to the core. Core functions relative abundances, on the other hand, appear highly conserved between samples (Fig. ##SUPPL##0##S15##: Supplementary material), with processes such as carbohydrate, amino acid, protein, RNA, and DNA metabolisms being the most abundant ones, unsurprisingly. PCoA ordination method suggest a seasonal pattern of functions, as the dry season samples of 2019 and 2016 were grouped in one cluster, while the rainy season samples of 2016 and 2018 were close to each other in another group (Fig. ##SUPPL##0##S15##: Supplementary material). The dry season sample of 2017 and the rainy season sample from 2019 does not cluster to any of the aforementioned groups. If interpreted as a stability landscape, the core community do return to the same seasonal stable state despite the press disturbance, unlike the global community. A bigger sample size will determine if these groups do preserve a seasonal pattern or not.</p>", "<p id=\"Par30\">Core co-occurrence networks at the genus level also provide insights into the global core dynamics for both the dry and rainy seasons (Fig. ##FIG##5##6##b). To begin with, there are six shared clusters of genera in both, dry and rainy seasons. Consistent with the networks built at the phylum level, the rainy season network for the 250 core genera displayed the addition of a new cluster that was not previously present in the dry season network. Additionally, many of the present genera relocate to different clusters between the dry and rainy seasons. This behavior could reflect how the core taxa differentially interact with each other in response to differential environmental pressures. Even though these taxa are present in the whole community, regardless of the season, it is natural to infer that interactions within this core community are the ones that change through the seasons. For both networks, global metrics were calculated, and once again, modularity and positive/negative ratio show consistency with the whole-community phylum networks (Table ##SUPPL##0##S13##: Supplementary material); dry and rainy seasons displayed relatively high modularity values (0.17 and 0.22, respectively), and the slightly lower value during the dry season could reflect a drop in community stability during this state. Positive edges in both networks account for the 41%, which result in high positive/negative ratios that further suggest a resistant and resilient community [##UREF##25##26##, ##UREF##110##111##]. Finally, hub taxa were predicted for each network, and among them, <italic>Coleofasciculus</italic>, <italic>Chitinispirillum</italic>, <italic>Desulfonatronovibrio</italic>, <italic>Desulfovermiculus</italic>, <italic>Halanaerobium</italic>, <italic>Halomonas</italic>, <italic>Halorhabdus</italic>, and <italic>Halorubrum</italic> are shared hubs between the seasons. Two hub groups appear during the dry season, whereas during the rainy season, every hub genus belong to the same cluster. It seems that some hub taxa (including <italic>Desulfonatronovibrio</italic>, <italic>Coleofasciculus</italic>, <italic>Halanaerobium</italic>, and <italic>Chitinispirillum</italic>) are also involved in the differential interactions between seasons. Given that sample size is small, detailed interaction analysis should be taken with caution. Thus, we restrain ourselves to just an exploratory, non-conclusive, global analysis of these networks.</p>" ]	[ "<title>Results and Discussion</title>", "<title>Functional Inference and Changes Through the Seasons</title>", "<p id=\"Par13\">Coding sequences were functionally classified. As expected, basic functions shared between all living beings are widely distributed among all samples, such as carbohydrate (14.5%), amino acid (11.9%), protein (8.9%), DNA (5.9%), RNA (5.0%), and fatty acids and lipids (3.1%) metabolisms; other processes regarding cofactor, vitamins, and pigments (10.7%), cell wall and capsule (4.2%), respiration (3.9%), and stress response (3.8%) are also among the top functions for all samples (Table ##SUPPL##0##S10##: Supplementary material). The fact that stress response genes appear in a relative high abundance is plausibly an adaptation to a community that is subject to ceaseless environmental pressures [##UREF##84##85##, ##UREF##85##86##], such as those found in the Archean Domes system. Differences in function abundance for every major process according to SUPER-FOCUS classification are depicted in Fig. ##FIG##1##2##a. Overall, samples appear to be similar among them, despite some functions with differential distribution among the samples, such as amino acid, fatty acids and lipids, central, secondary, nitrogen, potassium, and RNA metabolisms.</p>", "<p id=\"Par14\">We inspect in detail the functional role of stress response genes present at the Archean Domes. Using the GO classification, we identify resistance genes related to pH (both, alkaline and acidic genes as well as not specified, general pH control genes) salt, dormancy, and endosporulation conditions. Alkaline and salt resistance genes were the most abundant, with a mean proportion of 56.5% and 31.5%, respectively (Fig. ##SUPPL##0##S5##: Supplementary material). This behavior is expected, since salt and pH fluctuate considerably between seasons, and might exert a selection pressure on the organisms thriving on this site.</p>", "<p id=\"Par15\">Pfam protein groups were used to infer energy metabolisms and nutrient cycling within the mat samples (Fig. ##FIG##1##2##b). Based on normalized abundance, Wood-Ljungdahl pathway rules carbon metabolism among the mat, followed by the Calvin cycle. These results are consistent with other microbial mats previously described, where Wood-Ljungdahl dominance is regarded as a result of energy limitation, since this mechanism of carbon fixation is inefficient compared to other pathways [##UREF##63##64##, ##UREF##86##87##, ##UREF##87##88##]. Anoxygenic photosynthesis genes dominate over those specific to oxygenic photosynthesis, while sulfur oxidation and nitrogen fixation are potentially the main processes for sulfur and nitrogen metabolisms. Dissimilatory sulfate reduction is portrayed as a process with low gene abundances in the Archean Domes, despite the highly abundant sulfate reducing bacteria previously described; as such, metabolism inference based on gene abundances should be taken cautiously. Further reconstruction of full pathways would provide more accuracy in the relative abundances.</p>", "<p id=\"Par16\">Ecological resilience is not straightforward to assess in this system, as press disturbances are continuous and seasonal. Rather, inferences on ecological resilience could be evaluated under the assumption of many stable states in which a community may thrive. PCoA plots could be visualized as stability landscapes, where each snapshot of the community’s composition/function could be envisioned as a ball and where the different alternative stable states represent basins in the stability landscape. If resistance and resilience is high, a disturbance would not modify the current stable state of the community. On the contrary, if overall stability is low, and the disturbance powerful enough, the community will leave its current stable state to fall into an alternative stable state [for an in-depth review on the stability landscape, cf. ##UREF##11##12##, ##UREF##88##89##]. Looking at the PCoA plot with a Bray-Curtis measure for functions (Fig. ##FIG##2##3##a) we could see that seasonal “valleys” of alternative equilibria are formed, and that these equilibrium states are arranged into seasonal groups, although ordination is sparse. Further robust sampling will support the predictability of this clustering method.</p>", "<p id=\"Par17\">We modify a differential expression analysis to adapt it to our metagenomic using the classification defined by SUPER-FOCUS. Although none of the metabolic subsystems had a significant difference between seasons (<italic>p</italic> > 0.5), there were some processes that had a higher or lower abundance as seen by their fold change (Log Fold Change , Fig. ##SUPPL##0##S6##: Supplementary material). In the dry season, there were three slightly more abundant functions: the pentose phosphate pathway of plants, the alpha-acetolactate operon, and the biotin biosynthesis. From the pentose phosphate pathway, we had the glucose 6 phosphate dehydrogenase, the key enzyme of the Oxidative Pentose Phosphate Pathway (OPPP), which is related to the response of short- or long-term exposure to drought stress in plants [##UREF##89##90##]. The alpha-acetolactate operon has been described as a component in the mixed acid fermentation, done by some bacteria such as <italic>Bacillus subtilis</italic>, to produce acetoin in the absence of nitrate [##UREF##90##91##]; this could be associated to a shortage of nutrients in the dry season. Lastly, biotin biosynthesis is an important process, since biotin is a key cofactor in the fatty acids and amino acid metabolisms, as well as in the replenishment of the tricarboxylic acid cycle [##UREF##91##92##] which could be a relevant resistance process at low water activity. For the rainy season, some functions with a higher fold change were: the acyl homoserine lactone (AHL) inducer, which is involved in primary quorum sensing signals by Gram-negative bacteria [##UREF##92##93##]; the phage carbon metabolism auxiliary metabolic genes (AMGs), which consist of phage strategies for resource management during host infection [##UREF##93##94##, ##UREF##94##95##]; some archaeal hydrogenases involved in carbon fixation [##UREF##95##96##]; prenylated indole alkaloids production from actinomycetes, which have multiple biological functions such as antifungal and antibacterial activity [##UREF##96##97##]; and lastly, chlorophyll degradation related genes. Some of these functions could be directly associated with the presence of the green, cyanobacterial built, layer seen in the rainy seasons, such as in the phage-cyanobacterial AMGs [##UREF##93##94##], the quorum sensing for biofilm formation [##UREF##97##98##], and the chlorophyll degradation.</p>", "<p id=\"Par18\">Moreover, we were interested in how functions have changed over time and if there is a group of functions that leads global patterns in the community. According to k-means and hierarchical clustering, two main groups of functions were predicted. PCA analysis showed how these functions are projected, where high abundant functions are sparsely distributed in the plot, and most functions with low abundance functions were tightly clustered together (Fig. ##FIG##2##3##b). Each function’s class is provided as a supplementary.csv file. Comparing function abundance across samples suggest that functions are more similar between adjacent samples (Fig. ##FIG##2##3##c), despite the high similarity in function abundance for each sample. In consequence, the correlation cloud appears to be scattering when samples are more distant in time. For instance, sample Dry-2016 showed higher correlation with sample Wet-2016 than with the last sample from 2019 (Wet-2019). While major functions appear to be constant over time, this result suggests that overall functions are changing in abundance, perhaps slightly, between samples, and that cumulative changes in abundance for the final sample differ drastically from the initial function state. Further sampling may reinforce this hypothesis.</p>", "<p id=\"Par19\">Since functions are mostly preserved (in abundance) through the seasons, the microbial community might harbor a high degree of functionally redundant taxa [##UREF##23##24##]. This grants the community a robust capability to withstand taxonomic replacement, a phenomenon detected at the Archean Domes system which is the outcome of a non-resistant community in terms of phylogenetic composition (see the following section).</p>", "<title>Taxonomical Characterization, Compositional Dynamics, and Seasonal Comparison</title>", "<p id=\"Par20\">We built rarefaction curves to evaluate diversity coverage for all samples. For genera richness, each sample reaches saturation and comparisons between them is suitable (Fig. ##SUPPL##0##S7##: Supplementary material). Open read-frames were predicted for reads, and further annotated for taxonomic classification with CAT and ribosomal protein families. With CAT, we detected 162 phyla, 2250 genera (across all samples), and more than 8,000 phylotypes per sample (Table ##SUPPL##0##S7##: Supplementary material). Nevertheless, only 30-58% of the total predicted genes for each sample were classified, suggesting a considerable amount of potential novel taxonomic groups, which comprise the so called microbial dark matter; these potentially uncultured organisms are by no means irrelevant, as they have shown to be of importance in other hypersaline microbial mats [##UREF##98##99##]. From the 2250 total genera found in the system, only between 16-19 for each sample belong to the abundant genera, that is, with an abundance >1%. In contrast, between 426-619 genera have abundances <0.1%, and belong to the so called rare biosphere. Rare taxa account for the 11.218.9% of the whole community, whereas abundant taxa comprises the 43.367.6% (Table S11 and Fig. ##SUPPL##0##S8##: Supplementary material). Therefore, although taxa that are abundant only consists of a few genera, these taxa often build most of the microbial community biomass. Moderately abundant taxa (>0.1% and <1%) sits between the abundant and rare, with a relative abundance of 19.637.7% in the samples studied.</p>", "<p id=\"Par21\">Regarding the taxonomic composition, overall, mean abundances per domain show consistent results between CAT and ribosomal gene annotation. For CAT taxonomic assignment we got mean abundances of: 85.24% for Bacteria, 14.43% for Archaea, and 0.3% for Eukaryota (Table ##SUPPL##0##S7##: Supplementary material); whereas ribosomal gene annotation showed: 86.56% for Bacteria, 13.35% for Archaea, and 0.08% for Eukaryota (Table ##SUPPL##0##S8##: Supplementary material). At the phylum level, samples consistently displayed Proteobacteria (23.51%), Euryarchaeota (11.42%), Bacteroidetes (10.26%), Firmicutes (4.35%), Cyanobacteria (3.30%), Spirochaetes (2.84%), Planctomycetes (1.99%) and Chloroflexi (1.42%) as the most abundant phyla (Fig. ##FIG##3##4##). The taxonomic annotation with ribosomal genes is also consistent with the phyla relative abundances of CAT annotation (taxonomic profile based on ribosomal proteins is shown in Fig. ##SUPPL##0##S9##: Supplementary material).</p>", "<p id=\"Par22\">At the genus level, we find <italic>Coleofasciculus</italic> as the most abundant Cyanobacteria between all samples, which is widely known as a key mat-forming genus in sandy environments [##UREF##8##9##, ##UREF##10##11##, ##UREF##99##100##, ##UREF##100##101##]. Other cyanobacterial genera such as <italic>Leptolyngbya</italic>, <italic>Halothece</italic>, and <italic>Phormidium</italic> are also abundant between samples, and have also been previously reported in microbial mats [##UREF##99##100##, ##UREF##101##102##, ##UREF##102##103##]. Anaerobic, halophilic, sulfate-reducing members of the Deltaproteobacteria such as <italic>Desulfonatronovibrio</italic>, <italic>Desulfonatronospira</italic>, and <italic>Desulfovermiculus</italic> [##UREF##103##104##] also appear in abundance in the Archean Domes samples. Other relevant and abundant taxonomic genera present in the samples include <italic>Halorubrum</italic> (Euryarchaeota), <italic>Halanaerobium</italic> (Firmicutes), <italic>Spirocheta</italic> (Spirochetes), <italic>Chitinispirillum</italic> (Fibrobacteres), and <italic>Tangfeifania</italic> (Bacteroidetes).</p>", "<p id=\"Par23\">Figure ##FIG##4##5##a show the community composition changes through the years. One of the most noticeable changes through the years was a rise of Archaea (from 1-4% to 33%) in the samples of 2019 (Tables ##SUPPL##0##S5## and ##SUPPL##0##S6##: Supplementary material). Consequently, Bacteria reduced their abundance up to 65%, a third less from previous years. Viruses followed the same tendency as the Archaea during 2019, in a subtle rise of abundance (0.080.2% to 0.4%), while Eukaryota had an apparent seasonal pattern in the first two years (2016–2018), continuing with a steady state in 2019. Since the increased abundance of Archaea was considerable, the compositional dynamics between 2016-2018 is not readily noticeable. Considering only the abundance shifts between 2016-2018, all domains presented a plausible seasonal pattern: archaea, eukaryotes and viruses rose proportionally in the rainy season compared to the dry one. To explore which organisms may drive these seasonal patterns, we examined phyla changes in abundance through time. Interactive streamgraphs for phyla shifts are provided as.html supplementary files. Phyla with prominent shifts were Spirochaetes, Proteobacteria, Cyanobacteria, Cloroflexi, Bacteroidetes, and the Euryarchaeota. Euryarchaeota became one of the main groups in the communities of 2019 (from 2% to 28%), and the phylum responsible for the overall increase in Archaea. In contrast, Cyanobacteria, Chloroflexi and Bacteroidetes showed a diminished abundance during that same year. Spirochaetes had increased in abundance in October 2016 to end in a constant frequency in the following samples. From this initial domain and phyla description, we could infer that the community’s composition is heavily affected by each seasonal-and overall, temporal-shift(s), pointing towards a sensitive, non-resistant, microbial community [##UREF##104##105##].</p>", "<p id=\"Par24\">At the genus level, the taxonomic replacement is even more noticeable (Fig. ##FIG##4##5##b). For each sample, we could observe two main phenomena: i) some genera are present in every sample (core genera), while ii) most genera are new additions or become undetected between each sample. As a matter of fact, taxonomic replacement becomes increasingly complex with each new sample, which reflects how the community has changed since the first sampling in April 2016. We were interested to evaluate which taxa are key in driving the community to new compositional states, based on the differential abundances between samples. Coupling UMAP (Uniform Manifold Approximation and Projection), a nonlinear dimensionality reduction method, with HDBSCAN (Hierarchical Density-Based Spatial Clustering of Applications with Noise), a clustering algorithm, we find groups that might be leading the community dynamics (Fig. ##FIG##4##5##c). First, the main cluster contains most of the genera, with the inclusion of all the abundant taxa (1734 genera in class 4). In contrast, four small groups with fewer genera in each one (22, 116, 200, and 182 genera in classes 0,1,2, and 3, respectively. Group composition is supplied as a supplementary.csv file); these groups are made up entirely of genera belonging to the rare biosphere, and shifts in their abundance seem to be major ecological drivers in the system. This result could further support the relevance of the rare biosphere in biogeochemical processes and microbial community assembly, particularly, under fluctuating conditions as those met in the Archean Domes system [for reviews on rare biosphere, see ##UREF##21##22##, ##UREF##105##106##].</p>", "<p id=\"Par25\">On account of the morphological changes of the pond in response to environmental perturbations, we conduct statistical analyses to evaluate if samples have higher resemblance to those collected in the same seasonal state. Alpha diversity indexes were calculated for each sample (Table S12 and Fig. ##SUPPL##0##S10##: Supplementary material), and no statistical significance was found between seasonal states (Wilcoxon Rank Sum test: Chao1 <italic>p</italic>=0.4, Shannon <italic>p</italic>=1, Inverse Simpson <italic>p</italic>=0.8); nonetheless, the Archean Domes have a high alpha diversity for both seasonal states as seen in Chao (143-271), Shannon (2.53.1) and inverse Simpson (4.68.3) indexes, and overall, the microbial system during the 2016-2019 dry seasons is less diverse. This fact is remarkable, as ecological resistance has been classically associated with the species/genera richness, where an increase or decrease in biodiversity could point to a decrease in compositional stability [##UREF##106##107##].</p>", "<p id=\"Par26\">Principal coordinates analysis (PCoA) and non-metric multidimensional scaling (NMDS) at the genus, order, and phylum level showed no seasonal aggregation of samples (Fig. ##SUPPL##0##S11##: Supplementary material); rather, three temporally-related groups seem to have formed: one with both 2016 samples, a second group with the 2017-2018 samples, and a last one more closely arranged which comprises the samples from 2019. This last cluster is expected, as taxonomic profiles from the dry and rainy seasons of 2019 showed noticeable similar compositions (Fig. ##FIG##3##4##) as noted previously (i.e., an increase in the Archaea relative abundances). Interpreting the resulting PCoA plot for taxonomic composition as a stability landscape (as mentioned above), it seems that the community transitioned towards different compositional states from 2016 until 2018, but in the 2019 samples the community remained in the same compositional equilibrium state. Aditionally, canonical correspondence analyses (CCA) were performed at the genus and phylum level along with the environmental variables provided by the EMA meteorological station (Fig. ##SUPPL##0##S12##: Supplementary material). From these analyses, apparently, 2017-2018 samples were driven by precipitation, whereas 2019 samples were driven by wind speed and humidity. These associations should be regarded with care due to the low sample number.</p>", "<p id=\"Par27\">Co-occurrence networks were built for each seasonal state to inspect general properties at the phylum level (Table S13 and Fig. ##SUPPL##0##S13##: Supplementary material). Both seasons show mainly two clusters, which might be interpreted as groups of highly interacting organisms or functional guilds with niche overlapping to some degree [##UREF##83##84##]. During the rainy season, several phyla from both groups transition to build a third cluster; hence, it is possible that these fluctuating environmental conditions directly influence differential interactions between phyla or niche overlaps, plausible consequences of phenotypic plasticity [##UREF##107##108##–##UREF##109##110##]. The phylum-level networks showed a positive edge percentage of 49.02% and 48.77% during the dry and rainy seasons, respectively; this network metric has been used to evaluate resilience and resistance in microbial co-occurrence networks: high positive/negative ratios, such as those found in these networks, have been interpreted to increase the community stability by avoiding feedback loops in taxa with overlapping niches [##UREF##25##26##]. High modularity has also been considered as a measure of community stability, diminishing the propagation of perturbations through the network [##UREF##25##26##, ##UREF##110##111##]. Modules in these networks might reliably represent functional guilds or niche overlapping [##UREF##25##26##, ##UREF##83##84##], and the Archean Domes microbial mats seem to change in modularity between the dry season (0.01) and rainy season (0.07) states. Lower modularity during the dry season might reflect the exposure and vulnerability of the system relative to when the mats are wet. We restrain to make inferences on specific biological interactions, as the small sample size might induce spurious correlations in the microbial networks.</p>", "<title>The Core Community</title>", "<p id=\"Par28\">Taxonomic composition and functions changed through time to some extent, as described in the previous sections. Still, there is a core community shared between all samples and seasons. The (global) core community consists of 250 genera out of the 967 total genera detected across the samples; just about 26% of the total diversity found in the Archean Domes (Fig. ##FIG##5##6##a). Conversely, the core community accounts for much of the genera relative abundance, ranging from 75.6%, 77.5% and 78.7% in samples Dry-2019, Wet-2019 and Wet-2016, respectively, to 80.8%, 81.4% and 92.9% in samples Dry-2017, Wet-2018 and Dry-2016, accordingly (Fig. ##SUPPL##0##S14##: Supplementary material). These genera can be portrayed as microbes with high physiological plasticity, able to cope with both environmental conditions (dry and rainy seasonal states) [##UREF##19##20##]. Seasonal cores were identified, that is, genera that only appeared in rainy or in dry season exclusively. Unlike the core community, seasonal cores were particularly small, with just 1 and 10 genera for dry and rainy seasons, accordingly (Fig. ##FIG##5##6##a). Every genus in the seasonal cores have a low abundance (<0.01%), and belong to the rare biosphere during each season. The organisms found only in rainy samples comprise several Alphaproteobacteria (<italic>Croceicoccus</italic>, <italic>Shimia</italic>, <italic>Rhodoplanes</italic>, and <italic>Polymorphum</italic>), Gammaproteobacteria (<italic>Teredinibacter</italic> and <italic>Allochromatium</italic>), Bacteroidetes (<italic>Ohtaekwangia</italic>), Cyanobacteria (<italic>Geminocystis</italic>), one Euryarchaeota (<italic>Methanosalsum</italic>) and a novel genus of Planctomycetes (Candidatus <italic>Jettenia</italic>) previously described in an anammox bioreactor [##UREF##111##112##]. Among these genera present only in rainy season, it is noticeable the presence of the phototrophs <italic>Allochromatium</italic> (purple sulfur bacteria), <italic>Rhodoplanes</italic> (photoheterotroph) and <italic>Geminocystis</italic> (oxygenic phototroph) [##UREF##112##113##, ##UREF##113##114##]. Recently, a <italic>Croceicoccus</italic> species has been found to be capable to produce AHL [##UREF##114##115##], which could be consistent with the slight increase in the AHL inducer genes during the rainy season. <italic>Teredinibacter</italic> have nitrogen fixation capabilities [##UREF##115##116##], while <italic>Methanosalum</italic> is a methylotrophic methanogen [##UREF##116##117##], which might aid in nutrient cycling during the rainy season. In contrast, the dry season core only contained the <italic>Maledivibacter</italic> genus, a member of the Clostridiales, Firmicutes. This genus produces hydrogen sulfide and ammonia under obligately halophilic conditions [##UREF##117##118##]. In fact, all the genera found in the seasonal cores are halophilic to some extent.</p>", "<p id=\"Par29\">We further analyzed the taxonomical structure and functions of the global core community. Most of the 250 core genera belong to the Proteobacteria (102), Bacteroidetes (43), Firmicutes (28), Euryarchaeota (12), Actinobacteria (11), and Cyanobacteria (10) (Fig. ##SUPPL##0##S15##: Supplementary material). Although these genera appear in every sample, their relative abundances fluctuate drastically between samples (Fig. ##SUPPL##0##S16##: Supplementary material). For instance, <italic>Coleofasciculus</italic> transitioned from being one of the genera with the highest abundance (10.2%) in 2017 to belong to the rare biosphere during the dry and rainy season of 2019 (0.06% and 0.05%, respectively). This change in abundance could be responsible for the reduced dome size and abundance in later samplings (cf. Figure ##SUPPL##0##S2##: Supplementary material), as EPS production has significant relevance in containing gases, inhibiting gas exchange between water, microbial mats, and the atmosphere [##UREF##10##11##]. Remarkably, most of the genera belonging to the core are part of the rare biosphere as well; likewise, every abundant genus belong to the core. Core functions relative abundances, on the other hand, appear highly conserved between samples (Fig. ##SUPPL##0##S15##: Supplementary material), with processes such as carbohydrate, amino acid, protein, RNA, and DNA metabolisms being the most abundant ones, unsurprisingly. PCoA ordination method suggest a seasonal pattern of functions, as the dry season samples of 2019 and 2016 were grouped in one cluster, while the rainy season samples of 2016 and 2018 were close to each other in another group (Fig. ##SUPPL##0##S15##: Supplementary material). The dry season sample of 2017 and the rainy season sample from 2019 does not cluster to any of the aforementioned groups. If interpreted as a stability landscape, the core community do return to the same seasonal stable state despite the press disturbance, unlike the global community. A bigger sample size will determine if these groups do preserve a seasonal pattern or not.</p>", "<p id=\"Par30\">Core co-occurrence networks at the genus level also provide insights into the global core dynamics for both the dry and rainy seasons (Fig. ##FIG##5##6##b). To begin with, there are six shared clusters of genera in both, dry and rainy seasons. Consistent with the networks built at the phylum level, the rainy season network for the 250 core genera displayed the addition of a new cluster that was not previously present in the dry season network. Additionally, many of the present genera relocate to different clusters between the dry and rainy seasons. This behavior could reflect how the core taxa differentially interact with each other in response to differential environmental pressures. Even though these taxa are present in the whole community, regardless of the season, it is natural to infer that interactions within this core community are the ones that change through the seasons. For both networks, global metrics were calculated, and once again, modularity and positive/negative ratio show consistency with the whole-community phylum networks (Table ##SUPPL##0##S13##: Supplementary material); dry and rainy seasons displayed relatively high modularity values (0.17 and 0.22, respectively), and the slightly lower value during the dry season could reflect a drop in community stability during this state. Positive edges in both networks account for the 41%, which result in high positive/negative ratios that further suggest a resistant and resilient community [##UREF##25##26##, ##UREF##110##111##]. Finally, hub taxa were predicted for each network, and among them, <italic>Coleofasciculus</italic>, <italic>Chitinispirillum</italic>, <italic>Desulfonatronovibrio</italic>, <italic>Desulfovermiculus</italic>, <italic>Halanaerobium</italic>, <italic>Halomonas</italic>, <italic>Halorhabdus</italic>, and <italic>Halorubrum</italic> are shared hubs between the seasons. Two hub groups appear during the dry season, whereas during the rainy season, every hub genus belong to the same cluster. It seems that some hub taxa (including <italic>Desulfonatronovibrio</italic>, <italic>Coleofasciculus</italic>, <italic>Halanaerobium</italic>, and <italic>Chitinispirillum</italic>) are also involved in the differential interactions between seasons. Given that sample size is small, detailed interaction analysis should be taken with caution. Thus, we restrain ourselves to just an exploratory, non-conclusive, global analysis of these networks.</p>" ]	[ "<title>Conclusions and Perspectives</title>", "<p id=\"Par31\">Based on our results, we have concluded that the Archean Domes microbial system is able to maintain its stability despite seasonal fluctuations, including prolonged drought periods. This stability can be attributed to the diverse yet resilient-poor community and the functional redundancy that enables the system to resist significant alterations during and after perturbations. To gain a deeper understanding of the microbial dynamics of this system, future studies should focus on tracking its evolution over a longer timespan, measuring more environmental parameters, and increasing the robustness of sampling through replicates. Specifically, future studies should aim to identify the mechanisms through which moderately-abundant and rare biosphere taxa contribute to the system’s stability, confidently identify hub taxa and their interactions, and comprehend the interplay between Archaea and Bacteria. Overall, our findings highlight the importance of understanding the mechanisms that enable microbial systems to maintain stability in response to environmental fluctuations, which can have significant implications for ecosystem functioning and resilience.</p>", "<p id=\"Par32\">Further work on the ecological stability of microbial mats have the potential to aid in our understanding of early life on Earth. Previous studies have suggested that laminae within stromatolites represent successions of microbial communities as a response to environmental fluctuations [##UREF##118##119##, ##UREF##119##120##]. This concept applies to non-lithifying microbial mats as well. For instance, colonization-growth-burial dynamics are easily recognized in siliciclastic rocks from the Moodies Group (3.22 Ga) [cf. photographs of polished slabs in ##UREF##5##6##, ##UREF##120##121##]; during times of low hydrodynamic energy, microbial mats develop where the deposited sand is recolonized by planktonic or mat-dwelling microbes, after which sandy sediment deposition buries the previous microbial community (i.e., an ecological disturbance). Individual kerogenous laminae derived from the decay of microbial mats most likely represent a snapshot of the microbial community, and could potentially display diversity in geochemical signals such as those reported in organic films from the Buck Reef Chert (3.4 Ga) [##UREF##121##122##], perhaps inherited from taxonomic turnover and drift of a functionally stable ecosystem. To gain a better understanding of how these systems have responded to environmental perturbations in the past, it is essential to develop mechanistic models that explain microbial dynamics under environmental pressures within modern microbial mats.</p>" ]	[ "<p id=\"Par1\">Microbial mats are complex ecological assemblages that have been present in the rock record since the Precambrian and can still be found in extant marginalized environments. These structures are considered highly stable ecosystems. In this study, we evaluate the ecological stability of dome-forming microbial mats in a modern, water-level fluctuating, hypersaline pond located in the Cuatro Ciénegas Basin, Mexico. We conducted metagenomic sampling of the site from 2016 to 2019 and detected 2250 genera of Bacteria and Archaea, with only <20 belonging to the abundant taxa (>1%). The microbial community was dominated by Proteobacteria, Euryarchaeota, Bacteroidetes, Firmicutes, and Cyanobacteria, and was compositionally sensitive to disturbances, leading to high taxonomic replacement even at the phylum level, with a significant increase in Archaea from 1-4% to 33% throughout the 2016-2019 study period. Although a core community represented most of the microbial community (>75%), relative abundances shifted significantly between samples, as demonstrated by changes in the abundance of <italic>Coleofasciculus</italic> from 10.2% in 2017 to 0.05% in 2019. Although functional differences between seasons were subtle, co-occurrence networks suggest differential ecological interactions between the seasons, with the addition of a new module during the rainy season and the potential shift in hub taxa. Functional composition was slightly more similar between samples, but basic processes such as carbohydrate, amino acid, and nucleic acid metabolisms were widely distributed among samples. Major carbon fixation processes included sulfur oxidation, nitrogen fixation, and photosynthesis (both oxygenic and anoxygenic), as well as the Wood-Ljundgahl and Calvin cycles.</p>", "<title>Supplementary Information</title>", "<p>The online version contains supplementary material available at 10.1007/s00248-023-02231-9.</p>", "<title>Keywords</title>" ]	[ "<title>Supplementary Information</title>", "<p>Below is the link to the electronic supplementary material.</p>" ]	[ "<title>Acknowledgements</title>", "<p>We thank Rosalinda Tapia, Erika Aguirre, and Saúl Pilatowsky for technical support. We also thank Pronatura Noreste for granting us access to Rancho Pozas Azules. We appreciate the assistance of Manuel Rosas, Mariette Viladomat, Manuel II García-Ulloa, Jhoselinne Buenrostro, Maria Kalambokidis, Jesica Hernández, Mateo Saldivar, Julián F. Cifuentes, and Juan D. Villar during the 2016-2019 samplings and DNA extractions. We greatly acknowledge Frédéric Thalasso for CO and CH measurements. Additionally, we thank Elizabeth Márquez and Fabián A. Pascual for their contributions to the resistance genes, and UMAP/HDBSCAN/k-means analyses respectively.</p>", "<title>Funding</title>", "<p>This research was supported by DGAPA/UNAM-PAPIIT Project IG200319, CEQUA project ANID R20F0009, and PhD scholarship 970341 granted to J.S.P. by Consejo Nacional de Ciencia y Tecnologia (CONACyT).</p>", "<title>Data availability</title>", "<p>Raw reads for all samples can be found at the NIH BioProject: Cuatro Cienegas Basin, Archaean Domes, under the accession number PRJNA847603 (<ext-link ext-link-type=\"uri\" xlink:href=\"https://www.ncbi.nlm.nih.gov/sra/PRJNA847603\">https://www.ncbi.nlm.nih.gov/sra/PRJNA847603</ext-link>). This study comprises SRA accessions SRX15887985-SRX15887990.</p>", "<title>Financial disclosure statement</title>", "<p>This research was supported by DGAPA/UNAM-PAPIIT Project IG200319, CEQUA project ANID R20F0009, and PhD scholarship 970341 granted to J.S.P. by Consejo Nacional de Ciencia y Tecnologia (CONACyT).</p>", "<title>Declarations</title>", "<title>Conflict of interest</title>", "<p id=\"Par37\">The authors declare no competing financial interests.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><p>The Archean Domes microbial system. The pond (50x25 m) displays different features during <italic>a)</italic> dry season (sampling of March 2019) and <italic>b)</italic> rainy season (sampling of March 2016). <italic>c)</italic> Detail of the dome-like structures of 10-15 cm in diameter. <italic>d)</italic> 10X magnification of the microbial mat; functional stratification and sediment grains can be appreciated at this scale. Photo credit for <italic>a-c)</italic>: David Jaramillo</p></caption></fig>", "<fig id=\"Fig2\"><label>Fig. 2</label><caption><p>Potential functional profile based on metagenomic inference. <italic>a)</italic> Heatmap of SUPER-FOCUS major functions, with color intensity reflecting differences in normalized abundance between samples. <italic>b)</italic> Normalized abundance of selected pathways based on pathway-specific Pfam protein groups. HP/HB=3-hydroxypropionate/4-hydroxybutyrate, TCA=tricarboxylic acid</p></caption></fig>", "<fig id=\"Fig3\"><label>Fig. 3</label><caption><p>Functional comparison between seasons and functional changes throughout the years. <italic>a)</italic> Dry and rainy season comparison based on top SUPER-FOCUS processes. Similar abundances can be inferred from both dry and rainy seasons (green dots lay mostly on top of the orange dots). <italic>a)</italic> PCoA of functions with Bray-Curtis measure, where samples are grouped, to some extent, by season. <italic>b)</italic> PCA analysis showing main groups of functions by k-means clustering. cluster 1 (red) shows high sparsity, and it is associated with the most abundant functions, while cluster 2 (blue) has functions with lower abundance. <italic>c)</italic> Correlations of function abundance between each sample, where each sample is more similar to the adjacent ones in time. X and Y axes show number of counts</p></caption></fig>", "<fig id=\"Fig4\"><label>Fig. 4</label><caption><p>Taxonomic profile of the Archean Domes based on CAT annotation. Only the top abundant phyla are displayed. Not annotated phyla were grouped into NA category for each superkingdom, accordingly. Sequences not annotated at the superkingdom level are not shown</p></caption></fig>", "<fig id=\"Fig5\"><label>Fig. 5</label><caption><p>Taxonomic replacement and community dynamics throughout the years. <italic>a)</italic> Changes in superkingdom abundances from 2016 to 2019. Notice differences in scales. <italic>b)</italic> Community dynamics at the genus level. Flows show genera that remain, appeared or disappeared from the system through the samples. Genera that are not detected within a given sample are grouped as undetected. Undetected genera that appeared in the subsequent sample are grouped as new genera, whereas they remain in the undetected group otherwise. Genera detected in one sample can also become undetected genera in the one that follows. <italic>c)</italic> UMAP dimension reduction and HDBSCAN clustering technique applied on the differences in genus abundance for each sample. 5 clusters were generated (0-5)</p></caption></fig>", "<fig id=\"Fig6\"><label>Fig. 6</label><caption><p>The core community at the Archean Domes microbial system. <italic>a)</italic> Upset plot showing the number of shared genera between different sample intersections. Global core showed 250 genera, while rainy core and dry core showed 10 and 1 genera, respectively. <italic>b)</italic> Co-occurrence networks for core genera during the dry and rainy seasons, where color indicates different clusters. Six clusters are shared between dry and rainy seasons. Note the addition of a red cluster during the rainy season. Green and red edges represent positive and negative relationships, respectively. Hub taxa are shown with labels</p></caption></fig>" ]	[]	[ "<inline-formula id=\"IEq1\"><alternatives><tex-math id=\"M1\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M2\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq2\"><alternatives><tex-math id=\"M3\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M4\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq3\"><alternatives><tex-math id=\"M5\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M6\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq4\"><alternatives><tex-math id=\"M7\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M8\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq5\"><alternatives><tex-math id=\"M9\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$^{\\circ }$$\\end{document}</tex-math><mml:math id=\"M10\"><mml:msup><mml:mrow/><mml:mo>∘</mml:mo></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq6\"><alternatives><tex-math id=\"M11\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$^{\\circ }$$\\end{document}</tex-math><mml:math id=\"M12\"><mml:msup><mml:mrow/><mml:mo>∘</mml:mo></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq7\"><alternatives><tex-math id=\"M13\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M14\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq8\"><alternatives><tex-math id=\"M15\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M16\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq9\"><alternatives><tex-math id=\"M17\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mu $$\\end{document}</tex-math><mml:math id=\"M18\"><mml:mi>μ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq10\"><alternatives><tex-math id=\"M19\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mu $$\\end{document}</tex-math><mml:math id=\"M20\"><mml:mi>μ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq11\"><alternatives><tex-math id=\"M21\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M22\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq12\"><alternatives><tex-math id=\"M23\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M24\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq13\"><alternatives><tex-math id=\"M25\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M26\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq14\"><alternatives><tex-math id=\"M27\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M28\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq15\"><alternatives><tex-math id=\"M29\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M30\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq16\"><alternatives><tex-math id=\"M31\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M32\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq17\"><alternatives><tex-math id=\"M33\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M34\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq18\"><alternatives><tex-math id=\"M35\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M36\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq19\"><alternatives><tex-math id=\"M37\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M38\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq20\"><alternatives><tex-math id=\"M39\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M40\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq21\"><alternatives><tex-math id=\"M41\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M42\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq22\"><alternatives><tex-math id=\"M43\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$^{\\circ }$$\\end{document}</tex-math><mml:math id=\"M44\"><mml:msup><mml:mrow/><mml:mo>∘</mml:mo></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq23\"><alternatives><tex-math id=\"M45\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$^{\\circ }$$\\end{document}</tex-math><mml:math id=\"M46\"><mml:msup><mml:mrow/><mml:mo>∘</mml:mo></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq24\"><alternatives><tex-math id=\"M47\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$^{\\circ }$$\\end{document}</tex-math><mml:math id=\"M48\"><mml:msup><mml:mrow/><mml:mo>∘</mml:mo></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq25\"><alternatives><tex-math id=\"M49\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_4$$\\end{document}</tex-math><mml:math id=\"M50\"><mml:msub><mml:mrow/><mml:mn>4</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq26\"><alternatives><tex-math id=\"M51\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_2$$\\end{document}</tex-math><mml:math id=\"M52\"><mml:msub><mml:mrow/><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq27\"><alternatives><tex-math id=\"M53\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_4$$\\end{document}</tex-math><mml:math id=\"M54\"><mml:msub><mml:mrow/><mml:mn>4</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq28\"><alternatives><tex-math id=\"M55\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_2$$\\end{document}</tex-math><mml:math id=\"M56\"><mml:msub><mml:mrow/><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq29\"><alternatives><tex-math id=\"M57\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_2$$\\end{document}</tex-math><mml:math id=\"M58\"><mml:msub><mml:mrow/><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq30\"><alternatives><tex-math id=\"M59\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_4$$\\end{document}</tex-math><mml:math id=\"M60\"><mml:msub><mml:mrow/><mml:mn>4</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq31\"><alternatives><tex-math id=\"M61\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_2$$\\end{document}</tex-math><mml:math id=\"M62\"><mml:msub><mml:mrow/><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq32\"><alternatives><tex-math id=\"M63\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_4$$\\end{document}</tex-math><mml:math id=\"M64\"><mml:msub><mml:mrow/><mml:mn>4</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq33\"><alternatives><tex-math id=\"M65\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_2$$\\end{document}</tex-math><mml:math id=\"M66\"><mml:msub><mml:mrow/><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq34\"><alternatives><tex-math id=\"M67\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_4$$\\end{document}</tex-math><mml:math id=\"M68\"><mml:msub><mml:mrow/><mml:mn>4</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq35\"><alternatives><tex-math id=\"M69\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_2$$\\end{document}</tex-math><mml:math id=\"M70\"><mml:msub><mml:mrow/><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq36\"><alternatives><tex-math id=\"M71\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M72\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq37\"><alternatives><tex-math id=\"M73\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$^{-6}$$\\end{document}</tex-math><mml:math id=\"M74\"><mml:msup><mml:mrow/><mml:mrow><mml:mo>-</mml:mo><mml:mn>6</mml:mn></mml:mrow></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq38\"><alternatives><tex-math id=\"M75\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_2$$\\end{document}</tex-math><mml:math id=\"M76\"><mml:msub><mml:mrow/><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq39\"><alternatives><tex-math id=\"M77\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$>\|2.5\|$$\\end{document}</tex-math><mml:math id=\"M78\"><mml:mrow><mml:mo>></mml:mo><mml:mo stretchy=\"false\">\|</mml:mo><mml:mn>2.5</mml:mn><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq40\"><alternatives><tex-math id=\"M79\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M80\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq41\"><alternatives><tex-math id=\"M81\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M82\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq42\"><alternatives><tex-math id=\"M83\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M84\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq43\"><alternatives><tex-math id=\"M85\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M86\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq44\"><alternatives><tex-math id=\"M87\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M88\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq45\"><alternatives><tex-math id=\"M89\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M90\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq46\"><alternatives><tex-math id=\"M91\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M92\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq47\"><alternatives><tex-math id=\"M93\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M94\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq48\"><alternatives><tex-math id=\"M95\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M96\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq49\"><alternatives><tex-math id=\"M97\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M98\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq50\"><alternatives><tex-math id=\"M99\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M100\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq51\"><alternatives><tex-math id=\"M101\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M102\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq52\"><alternatives><tex-math id=\"M103\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-$$\\end{document}</tex-math><mml:math id=\"M104\"><mml:mo>-</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq53\"><alternatives><tex-math id=\"M105\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M106\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq54\"><alternatives><tex-math id=\"M107\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sim $$\\end{document}</tex-math><mml:math id=\"M108\"><mml:mo>∼</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq55\"><alternatives><tex-math id=\"M109\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_2$$\\end{document}</tex-math><mml:math id=\"M110\"><mml:msub><mml:mrow/><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq56\"><alternatives><tex-math id=\"M111\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$_4$$\\end{document}</tex-math><mml:math id=\"M112\"><mml:msub><mml:mrow/><mml:mn>4</mml:mn></mml:msub></mml:math></alternatives></inline-formula>" ]	[]	[]	[]	[]	[ "<supplementary-material content-type=\"local-data\" id=\"MOESM1\"></supplementary-material>" ]	[ "<fn-group><fn><p><bold>Publisher's Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn><fn><p><bold>Change history</bold></p><p>1/13/2024</p><p>The original version of this paper was updated due to missing supplementary material.</p></fn></fn-group>" ]	[ "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq1.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq2.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq3.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq4.gif\"/>", "<graphic xlink:href=\"248_2023_2231_Fig1_HTML\" id=\"MO1\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq5.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq6.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq7.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq8.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq9.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq10.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq11.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq12.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq13.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq14.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq15.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq16.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq17.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq18.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq19.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq20.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq21.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq22.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq23.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq24.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq25.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq26.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq27.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq28.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq29.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq30.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq31.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq32.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq33.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq34.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq35.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq36.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq37.gif\"/>", "<graphic xlink:href=\"248_2023_2231_Fig2_HTML\" id=\"MO2\"/>", "<graphic xlink:href=\"248_2023_2231_Fig3_HTML\" id=\"MO3\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq38.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq39.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq40.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq41.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq42.gif\"/>", "<graphic xlink:href=\"248_2023_2231_Fig4_HTML\" id=\"MO4\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq43.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq44.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq45.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq46.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq47.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq48.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq49.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq50.gif\"/>", "<graphic xlink:href=\"248_2023_2231_Fig5_HTML\" id=\"MO5\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq51.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq52.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq53.gif\"/>", "<graphic xlink:href=\"248_2023_2231_Fig6_HTML\" id=\"MO6\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq54.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq55.gif\"/>", "<inline-graphic xlink:href=\"248_2023_2231_Article_IEq56.gif\"/>" ]	[ "<media xlink:href=\"248_2023_2231_MOESM1_ESM.pdf\"><caption><p>Supplementary file 1 (pdf 49450 KB)</p></caption></media>" ]	[{"label": ["1."], "mixed-citation": ["Lepot k (2020) Signatures of early microbial life from the Archean (4 to 2.5 Ga) eon. Earth-Science Reviews, 209:103296, 10 ISSN 00128252. 10.1016/j.earscirev.2020.103296"]}, {"label": ["2."], "mixed-citation": ["Noffke N, Christian D, Wacey D, Hazen RM (2013) Microbially induced sedimentary structures recording an ancient ecosystem in the ca. 3.48 Billion-year-old dresser formation, pilbara, Western Australia. Astrobiology, 13(12):1103\u20131124, 12 ISSN 15311074. 10.1089/AST.2013.1030/ASSET/IMAGES/LARGE/FIGURE19.JPEG. "], "ext-link": ["https://www.liebertpub.com/doi/abs/10.1089/ast.2013.1030"]}, {"label": ["3."], "mixed-citation": ["Tice MM, Lowe DR, (2004) Photosynthetic microbial mats in the 3,416-Myr-old ocean. Nature, (2004) 431:7008, 431(7008):549\u2013552. ISSN 9:1476\u20134687. 10.1038/nature02888, "], "ext-link": ["https://www.nature.com/articles/nature02888"]}, {"label": ["4."], "mixed-citation": ["Tice M (2009) Environmental Controls on Photosynthetic Microbial Mat Distribution and Morphogenesis on a 3.42 Ga Clastic-Starved Platform. Astrobiology, 9(10):989\u20131000, 12 ISSN 1531-1074. 10.1089/ast.2008.0330"]}, {"label": ["5."], "mixed-citation": ["Noffke N, Eriksson KA, Hazen RM, Simpson, EL (2006) A new window into Early Archean life: Microbial mats in Earth\u2019s oldest siliciclastic tidal deposits (3.2 Ga Moodies Group, South Africa). Geology, 34(4):253\u2013256, 4 ISSN 0091-7613. 10.1130/G22246.1"]}, {"label": ["6."], "mixed-citation": ["Homann M, Heubeck C, Airo A, Tice MM (2015) Morphological adaptations of 3.22 Ga-old tufted microbial mats to Archean coastal habitats (Moodies Group, Barberton Greenstone Belt, South Africa). Precambrian Research, 266:47\u201364, 9 ISSN 0301-9268. 10.1016/J.PRECAMRES.2015.04.018"]}, {"label": ["7."], "mixed-citation": ["Homann M, Sansjofre P, Van\u00a0Zuilen M, Heubeck C, Gong J, Killingsworth B, Foster IS, Airo A, Van\u00a0Kranendonk MJ, Ader M, Lalonde SV (2018) Microbial life and biogeochemical cycling on land 3,220 million years ago. Nature Geoscience, 11(9):665\u2013671, 9 ISSN 17520908. 10.1038/S41561-018-0190-9"]}, {"label": ["8."], "mixed-citation": ["Dupraz C, Reid RP, Braissant O, Decho AW, Norman RS, Visscher PT (2009) Processes of carbonate precipitation in modern microbial mats. Earth-Science Reviews, 96(3):141\u2013162, 10 ISSN 0012-8252. 10.1016/J.EARSCIREV.2008.10.005"]}, {"label": ["9."], "mixed-citation": ["Prieto-Barajas CM, Valencia-Cantero E, Santoyo G (2018) Microbial mat ecosystems: Structure types, functional diversity, and biotechnological application. Electronic Journal of Biotechnology, 31:48\u201356, 1 ISSN 0717-3458. 10.1016/J.EJBT.2017.11.001"]}, {"label": ["10."], "mixed-citation": ["Burns BP, Anitori R, Butterworth P, Henneberger R, Goh F, Allen MA, Iba\u00f1ez-Peral R, Bergquist LP, Walter MR, Neilan BA (2009) Modern analogues and the early history of microbial life. Precambrian Research, 173(1-4):10\u201318, 9 ISSN 0301-9268. 10.1016/J.PRECAMRES.2009.05.006"]}, {"label": ["11."], "mixed-citation": ["Noffke N (2010) Geobiology: Microbial Mats in Sandy Deposits from the Archean Era to Today. Springer, Berlin Heidelberg, Berlin, Heidelberg. 978-3-642-12771-7. 10.1007/978-3-642-12772-4"]}, {"label": ["12."], "mixed-citation": ["Shade A, Peter H, Allison SD, Baho D, Berga M, Buergmann H, Huber DH, Langenheder S, Lennon JT, Martiny JBH, Matulich KL, Schmidt TM, Handelsman J (2012) Fundamentals of Microbial Community Resistance and Resilience. Frontiers in Microbiology, 0(DEC):417, ISSN 1664-302X. 10.3389/FMICB.2012.00417"]}, {"label": ["13."], "mixed-citation": ["Song HS, Renslow RS, Fredrickson JK, Lindemann SR (2015) Integrating Ecological and Engineering Concepts of Resilience in Microbial Communities. Frontiers in Microbiology, 0(DEC):1298, ISSN 1664-302X. 10.3389/FMICB.2015.01298"]}, {"label": ["14."], "mixed-citation": ["Bender EA, Case TJ, Gilpin ME (1984) Perturbation Experiments in Community Ecology: Theory and Practice. Ecology, 65(1):1\u201313, 2 ISSN 1939-9170. 10.2307/1939452. "], "ext-link": ["https://onlinelibrary.wiley.com/doi/full/10.2307/1939452"]}, {"label": ["15."], "mixed-citation": ["Kolda A, Petri\u0107 I, Mucko M, Gottstein S, \u017dutinic P,Goreta G, Ternjej I, Rubini\u0107 J, Radi\u0161i\u0107 M, Udovi\u010d MG (2019) How environment selects: Resilience and survival of microbial mat community within intermittent karst spring Kr\u010di\u0107 (Croatia). Ecohydrology, 12(2), 3 ISSN 19360592. 10.1002/eco.2063"]}, {"label": ["16."], "mixed-citation": ["Ren Z, Qu X, Zhang M, Yu Y, Peng W (2019) Distinct bacterial communities in wet and dry seasons during a seasonal water level fluctuation in the largest freshwater lake (Poyang Lake) in China. Frontiers in Microbiology, 10(MAY):1167 ISSN 1664302X. 10.3389/FMICB.2019.01167/BIBTEX"]}, {"label": ["17."], "mixed-citation": ["Garc\u00eda-Garc\u00eda N, Tamames J, Linz AM, Pedr\u00f3s-Ali\u00f3 C, Puente-S\u00e1nchez F, (2019) Microdiversity ensures the maintenance of functional microbial communities under changing environmental conditions. The ISME Journal, (2019) 13:12, 13(12):2969\u20132983. ISSN 8:1751\u20137370. 10.1038/s41396-019-0487-8, "], "ext-link": ["https://www.nature.com/articles/s41396-019-0487-8"]}, {"label": ["18."], "mixed-citation": ["Okonkwo O, Escudie R, Bernet N, Mangayil R, Lakaniemi AM, Trably E (2020) Bioaugmentation enhances dark fermentative hydrogen production in cultures exposed to short-term temperature fluctuations. Applied Microbiology and Biotechnology, 104(1):439\u2013449, 1 ISSN 14320614. 10.1007/S00253-019-10203-8/FIGURES/5. "], "ext-link": ["https://link.springer.com/article/10.1007/s00253-019-10203-8"]}, {"label": ["19."], "mixed-citation": ["Jiang R, Wang M, Chen W, Li X, Balseiro-Romero M (2020) Changes in the integrated functional stability of microbial community under chemical stresses and the impacting factors in field soils. Ecological Indicators, 110: 105919, 3 ISSN 1470-160X. 10.1016/J.ECOLIND.2019.105919"]}, {"label": ["20."], "mixed-citation": ["Pett-Ridge J, Firestone MK (2005) Redox fluctuation structures microbial communities in a wet tropical soil. Applied and Environmental Microbiology, 7(11):6998\u20137007, 11 ISSN 00992240. 10.1128/AEM.71.11.6998-7007.2005/ASSET/AEEDB38D-8F74-4841-BB29-3E8420CB32E0/ASSETS/GRAPHIC/ZAM0110560800004.JPEG. "], "ext-link": ["https://journals.asm.org/doi/abs/10.1128/AEM.71.11.6998-7007.2005"]}, {"label": ["21."], "mixed-citation": ["Berga M, Zha Y, Sz\u00e9kely AJ, and Silke Langenheder. Functional and compositional stability of bacterial metacommunities in response to salinity changes. Frontiers in Microbiology, 8(JUN):948, 6 ISSN 1664302X. 10.3389/FMICB.2017.00948/BIBTEX"]}, {"label": ["22."], "mixed-citation": ["Jousset A, Bienhold C, Chatzinotas A, Gallien L, Gobet A, Kurm V, K\u00fcsel K, Rillig MC, Rivett DW, Salles JF, Van Der Heijden MGA, Youssef NH, Zhangv X, Wei Z, Hol GWH, (2017) Where less may be more: how the rare biosphere pulls ecosystems strings. The ISME Journal, (2017) 11:4, 11(4):853\u2013862. ISSN 1:1751\u20137370. 10.1038/ismej.2016.174, "], "ext-link": ["https://www.nature.com/articles/ismej2016174"]}, {"label": ["23."], "mixed-citation": ["Louca S, Polz MF, Mazel F, Albright MBN, Huber JA, O\u2019Connor MI, Ackermann M, Hahn AS, Srivastava DS, Crowe SA, Doebeli M, Parfrey LW ( 2018) Function and functional redundancy in microbial systems. Nature Ecology & Evolution, 2(6):936\u2013943, ISSN 2397-334X. 10.1038/s41559-018-0519-1. "], "pub-id": ["10.1038/s41559-018-0519-1"]}, {"label": ["24."], "mixed-citation": ["Allison SD, Martiny JBH (2008) Resistance, resilience, and redundancy in microbial communities. Proceedings of the National Academy of Sciences, 105(Supplement 1):11512\u201311519, 8 ISSN 0027-8424. 10.1073/PNAS.0801925105. "], "ext-link": ["https://www.pnas.org/content/105/Supplement_1/11512"]}, {"label": ["25."], "mixed-citation": ["Delgado-Baquerizo M, Giaramida L, Reich PB, Khachane AN, Hamonts K, Edwards C, Lawton LA, Singh BK (2016) Lack of functional redundancy in the relationship between microbial diversity and ecosystem functioning. Journal of Ecology, 104(4):936\u2013946, 7 ISSN 1365-2745. 10.1111/1365-2745.12585. "], "ext-link": ["https://onlinelibrary.wiley.com/doi/full/10.1111/1365-2745.12585", "https://onlinelibrary.wiley.com/doi/abs/10.1111/1365-2745.12585", "https://besjournals.onlinelibrary.wiley.com/doi/10.1111/1365-2745.12585"]}, {"label": ["26."], "mixed-citation": ["Hernandez DJ, David AS, Menges ES, Searcy CA, Afkhami ME, (2021) Environmental stress destabilizes microbial networks. The ISME Journal, (2021) 15:6, 15(6):1722\u20131734. ISSN 1:1751\u20137370. 10.1038/S41396-020-00882-X, "], "ext-link": ["https://www-nature-com.pbidi.unam.mx:2443/articles/s41396-020-00882-x"]}, {"label": ["27."], "mixed-citation": ["Ossowicki A, Raaijmakers JM, Garbeva P (2021) Disentangling soil microbiome functions by perturbation. Environmental Microbiology Reports, 13(5):582\u2013590, 10 ISSN 1758-2229. 10.1111/1758-2229.12989. "], "ext-link": ["https://onlinelibrary.wiley.com/doi/full/10.1111/1758-2229.12989", "https://onlinelibrary.wiley.com/doi/abs/10.1111/1758-2229.12989", "https://ami-journals.onlinelibrary.wiley.com/doi/10.1111/1758-2229.12989"]}, {"label": ["28."], "mixed-citation": ["Bowlin EM, Klaus JS, Foster JS, Andres MS, Custals L, Reid RP (2012) Environmental controls on microbial community cycling in modern marine stromatolites. Sedimentary Geology, 263-264:45\u201355, 7 ISSN 0037-0738. 10.1016/J.SEDGEO.2011.08.002"]}, {"label": ["29."], "mixed-citation": ["De\u00a0Anda V, Zapata-Pe\u00f1ascon I, Blaz J, Poot-Hern\u00e1ndez AC, Contreras-Moreira B, Gonz\u00e1lez-Laffitte M, G\u00e1mez-Tamariz N, Hern\u00e1ndez-Rosales M, Eguiarte LE, Souza V (2018) Understanding the mechanisms behind the response to environmental perturbation in microbial mats: A metagenomic-network based approach. Frontiers in Microbiology, 9(NOV):2606, 11 ISSN 1664302X. 10.3389/FMICB.2018.02606/BIBTEX"]}, {"label": ["30."], "mixed-citation": ["Reinold M, Wong HL, MacLeod FI, Meltzer J, Thompson A, Burns BP (2019) The Vulnerability of Microbial Ecosystems in a Changing Climate Potential Impact in Shark Bay. Life, 9(3), 9 ISSN 20751729. 10.3390/LIFE9030071. "], "ext-link": ["http://www.pmc/articles/PMC6789446/"]}, {"label": ["31."], "mixed-citation": ["Lingappa UF, Stein NT, Metcalfe KS, Present TM, Orphan VJ, Grotzinger JP, Knoll AH, Trower EJ, Gomes ML, Fischer WW (2022) Early impacts of climate change on a coastal marine microbial mat ecosystem. Science Advances, 8 (21): 7826, 5 ISSN 23752548. 10.1126/SCIADV.ABM7826/SUPPL_FILE/SCIADV.ABM7826_SM.PDF. "], "ext-link": ["https://www.science.org/doi/10.1126/sciadv.abm7826"]}, {"label": ["32."], "mixed-citation": ["Berlanga M, Palau M, Guerrero Ri (2022) Community homeostasis of coastal microbial mats from the Camargue during winter (cold) and summer (hot) seasons. Ecosphere, 13(2):e3922, 2 ISSN 2150-8925. 10.1002/ECS2.3922. "], "ext-link": ["https://onlinelibrary.wiley.com/doi/full/10.1002/ecs2.3922", "https://onlinelibrary.wiley.com/doi/abs/10.1002/ecs2.3922", "https://esajournals.onlinelibrary.wiley.com/doi/10.1002/ecs2.3922"]}, {"label": ["33."], "mixed-citation": ["Medina-Ch\u00e1vez NO, Viladomat-Jasso M, Olmedo-\u00c1lvarez G, Eguiarte LE, Souza V, De\u00a0La Torre\u00a0Zavala S (2019) Diversity of Archaea Domain in Cuatro Cienegas Basin: Archaean Domes. bioRxiv, page 766709, 9 ISSN 2692-8205. 10.1101/766709. "], "ext-link": ["https://www.biorxiv.org/content/10.1101/766709v1"]}, {"label": ["34."], "mixed-citation": ["Medina-Ch\u00e1vez NO, De\u00a0la Torre-Zavala S, Arreola-Triana AE, Souza V (2020) Cuatro Ci\u00e9negas as an Archaean Astrobiology Park. Astrobiology and Cuatro Ci\u00e9negas Basin as an Analog of Early Earth, pages 219\u2013228. Springer, Cham, 10.1007/978-3-030-46087-7_11. "], "ext-link": ["https://link.springer.com/chapter/10.1007/978-3-030-46087-7_11"]}, {"label": ["35."], "mixed-citation": ["Espinosa-Asuar L, Monroy-Guzm\u00e1n C, Madrigal-Trejo D, Navarro-Miranda M, S\u00e1nchez-P\u00e9rez J, Buenrostro\u00a0Mu\u00f1oz J, Villar J, Felipe J, Camargo C, Kalambokidis M, Esquivel-Hernandez DA, Jasso MV, Escalante AE, Velez P, Figueroa M, Martinez-Cardenas A, Ramirez-Barahona S, Gasca-Pineda J, Eguiarte LE, Souz V (202) Diversity of an uncommon elastic hypersaline microbial mat along a small-scale transect. PeerJ, 10:e13579, 6 ISSN 2167-8359. 10.7717/PEERJ.13579. "], "ext-link": ["https://peerj.com/articles/13579"]}, {"label": ["36."], "mixed-citation": ["Gerdes G, Claes M, Dunajtschik-Piewak K, Riege H, Krumbein WE, Reineck HE, (1993) Contribution of microbial mats to sedimentary surface structures. Facies, (1993) 29:1, 29(1):61\u201374. ISSN 12:1612\u20134820. 10.1007/BF02536918, "], "ext-link": ["https://link-springer-com.pbidi.unam.mx:2443/article/10.1007/BF02536918"]}, {"label": ["37."], "mixed-citation": ["Cuadrado DG, Bournod CN, Pan J, Carmona NB (2013) Microbially-induced sedimentary structures (MISS) as record of storm action in supratidal modern estuarine setting. Sedimentary Geology, 296: 1\u20138, ISSN 0037-0738. 10.1016/J.SEDGEO.2013.07.006"]}, {"label": ["38."], "mixed-citation": ["Lakhdar R, Soussi M, Talbi R (2021) Modern and Holocene microbial mats and associated microbially induced sedimentary structures (MISS) on the southeastern coast of Tunisia (Mediterranean Sea). Quaternary Research, 100: 77\u201397, 3 ISSN 0033-5894. 10.1017/QUA.2020.91."], "ext-link": ["https://www.cambridge.org/core/journals/quaternary-research/article/modern-and-holocene-microbial-mats-and-associated-microbially-induced- sedimentary-structures-miss-on-the-southeastern- coast-of-tunisia-mediterranean-sea/F40527FC87BDBF79087E75E6A02748DC"]}, {"label": ["39."], "mixed-citation": ["Thomas GW (1996) Soil pH and Soil Acidity. Methods of Soil Analysis, chapter\u00a016, pages 475\u2013490. John Wiley & Sons, Ltd, ISBN 9780891188667. 10.2136/sssabookser5.3.c16. "], "ext-link": ["https://acsess.onlinelibrary.wiley.com/doi/abs/10.2136/sssabookser5.3.c16"]}, {"label": ["40."], "mixed-citation": ["Nelson DW, Sommers LE (1996) Total Carbon, Organic Carbon, and Organic Matter. Methods of Soil Analysis, chapter\u00a034, pages 961\u20131010. John Wiley & Sons, Ltd, ISBN 9780891188667. 10.2136/sssabookser5.3.c34. "], "ext-link": ["https://acsess.onlinelibrary.wiley.com/doi/abs/10.2136/sssabookser5.3.c34"]}, {"label": ["41."], "mixed-citation": ["Bremner JM (1996) Nitrogen-Total. Methods of Soil Analysis, chapter\u00a037, pages 1085\u20131121. John Wiley & Sons, Ltd, ISBN 9780891188667. 10.2136/sssabookser5.3.c37. "], "ext-link": ["https://acsess.onlinelibrary.wiley.com/doi/abs/10.2136/sssabookser5.3.c37"]}, {"label": ["42."], "mixed-citation": ["Mulvaney RL (1996) Nitrogen-Inorganic Forms. Methods of Soil Analysis, chapter\u00a038, pages 1123\u20131184. John Wiley & Sons, Ltd, ISBN 9780891188667. 10.2136/sssabookser5.3.c38. "], "ext-link": ["https://acsess.onlinelibrary.wiley.com/doi/abs/10.2136/sssabookser5.3.c38"]}, {"label": ["43."], "mixed-citation": ["Perroni Y, Garc\u00eda-Oliva F, Tapia-Torres Y, Souza V (2014) Relationship between soil P fractions and microbial biomass in an oligotrophic grassland-desert scrub system. Ecological Research (2014) 29:3, 29(3):463\u2013472. ISSN 3:1440\u20131703, 10.1007/S11284-014-1138-1. "], "ext-link": ["https://link.springer.com/article/10.1007/s11284-014-1138-1"]}, {"label": ["44."], "mixed-citation": ["Kuo S (1996) Phosphorus. Methods of Soil Analysis, chapter\u00a032, pages 869\u2013919. John Wiley & Sons, Ltd, 1996. ISBN 9780891188667. 10.2136/sssabookser5.3.c32. "], "ext-link": ["https://acsess.onlinelibrary.wiley.com/doi/abs/10.2136/sssabookser5.3.c32"]}, {"label": ["45."], "mixed-citation": ["Gee GW, Bauder JW (1986) Particle-size Analysis. Methods of Soil Analysis, chapter\u00a015, pages 383\u2013411. John Wiley & Sons, Ltd, ISBN 9780891188643. 10.2136/sssabookser5.1.2ed.c15. "], "ext-link": ["https://acsess.onlinelibrary.wiley.com/doi/abs/10.2136/sssabookser5.1.2ed.c15"]}, {"label": ["46."], "mixed-citation": ["National Institute of Standard Technology. NIST Chemistry WebBook, 2020. "], "ext-link": ["https://webbook.nist.gov/"]}, {"label": ["47."], "mixed-citation": ["Purdy KJ (2005) Nucleic Acid Recovery from Complex Environmental Samples. Methods in Enzymology, 397:271\u2013292, 1 ISSN 0076-6879. 10.1016/S0076-6879(05)97016-X"]}, {"label": ["48."], "mixed-citation": ["Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics, 30(15):2114\u20132120, 8 ISSN 1367-4803. 10.1093/BIOINFORMATICS/BTU170. "], "ext-link": ["https://academic.oup.com/bioinformatics/article/30/15/2114/2390096"]}, {"label": ["49."], "mixed-citation": ["Li D, Liu CM, Luo R, Sadakane K, Lam TW (2015) MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph. Bioinformatics, 31(10):1674\u20131676, 5 ISSN 1367-4803. 10.1093/BIOINFORMATICS/BTV033. "], "ext-link": ["https://academic.oup.com/bioinformatics/article/31/10/1674/177884"]}, {"label": ["50."], "mixed-citation": ["Bandla A, Pavagadhi S, Sridhar\u00a0Sudarshan A, Hong Poh MC, Swarup S (2020) 910 metagenome-assembled genomes from the phytobiomes of three urban-farmed leafy Asian greens. "], "italic": ["Scientific Data 2020 7:1"], "ext-link": ["https://www.nature.com/articles/s41597-020-00617-9"]}, {"label": ["51."], "mixed-citation": ["Yan H, Zhu L, Wang Y, Zhang S, Liu P, Dong TTX, Wu Q, Duan JA (2021) Comparative metagenomics analysis of the rhizosphere microbiota influence on Radix Angelica sinensis in different growth soil environments in China. Food Science and Technology, 4 ISSN 0101-2061. 10.1590/FST.65120. "], "ext-link": ["http://www.scielo.br/j/cta/a/yzqmHYfCzjWwwPXtwjTT7Th/?lang=en"]}, {"label": ["52."], "mixed-citation": ["Bushnell B (2020) BBmap. "], "ext-link": ["https://sourceforge.net/projects/bbmap/"]}, {"label": ["53."], "mixed-citation": ["Li H, Handsaker B,Wysoker A, Fennell T, Ruan J,Homer N, Marth G, Abecasis G,Durbin R, (2009) 1000 Genome Project Data\u00a0Processing Subgroup. The Sequence Alignment/Map format and SAMtools. Bioinformatics, 25(16):2078\u20132079, 8 ISSN 1367-4803. 10.1093/BIOINFORMATICS/BTP352. "], "ext-link": ["https://academic.oup.com/bioinformatics/article/25/16/2078/204688"]}, {"label": ["54."], "mixed-citation": ["von Meijenfeldt FAB, Arkhipova K, Cambuy DD, Coutinho FH, Dutilh BE, (2019) Robust taxonomic classification of uncharted microbial sequences and bins with CAT and BAT. Genome Biology, (2019) 20:1, 20 (1):1\u201314. ISSN 10:1474\u2013760X, 10.1186/S13059-019-1817-X. "], "ext-link": ["https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1817-x"]}, {"label": ["55."], "mixed-citation": ["Hyatt D, Chen G-L, LoCascio PF, Land ML, Larimer FW, Hauser LJ, (2010) Prodigal: prokaryotic gene recognition and translation initiation site identification. BMC Bioinformatics, (2010) 11:1, 11 (1): 1\u201311. ISSN 3:1471\u20132105, 10.1186/1471-2105-11-119, "], "ext-link": ["https://bmcbioinformatics.biomedcentral.com/articles/10.1186/1471-2105-11-119"]}, {"label": ["56."], "mixed-citation": ["Buchfink B, Xie C, Huson DH, (2014) Fast and sensitive protein alignment using DIAMOND. Nature Methods, (2014) 12:1, 12(1):59\u201360. ISSN 11:1548\u20137105, 10.1038/nmeth.3176. "], "ext-link": ["https://www.nature.com/articles/nmeth.3176"]}, {"label": ["57."], "mixed-citation": ["NCBI Resource Coordinators. Database resources of the National Center for Biotechnology Information. "], "italic": ["Nucleic Acids Research"], "ext-link": ["https://academic.oup.com/nar/article/46/D1/D8/4621330"]}, {"label": ["58."], "mixed-citation": ["Mistry J, Chuguransky S, Williams L, Qureshi M, Salazar GA, Sonnhammer ELL, Tosatto SCE, Paladin L, Raj S, Richardson LJ, Finn RD, Bateman A, (2021) Pfam: The protein families database in, (2021) Nucleic Acids Research, 49(D1), D412\u2013D419. ISSN 1:0305\u20131048, 10.1093/NAR/GKAA913, "], "ext-link": ["https://academic.oup.com/nar/article/49/D1/D412/5943818"]}, {"label": ["59."], "mixed-citation": ["Eddy SR (2011) Accelerated Profile HMM Searches. "], "italic": ["PLOS Computational Biology"], "ext-link": ["https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1002195"]}, {"label": ["60."], "mixed-citation": ["Silva GGZ, Green KT, Dutilh BE, Edwards RA (2016) SUPER-FOCUS: a tool for agile functional analysis of shotgun metagenomic data. "], "italic": ["Bioinformatics"], "ext-link": ["https://academic.oup.com/bioinformatics/article/32/3/354/1743726"]}, {"label": ["61."], "mixed-citation": ["Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene Ontology: tool for the unification of biology. "], "italic": ["Nature genetics"]}, {"label": ["62."], "mixed-citation": ["Carbon S, Douglass E, Good BM, Unni DR, Harris NL, Mungall CJ, Basu S, Chisholm RL, Dodson RJ, Hartline E, Fey P, Thomas PD, ALP, Ebert D, Kesling MJ, Mi H, Muruganujan A, Huang X, Mushayahama T, LaBonte SA, Siegele DA, Antonazzo G, Attrill H, Brown NH, Garapati P, Marygold SJ, Trovisco V, dos Santos G, Falls K, Tabone C, Zhou C, Goodman JL, Strelets VB, Thurmond J, Garmiri P, Ishtiaq R, Rodr\u00edguez-L\u00f3pez M, Acencio ML, Kuiper M, L\u00e6greid A, Logie C, Lovering RC, Kramarz B, Saverimuttu SCC, Pinheiro SM, Gunn H, Su R, Thurlow KE, Chibucos M, Giglio M, Nadendla S, Munro J, Jackson R, Duesbury MJ, Del-Toro N, Meldal BHM, Paneerselvam K, Perfetto L, Porras P, Orchard S, Shrivastava A, Chang HY, Finn RD, Mitchell AL, Rawlings ND, Richardson L, Sangrador-Vegas A, Blake JA, Christie KR, Dolan ME, Drabkin HJ, Hill DP, Ni L, Sitnikov DM, Harris MA, Oliver SG, Rutherford K, Wood V, Hayles J, B\u00e4hler J, Bolton ER, de\u00a0Pons JL, Dwinell MR, Hayman GT, Kaldunski ML, Kwitek AE, Laulederkind SJF, Plasterer C, Tutaj MA, Vedi M, Wang SJ, D\u2019Eustachio P, Matthews L, Balhoff JP, Aleksander SA, Alexander MJ, Cherry JM, Engel SR, Gondwe Felix, Karra K, Miyasato SR, Nash RS, Simison M, Skrzypek MS, Weng S, Wong ED, Feuermann M, Gaudet P, Morgat A, Bakker E, Berardini TZ, Reiser L, Subramaniam S, Huala E, Arighi CN, Auchincloss A, Axelsen K, Argoud-Puy G, Bateman A, Blatter MC, Boutet E, Bowler E, Breuza L, Bridge A, Britto R, Bye-A-Jee H, Casas CC, Coudert E, Denny P, Es-Treicher A, Famiglietti ML, Georghiou G, Gos AN, Gruaz-Gumowski N, Hatton-Ellis E, Hulo C, Ignatchenko A, Jungo F, Laiho K, Le\u00a0Mercier P, Lieberherr D, Lock A, Lussi Y, MacDougall A, Ma-Grane M, Martin MJ, Masson P, Natale DA, Hyka-Nouspikel N, Orchard S, Pedruzzi I, Pourcel L, Poux S, Pundir S, Rivoire C, Speretta E, Sundaram S, Tyagi N, Warner K, Zaru R, Wu CH, Diehl AD, Chan JN, Grove C, Lee RYN, Muller HM, Raciti D, van Auken K, Sternberg PW, Berriman M, Paulini M, Howe K, Gao S, Wright A, Stein L, Howe DG, Toro S, Westerfield M, Jaiswal P, Cooper L, Elser J (2021) The Gene Ontology resource: enriching a GOld mine. "], "italic": ["Nucleic acids research"], "ext-link": ["https://pubmed.ncbi.nlm.nih.gov/33290552/"]}, {"label": ["63."], "mixed-citation": ["Altschul SF, Gish W, Miller W, Myers E, Lipman DJ (1990) Basic local alignment search tool. "], "italic": ["Journal of Molecular Biology"]}, {"label": ["64."], "mixed-citation": ["Guti\u00e9rrez-Preciado A, Sagha\u00ef A, Moreira D, Zivanovic Y, Deschamps P, L\u00edpez-Garc\u00eda P (2018) Functional shifts in microbial mats recapitulate early Earth metabolic transitions. Nature Ecology & Evolution 2018 2:11 , 2(11):1700\u20131708, 10 ISSN 2397-334X. 10.1038/s41559-018-0683-3. "], "ext-link": ["https://www.nature.com/articles/s41559-018-0683-3"]}, {"label": ["65."], "mixed-citation": ["Bateman A, Martin M, Orchard S, Magrane M, Agivetova R, Ahmad S, Alpi E, Bowler-Barnett EH, Britto R, Bursteinas B, Bye-A-Jee H, Coetzee R, Cukura A, Da Silva A, Denny P, Dogan T, Ebenezer T, Fan J, Castro LG, Garmiri P, Georghiou G, Gonzales L, Hatton-Ellis E, Hussein A, Ignatchenko A, Insana G, Ishtiaq R, Jokinen P, Joshi V, Jyothi D, Lock A, Lopez R, Luciani A, Luo J, Lussi Y, MacDougall A, Madeira F, Mahmoudy M, Menchi M, Mishra A, Moulang K, Nightingale A, Oliveira CS, Pundir S, Qi G, Raj S, Rice D, Lopez MR, Saidi R, Sampson J, Sawford T, Speretta E, Turner E, Tyagi N, Vasudev P, Volynkin V, Warner K, Watkins X, Zaru R, Zellner H, Bridge A, Poux S, Redaschi N, Aimo L, Argoud-Puy G, Auchincloss A, Axelsen K, Bansal P, Baratin D, Blatter M-C, Bolleman J, Boutet E, Breuza L, Casals-Casas C, de Castro E, Echioukh KC, Coudert E, Cuche B, Doche M, Dornevil D, Estreicher A, Famiglietti ML, Feuermann M, Gasteiger E, Gehant S, Gerritsen V, Gos A, Gruaz-Gumowski N, Hinz U, Hulo C, Hyka-Nouspikel N, Jungo F, Keller G, Kerhornou A, Lara V, Le Mercier P, Lieberherr D, Lombardot T, Martin X, Masson P, Morgat A, Neto TB, Paesano S, Pedruzzi I, Pilbout S, Pourcel L, Pozzato M, Pruess M, Rivoire C, Sigrist C, Sonesson K, Stutz A, Sundaram S, Tognolli M, Verbregue L, Wu CH, Arighi CN, Arminski L, Chen C, Chen Y, Garavelli JS, Huang H, Laiho K, McGarvey P, Natale DA, Ross K, Vinayaka CR, Wang Q, Wang Y, Yeh L-S, Zhang J, Ruch P, Teodoro D, (2021) UniProt: the universal protein knowledgebase in, (2021) Nucleic Acids Research, 49(D1). ISSN 1:0305\u20131048. 10.1093/nar/gkaa1100"]}, {"label": ["66."], "mixed-citation": ["Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M (2016) KEGG as a reference resource for gene and protein annotation. "], "italic": ["Nucleic Acids Research"], "ext-link": ["https://academic.oup.com/nar/article/44/D1/D457/2502600"]}, {"label": ["67."], "mixed-citation": ["R Core Team. R: A Language and Environment for Statistical Computing, 2020"]}, {"label": ["68."], "mixed-citation": ["Wickham H (2016) ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag, New York. ISBN 978-3-319-24277-4. "], "ext-link": ["https://ggplot2.tidyverse.org"]}, {"label": ["69."], "mixed-citation": ["Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. "], "italic": ["Bioinformatics"], "ext-link": ["https://academic.oup.com/bioinformatics/article/26/1/139/182458"]}, {"label": ["70."], "mixed-citation": ["Chen W, Simpson J, Levesque CA (2018) RAM: R for Amplicon-Sequencing-Based Microbial-Ecology, "], "ext-link": ["https://CRAN.R-project.org/package=RAM"]}, {"label": ["71."], "mixed-citation": ["Oksanen J, Blanchet FG, Friendly M, Kindt R, Legendre P, McGlinn D, Minchin PR, O\u2019Hara RB, Simpson GL, Solymos P, Stevens MHH, Szoecs E, Wagner H (2020) vegan: Community Ecology Package. "], "ext-link": ["https://CRAN.R-project.org/package=vegan"]}, {"label": ["72."], "mixed-citation": ["Lex A, Gehlenborg N, Strobelt H, Vuillemot R, Pfister H (2014) UpSet: Visualization of intersecting sets. "], "italic": ["IEEE Transactions on Visualization and Computer Graphics"]}, {"label": ["73."], "mixed-citation": ["Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. "], "italic": ["Genome Biology"], "ext-link": ["https://genomebiology.biomedcentral.com/articles/10.1186/s13059-014-0550-8"]}, {"label": ["74."], "mixed-citation": ["Blighe K, Rana S, Lewis M (2021) EnhancedVolcano: Publication-ready volcano plots with enhanced colouring and labeling. "], "ext-link": ["https://github.com/kevinblighe/EnhancedVolcano"]}, {"label": ["75."], "mixed-citation": ["Pedersen TL (2020) patchwork: The Composer of Plots. "], "ext-link": ["https://CRAN.R-project.org/package=patchwork"]}, {"label": ["76."], "mixed-citation": ["Nakazawa M (2021) fmsb: Functions for Medical Statistics Book with some Demographic Data. "], "ext-link": ["https://CRAN.R-project.org/package=fmsb"]}, {"label": ["77."], "mixed-citation": ["Rudis B (2019) streamgraph: streamgraph is an htmlwidget for building streamgraph visualizations. "], "ext-link": ["http://github.com/hrbrmstr/streamgraph"]}, {"label": ["78."], "mixed-citation": ["Koneswarakantha B (2021) easyalluvial: Generate Alluvial Plots with a Single Line of Code a. "], "ext-link": ["https://CRAN.R-project.org/package=easyalluvial"]}, {"label": ["79."], "mixed-citation": ["Koneswarakantha B (2021) parcats: Interactive Parallel Categories Diagrams for \u2018easyalluvial\u2019 b. "], "ext-link": ["https://CRAN.R-project.org/package=parcats"]}, {"label": ["80."], "mixed-citation": ["Peschel S, M\u00fcller CL, von Mutius E, Boulesteix AL, Depner M (2021) NetCoMi: network construction and comparison for microbiome data in R. "], "italic": ["Briefings in Bioinformatics"], "ext-link": ["https://academic.oup.com/bib/article/22/4/bbaa290/6017455"]}, {"label": ["81."], "mixed-citation": ["Bischl B, Lang M, Bossek J, Horn D, Richter J, Surmann D (2017) BBmisc: Miscellaneous Helper Functions for B. Bischl. "], "ext-link": ["https://CRAN.R-project.org/package=BBmisc"]}, {"label": ["82."], "mixed-citation": ["Wickham H, Fran\u00e7ois R, Henry Lionel, M\u00fcller K (2021) dplyr: A Grammar of Data Manipulation. "], "ext-link": ["https://CRAN.R-project.org/package=dplyr"]}, {"label": ["83."], "mixed-citation": ["Wickham H (2021) tidyr Tidy Messy Data. "], "ext-link": ["https://CRAN.R-project.org/package=tidyr"]}, {"label": ["84."], "mixed-citation": ["R\u00f6ttjers L, Faust K (2018) From hairballs to hypotheses-biological insights from microbial networks. "], "italic": ["FEMS Microbiology Reviews"], "ext-link": ["https://academic.oup.com/femsre/article/42/6/761/5061627"]}, {"label": ["85."], "mixed-citation": ["Varin T, Lovejoy C, Jungblut AD, Vincent WF, Corbeil J (2012) Metagenomic Analysis of Stress Genes in Microbial Mat Communities from Antarctica and the High Arctic. "], "italic": ["Applied and Environmental Microbiology"], "ext-link": ["http://www.pmc/articles/PMC3255749/"]}, {"label": ["86."], "mixed-citation": ["Le PT, Makhalanyane TP, Guerrero LD, Vikram S, De\u00a0Peer YV, Cowan DA (2016) Comparative Metagenomic Analysis Reveals Mechanisms for Stress Response in Hypoliths from Extreme Hyperarid Deserts. "], "italic": ["Genome Biology and Evolution"], "ext-link": ["https://academic.oup.com/gbe/article/8/9/2737/2236390"]}, {"label": ["87."], "mixed-citation": ["Wong HL, White RA, Visscher PT, Charlesworth JC, V\u00e1zquez-Campos X, Burns BP, (2018) Disentangling the drivers of functional complexity at the metagenomic level in Shark Bay microbial mat microbiomes. The ISME Journal, (2018) 12:11, 12(11):2619\u20132639. ISSN 7:1751\u20137370, 10.1038/s41396-018-0208-8. "], "ext-link": ["https://www.nature.com/articles/s41396-018-0208-8"]}, {"label": ["88."], "mixed-citation": ["Kurth D, Elias D, Rasuk MC, Contreras M, Farias ME (2021) Carbon fixation and rhodopsin systems in microbial mats from hypersaline lakes Brava and Tebenquiche, Salar de Atacama, Chile. "], "italic": ["PLOS ONE"], "ext-link": ["https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246656"]}, {"label": ["89."], "mixed-citation": ["Botton S, Van\u00a0Heusden M, Parsons JR, Smidt H, Van\u00a0Straalen N (2006) Resilience of Microbial Systems Towards Disturbances. "], "italic": ["Critical Reviews in Microbiology"], "ext-link": ["https://www.tandfonline.com/doi/abs/10.1080/10408410600709933"]}, {"label": ["90."], "mixed-citation": ["Landi S, Nurcato R, De\u00a0Lillo A, Lentini M, Grillo S, Esposito S (2016) Glucose-6-phosphate dehydrogenase plays a central role in the response of tomato (Solanum lycopersicum) plants to short and long-term drought. "], "italic": ["Plant Physiology and Biochemistry"]}, {"label": ["91."], "mixed-citation": ["H\u00e4rtig E and Jahn D (2012) Regulation of the Anaerobic Metabolism in Bacillus subtilis. "], "italic": ["Advances in Microbial Physiology"]}, {"label": ["92."], "mixed-citation": ["Salaemae W, Booker GW, Polyak SW (2016) The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for Mycobacterium tuberculosis. "], "italic": ["Microbiology Spectrum"], "ext-link": ["https://journals.asm.org/doi/abs/10.1128/microbiolspec.VMBF-0008-2015"]}, {"label": ["93."], "mixed-citation": ["Parsek MR, Val DL, Hanzelka BL, Cronan JE, Greenberg EP (1999) Acyl homoserine-lactone quorum-sensing signal generation. "], "italic": ["Proceedings of the National Academy of Sciences"], "ext-link": ["https://www.pnas.org/content/96/8/4360"]}, {"label": ["94."], "mixed-citation": ["Thompson LR, Zeng Q, Kelly L, Huang KH, Singer AU, Stubbe JA, Chisholm SW (2011) Phage auxiliary metabolic genes and the redirection of cyanobacterial host carbon metabolism. "], "italic": ["Proceedings of the National Academy of Sciences of the United States of America"], "ext-link": ["https://www.pnas.org/content/108/39/E757"]}, {"label": ["95."], "mixed-citation": ["Warwick-Dugdale J, Buchholz HH, Allen MJ, Temperton B (2019) Host-hijacking and planktonic piracy: how phages command the microbial high seas. "], "italic": ["Virology Journal 2019 16:1"], "ext-link": ["https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1120-1"]}, {"label": ["96."], "mixed-citation": ["Hedderich R (2004) Energy-converting [NiFe] hydrogenases from archaea and extremophiles: ancestors of complex I. "], "italic": ["Journal of bioenergetics and biomembranes"], "ext-link": ["https://pubmed.ncbi.nlm.nih.gov/15168611/"]}, {"label": ["97."], "mixed-citation": ["Netz N, Opatz T (2015) Marine Indole Alkaloids. "], "italic": ["Marine Drugs"], "ext-link": ["http://www.pmc/articles/PMC4557006/"]}, {"label": ["98."], "mixed-citation": ["Herrera N, Echeverri F (2021) Evidence of Quorum Sensing in Cyanobacteria by Homoserine Lactones: The Origin of Blooms. "], "italic": ["Water 2021, Vol. 13, Page 1831"], "ext-link": ["https://www.mdpi.com/2073-4441/13/13/1831/htm"]}, {"label": ["99."], "mixed-citation": ["Wong HL, MacLeod FI, White RA, Visscher PT, Burns BP, (2020) Microbial dark matter filling the niche in hypersaline microbial mats. Microbiome, (2020) 8:1, 8(1):1\u201314. ISSN 9:2049\u20132618, 10.1186/S40168-020-00910-0. "], "ext-link": ["https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-020-00910-0"]}, {"label": ["100."], "mixed-citation": ["Ramos VMC, Castelo-Branco R, Le\u00e3o PN, Martins J, Carvalhal-Gomes S, da\u00a0Silva FS, Filho JGM, Vasconcelos VM (2017) Cyanobacterial diversity in microbial mats from the hypersaline lagoon system of Araruama, Brazil: An in-depth polyphasic study. "], "italic": ["Frontiers in Microbiology"]}, {"label": ["101."], "mixed-citation": ["Cardoso DC, Cretoiu MS, Stal LJ, Bolhuis H, (2019) Seasonal development of a coastal microbial mat. Scientific Reports, (2019) 9:1, 9(1):1\u201314. ISSN 6:2045\u20132322. 10.1038/s41598-019-45490-8. "], "ext-link": ["https://www.nature.com/articles/s41598-019-45490-8"]}, {"label": ["102."], "mixed-citation": ["Sohm JA, Niederberger TD, Parker AE, Tirindelli J, Gunderson T, Cary SC, Capone DG, Carpenter EJ (2020) Microbial Mats of the McMurdo Dry Valleys, Antarctica: Oases of Biological Activity in a Very Cold Desert. Frontiers in Microbiology, 11:2599, 10 ISSN 1664302X. 10.3389/FMICB.2020.537960/BIBTEX"]}, {"label": ["103."], "mixed-citation": ["Brenes-Guill\u00e9n L, Vidaurre-Barahona D, Mora-L\u00f3pez M, Uribe-Lor\u00edo L (2021) Draft Genome Sequences of Two Cyanobacteria Leptolyngbya spp. Isolated from Microbial Mats in Miravalles Thermal Spring, Costa Rica . Microbiology Resource Announcements, 10 (41), 10 ISSN 2576098X. 10.1128/MRA.00553-21/ASSET/EE48F170-BE82-4739-9449-901C375640F3/ASSETS/IMAGES/LARGE/MRA.00553-21-F001.JPG. "], "ext-link": ["https://journals.asm.org/doi/abs/10.1128/MRA.00553-21"]}, {"label": ["104."], "surname": ["Kuever"], "given-names": ["J"], "source": ["The Family Desulfohalobiaceae"], "year": ["2014"], "publisher-loc": ["The Prokaryotes"], "publisher-name": ["Springer, Berlin Heidelberg, Berlin, Heidelberg"]}, {"label": ["105."], "mixed-citation": ["Baho DL, Peter H, Tranvik LJ (2012) Resistance and resilience of microbial communities - temporal and spatial insurance against perturbations. "], "italic": ["Environmental Microbiology"], "ext-link": ["https://onlinelibrary.wiley.com/doi/full/10.1111/j.1462-2920.2012.02754.x"]}, {"label": ["106."], "mixed-citation": ["Lynch MDJ, Neufeld JD (2015) Ecology and exploration of the rare biosphere. Nature Reviews Microbiology (2015) 13:4, 13(4):217\u2013229. ISSN 3:1740\u20131534, 10.1038/NRMICRO3400. "], "ext-link": ["https://www-nature-com.pbidi.unam.mx:2443/articles/nrmicro3400"]}, {"label": ["107."], "mixed-citation": ["Pennekamp F, Pontarp M, Tabi A, Altermatt F, Alther R, Choffat Y, Fronhofer EA, Ganesanandamoorthy P, Garnier A, Griffiths JI, Greene S, Horgan K, Massie TM, M\u00e4chler E, Palamara GM, Seymour M, Petchey OL, (2018 Biodiversity increases and decreases ecosystem stability. Nature, (2018) 563:7729, 563(7729):109\u2013112. ISSN 10:1476\u20134687, 10.1038/s41586-018-0627-8. "], "ext-link": ["https://www.nature.com/articles/s41586-018-0627-8"]}, {"label": ["108."], "mixed-citation": ["Stomp M, Van\u00a0Dijk MA, Van\u00a0Overzee HMJ, Wortel MT, Sigon CAM, Egas M, Hoogveld H, Gons HJ, Huisman J (2008) The timescale of phenotypic plasticity and its impact on competition in fluctuating environments. "], "italic": ["American Naturalist"], "pub-id": ["10.1086/591680/ASSET/IMAGES/LARGE/FG8.JPEG"]}, {"label": ["109."], "mixed-citation": ["Aguilera \u00c1, Suominen S, P\u00e9tursd\u00f3ttir S, Olgud\u00f3ttir E, Guomundsd\u00f3ttir EE, Altamirano M, Gonz\u00e1lez-Toril E, Hreggviosson G\u00d3 (2020) Physiological plasticity of high-temperature intertidal cyanobacterial microbial mats to temperature and salinity: daily and seasonal in situ photosynthetic performance, 55(2):223\u2013233, 4 ISSN 14694433. 10.1080/09670262.2019.1690165"]}, {"label": ["110."], "mixed-citation": ["Andrade-Dom\u00ednguez A, Trejo-Hern\u00e1ndez A, Vargas-Lagunas C, Encarnaci\u00f3n-Guevara S, (2021) Phenotypic plasticity and a new small molecule are involved in a fungal-bacterial interaction. Scientific Reports, (2021) 11:1, 11(1):1\u201310. ISSN 9:2045\u20132322, 10.1038/s41598-021-98474-y. "], "ext-link": ["https://www.nature.com/articles/s41598-021-98474-y"]}, {"label": ["111."], "mixed-citation": ["Feng W, Zhang Y, Lai Z, Qin S, Yan R, Sun Y, She W (2021) Soil bacterial and eukaryotic co-occurrence networks across a desert climate gradient in northern China. "], "italic": ["Land Degradation & Development"], "ext-link": ["https://onlinelibrary.wiley.com/doi/full/10.1002/ldr.3844"]}, {"label": ["112."], "mixed-citation": ["Mardanov AV, Beletsky AV, Ravin NV, Botchkova EA, Litti YV, Nozhevnikova AN (2019) Genome of a novel bacterium \u201ccandidatus jettenia ecosi\u201d reconstructed from the metagenome of an anammox bioreactor. "], "italic": ["Frontiers in Microbiology"]}, {"label": ["113."], "mixed-citation": ["Imhoff JF (2014) The Family Chromatiaceae. "], "italic": ["The Prokaryotes"]}, {"label": ["114."], "mixed-citation": ["Marcondes\u00a0de Souza JA, Carareto\u00a0Alves LM, de\u00a0Mello\u00a0Varani Al, de\u00a0Macedo\u00a0Lemos EG (2014) The Family\u00a0Bradyrhizobiaceae. "], "italic": ["The Prokaryotes"]}, {"label": ["115."], "mixed-citation": ["Huang Y, Zeng Y, Feng H, Wu Y, Xu X (2015) Croceicoccus naphthovorans sp. nov., a polycyclic aromatic hydrocarbons-degrading and acylhomoserine-lactone-producing bacterium isolated from marine biofilm, and emended description of the genus croceicoccus. "], "italic": ["International Journal of Systematic and Evolutionary Microbiology"], "ext-link": ["https://www.microbiologyresearch.org/content/journal/ijsem/10.1099/ijs.0.000132"]}, {"label": ["116."], "mixed-citation": ["Distel DL, Morrill W, MacLaren-Toussaint N, Franks D, Waterbury J (2002) Teredinibacter turnerae gen. nov., sp. nov., a dinitrogen-fixing, cellulolytic, endosymbiotic gamma-proteobacterium isolated from the gills of wood-boring molluscs (Bivalvia: Teredinidae). "], "italic": ["International Journal of Systematic and Evolutionary Microbiology"], "ext-link": ["https://www.microbiologyresearch.org/content/journal/ijsem/10.1099/00207713-52-6-2261"]}, {"label": ["117."], "mixed-citation": ["Oren A (2014) The Family Methanosarcinaceae. "], "italic": ["The Prokaryotes"]}, {"label": ["118."], "mixed-citation": ["Li G, Zeng X, Liu X, Zhang X, Shao Z (2016) Wukongibacter baidiensis gen. Nov., sp. Nov., an anaerobic bacterium isolated from hydrothermal sulfides, and proposal for the reclassification of the closely related clostridium halophilum and clostridium caminithermale within maledivibacter gen. Nov. and Paramaledivibacter gen. Nov., respectivel. "], "italic": ["International Journal of Systematic and Evolutionary Microbiology"], "ext-link": ["https://www.microbiologyresearch.org/content/journal/ijsem/10.1099/ijsem.0.001355"]}, {"label": ["119."], "mixed-citation": ["Reid P, Dupraz C D, Visscher PT, Sumner DY (2003) Microbial Processes Forming Marine Stromatolites. "], "italic": ["Fossil and Recent Biofilms"], "ext-link": ["https://link.springer.com/chapter/10.1007/978-94-017-0193-8_6"]}, {"label": ["120."], "mixed-citation": ["Petryshyn VA, Corsetti FA, Berelson WM, Beaumont W, Lund SP (2012) Stromatolite lamination frequency, Walker Lake, Nevada Implications for stromatolites as biosignatures. "], "italic": ["Geology"], "ext-link": ["http://pubs.geoscienceworld.org/gsa/geology/article-pdf/40/6/499/3542194/499.pdf"]}, {"label": ["121."], "mixed-citation": ["Homann M (2019) Earliest life on Earth: Evidence from the Barberton Greenstone Belt, South Africa. "], "italic": ["Earth-Science Reviews"]}, {"label": ["122."], "mixed-citation": ["Alleon J, Bernard S, Olivier N, Thomazo C, Marin-Carbonne J (2021) Inherited geochemical diversity of 3.4 Ga organic films from the Buck Reef Chert, South Africa. "], "italic": ["Communications Earth and Environment"], "ext-link": ["https://www.nature.com/articles/s43247-020-00066-7"]}]	{ "acronym": [], "definition": [] }	122	CC BY	no	2024-01-13 23:36:44	Microb Ecol. 2023 Jul 2; 86(4):2252-2270	oa_package/88/2c/PMC10640475.tar.gz
PMC10657436	37980403	[ "<title>Introduction</title>", "<p id=\"Par3\">The transport of microscopic colloidal particles suspended in fluids is relevant for a wide range of physical and biological phenomena including sedimentation<sup>##REF##17501616##1##</sup>, drug delivery<sup>##UREF##0##2##–##REF##22673692##4##</sup>, self-assembly<sup>##UREF##2##5##–##REF##34045705##7##</sup>, microfluidic devices<sup>##REF##12052952##8##–##REF##37355317##13##</sup>, and active systems<sup>##REF##24978345##14##–##REF##32149319##16##</sup>. External fields are often used to control the motion of colloidal particles<sup>##UREF##5##17##–##REF##27997373##19##</sup>. These include spatially uniform fields such as gravitational<sup>##REF##17155724##20##</sup>, electric<sup>##UREF##7##21##</sup>, and magnetic<sup>##REF##24061548##22##–##REF##19113458##24##</sup> fields, as well as spatially inhomogeneous fields such as the manipulation of colloidal particles with optical tweezers<sup>##REF##19730608##25##</sup>. Directed colloidal transport can be achieved via Brownian motors<sup>##REF##10054418##26##–##UREF##8##28##</sup> that combine non-equilibrium fluctuations with spatially inhomogeneous energy landscapes<sup>##REF##12840755##29##–##REF##29599239##31##</sup>.</p>", "<p id=\"Par4\">Usually, the colloidal particles are transported along the same direction but the simultaneous transport of different particles across different directions is useful and even a requisite in systems of various length scales. For example, the transport of cargo on traffic networks requires organizing various subtasks simultaneously<sup>##UREF##9##32##</sup>. Sorting of microparticles driven on periodic lattices is possible because the particles travel along different directions depending on, e.g. their size<sup>##REF##12225126##33##–##REF##15904204##36##</sup>. In biology, the metabolism and structural diversity of the cell demand the regulation of a vast array of molecular traffic across intracellular and extracellular membranes.</p>", "<p id=\"Par5\">In previous work, we have shown that robust, multidirectional, and simultaneous control of colloidal particles that differ in, e.g. their magnetic properties can be achieved with topological protection<sup>##REF##28703235##37##,##REF##32938912##38##</sup>. As illustrated in Fig. ##FIG##0##1##a, paramagnetic particles are placed above a periodic magnetic pattern made of regions of positive and negative magnetizations normal to the pattern. A uniform external magnetic field of varying orientation drives the motion. The particles are transported following the minima of the periodic magnetic potential which results from the interplay between the complex but static field of the pattern and the simple but time-dependent uniform external field. The orientation of the magnetic field varies in time-performing loops. Hence, after one loop the orientation returns to its initial value. Loops that wind around specific orientations induce the transport of the colloidal particles by one unit cell of the magnetic pattern. During the loop, minima of the magnetic potential cross from one unit cell to the adjacent. Once the loop ends, the particle is in a position equivalent to the initial one but in a different unit cell. The motion is topologically protected in the sense that the precise shape of the loop is irrelevant. Only the set of winding numbers of the modulation loop around the specific orientations (the topological invariant) determines the transport direction. The motion is therefore robust against perturbations.</p>", "<p id=\"Par6\">The specific orientations of the external field that are relevant to control the motion depend on both the symmetry of the pattern<sup>##REF##28703235##37##</sup> (e.g. square vs. hexagonal) and the particle properties. Hence, particles with different properties, e.g. paramagnetic and diamagnetic particles above hexagonal magnetic patterns<sup>##REF##27249049##39##</sup> as well as micro-rods of different lengths<sup>##REF##32938912##38##</sup>, can be transported in different directions independently and simultaneously using periodic patterns. However, the use of periodic patterns imposes several limitations on the transport. All particles that belong to the same topological class (e.g. identical paramagnetic particles or rods of the same length) are transported along the same direction, independently of their absolute position above the pattern as schematically represented in Fig. ##FIG##0##1##a. In addition, the location of the particles above the pattern is unknown a priori and it must be determined externally via, e.g. direct visualization via microscopy.</p>", "<p id=\"Par7\">These limitations are overcome here using inhomogeneous (non-periodic) patterns. We make either the symmetry, Fig. ##FIG##0##1##b, or the global orientation, Fig. ##FIG##0##1##c, of the magnetic pattern dependent on the absolute position above the pattern. As a result, the specific orientations of the external field that control the motion depend also on the space coordinate. The direction of the transport can then be locally controlled by the modulation loop of the external field and also via the local symmetry of the inhomogeneous magnetic pattern. We can imprint the complexity of the transport mainly to the pattern, and then use simple loops to generate complex transport as illustrated in Fig. ##FIG##0##1##b. Following this idea we create non-periodic patterns that transport the particles to a desired position by just repeating simple modulation loops. We also create patterns in which the colloidal particles follow arbitrarily complex trajectories driven by a simple time-periodic modulation loop. Additionally, we create simple patterns and encode the complexity of the transport in the modulation loops as sketched in Fig. ##FIG##0##1##c. This allows us to simultaneously and independently control the transport of identical colloidal particles located at different positions above the pattern. We design for example a complex modulation loop that controls the transport of 18 identical colloidal particles individually and simultaneously. Beyond its fundamental interest, our work opens a new route to control the transport in colloidal systems with potential applications in reconfigurable self-assembly<sup>##REF##25034966##40##–##REF##37788439##43##</sup>.</p>" ]	[ "<title>Methods</title>", "<title>System setup and computer simulations</title>", "<p id=\"Par37\">Identical paramagnetic colloidal particles immersed in a solvent are located above a magnetic pattern and are restricted to move in a plane parallel to the pattern (<italic>x</italic><italic>y</italic>-plane), which we call action space (Fig. ##FIG##0##1##a). The pattern contains regions of positive, , and negative, , uniform magnetization along the <italic>z</italic>-direction (normal to the pattern). The width of the domain walls between oppositely magnetized regions is negligible. The particles are driven by a time- and space-dependent external magnetic potential . The potential is generated by the static but space-dependent magnetic field of the pattern and a time-dependent but spatially homogeneous external magnetic field <bold>H</bold><sub>ext</sub>(<italic>t</italic>). Here is the space coordinate in action space and <italic>t</italic> denotes the time. The magnitude of the external field (constant) is much larger than that of the pattern field, i.e. for any position in . Hence, the magnetic potential, which is proportional to the square of the total magnetic field , is dominated by the coupling between the external and the pattern fields:Here <italic>μ</italic><sub>0</sub> is the vacuum permeability, <italic>χ</italic> is the magnetic susceptibility of the colloidal particle, and <italic>v</italic><sub>0</sub> is the particle volume<sup>##REF##28703235##37##</sup>. We have omitted the term proportional to <bold>H</bold><sub>ext</sub> ⋅ <bold>H</bold><sub>ext</sub> in since it is just a constant and therefore it does not affect the motion.</p>", "<p id=\"Par38\">In the overdamped limit, the equation of motion of one particle readswhere <italic>γ</italic> is the friction coefficient against the implicit solvent, the overdot denotes time derivative, is the derivative with respect to , and <bold><italic>η</italic></bold> is a delta-correlated Gaussian random force with zero mean that models the effect of the collisions between the molecules of the solvent and the colloidal particle (Brownian motion). We define our energy scale <italic>ε</italic> as the absolute value of the average external energy that a particle would have when the external magnetic field points normal to the pattern. Hence, absolute temperature <italic>T</italic> is given in reduced units <italic>k</italic><sub>B</sub><italic>T</italic>/<italic>ε</italic> where <italic>k</italic><sub>B</sub> is the Boltzmann’s constant. We use the magnitude of a lattice vector of the periodic pattern <italic>a</italic> as the length scale. The timescale is hence given by <italic>τ</italic> = <italic>γ</italic><italic>a</italic><sup>2</sup>/<italic>ε</italic>. We use adaptive Brownian dynamics<sup>##REF##34624993##66##</sup> to efficiently integrate the equation of motion. In the experiments, the magnetic forces strongly dominate over the random forces. Hence, random forces do not play any role. We use Brownian dynamics simulations due to the overdamped character of the motion in the viscous aqueous solvent. The code to simulate the colloidal motion and to generate the modulation loops is available via Zenodo<sup>##UREF##21##67##</sup>.</p>", "<p id=\"Par39\">As the external magnetic field is homogeneous in space, it can be solely described by its orientation. The set of all possible orientations of <bold>H</bold><sub>ext</sub> forms a spherical surface that we call control space . A point in indicates an orientation of <bold>H</bold><sub>ext</sub>. We drive the colloidal motion by performing closed loops of the orientation of <bold>H</bold><sub>ext</sub> in . Loops that wind around specific points in induce colloidal motion. That is, once the loop returns to its initial position, the colloidal particle has moved to a different unit cell of the pattern. The transport is topologically protected since the precise form of the loop is irrelevant. Only the winding numbers of the loop around the specific points in (which are the topological invariants) determine the transport.</p>", "<title>Experiments</title>", "<p id=\"Par40\">The magnetic films with the desired patterns imprinted are thin Co/Au multilayers with perpendicular magnetic anisotropy<sup>##REF##23117890##68##</sup> lithographically patterned via a home-built<sup>##REF##22667613##69##</sup> keV-He-ion bombardment<sup>##REF##9632386##70##</sup>. Further details about the fabrication process can be found in refs. <sup>##REF##28703235##37##,##REF##20868002##71##–##UREF##22##73##</sup>. The patterns have lattice vectors of magnitude 14 μm if not stated otherwise.</p>", "<p id=\"Par41\">To reduce the influence of lateral magnetic field fluctuations due to the fabrication procedure (which increases near the substrate) we coat the magnetic pattern with a photo-resist film (thickness 1.6 μm). The coating layer serves other two purposes: it protects the patterns and it acts as a spacer between the colloidal particles and the pattern (see Fig. ##FIG##0##1##), in order to secure the condition ∣<bold>H</bold><sub>ext</sub>∣ ≫ ∣<bold>H</bold><sub>p</sub>∣. We then place paramagnetic colloids of diameter 2.8 μm immersed in deionized water on top of the pattern. The microparticles sediment and are suspended roughly the Debye length above the negatively charged coating layer on the pattern. The motion above the pattern is effectively two-dimensional.</p>", "<p id=\"Par42\">The uniform external magnetic field is generated with three coils arranged around the pattern and controlled with a computer. The magnitude of the external field is approximately 4 × 10<sup>3</sup> A/m. Standard reflection microscopy techniques are used to visualize both the colloids and the pattern.</p>", "<title>Square and hexagonal periodic patterns</title>", "<p id=\"Par43\">Consider magnetic periodic <italic>N</italic>-fold symmetric patterns with either <italic>N</italic> = 2 (square patterns) or <italic>N</italic> = 3 (hexagonal patterns). Examples of both types are shown in Supplementary Fig. ##SUPPL##0##1##. In the limit of an infinitely thin pattern located at <italic>z</italic> = 0, the magnetization iswith <italic>δ</italic>(⋅) the Dirac distribution, the unit vector normal to the pattern, <bold>r</bold><sub>⊥</sub> = (<italic>x</italic>, <italic>y</italic>), andwhere <italic>m</italic><sub>p</sub> is the saturation magnetization of the domains. The wave vectors <bold>q</bold><sub><italic>i</italic></sub> in the square patterns arewith magnitude <italic>q</italic><sub>0</sub> = 2<italic>π</italic>/<italic>a</italic> and <italic>a</italic> being the magnitude of a lattice vector, which in square patterns can be defined with the wave vectors being the reciprocal lattice vectors. That is, <bold>a</bold><sub><italic>i</italic></sub> ⋅ <bold>q</bold><sub><italic>j</italic></sub> = 2<italic>π</italic><italic>δ</italic><sub><italic>i</italic><italic>j</italic></sub> (see Supplementary Fig. ##SUPPL##0##1##b). The global phase <italic>ψ</italic> sets the orientation of the lattice vectors with respect to a fixed laboratory frame.</p>", "<p id=\"Par44\">In the hexagonal patterns, the wave vectors arewith magnitude . Here, the three wave vectors can be related to three (linearly dependent) lattice vectors via <bold>q</bold><sub><italic>i</italic></sub> ⋅ <bold>a</bold><sub><italic>j</italic></sub> = 2<italic>π</italic><italic>δ</italic><sub><italic>i</italic><italic>j</italic></sub> for <italic>i</italic> = 1, 2 and <bold>a</bold><sub>3</sub> ⋅ <bold>q</bold><sub>3</sub> = 0 (see Supplementary Fig. ##SUPPL##0##1##b).</p>", "<p id=\"Par45\">In both square and hexagonal patterns, the wave vectors point into the <italic>N</italic> different symmetry directions. The translational vector <bold>b</bold> in Eq. (##FORMU##39##4##) plays a relevant role only in inhomogeneous patterns. In periodic patterns, we usually set <bold>b</bold> = <bold>0</bold>.</p>", "<p id=\"Par46\">In square patterns, the symmetry phase <italic>ϕ</italic> in the magnetization (see Eq. (##FORMU##39##4##)), simply causes a trivial shift of all Wigner–Seitz cells with respect to the origin of the pattern. Hence, for simplicity, we set it to zero. In hexagonal patterns however, the symmetry phase <italic>ϕ</italic> has a non-trivial effect since it determines the point symmetry of the pattern (see Supplementary Fig. ##SUPPL##0##1##c), and therefore the modulation loops required to transport the colloidal particles<sup>##REF##28703235##37##</sup>. The Wigner–Seitz cell of a hexagonal pattern contains in general three symmetry points with C<sub>3</sub> symmetry (rotation through an angle 2<italic>π</italic>/3 about the symmetry axis). For special values of the symmetry phase, one of the three-fold symmetric points acquires a higher symmetry; either six-fold hexagonal C<sub>6</sub> symmetry (for <italic>ϕ</italic> = 0 and <italic>ϕ</italic> = ± <italic>π</italic>/3) or S<sub>6</sub> symmetry, i.e. a C<sub>6</sub> followed by a perpendicular reflection (for <italic>ϕ</italic> = ± <italic>π</italic>/6).</p>", "<p id=\"Par47\">Finally, the parameter <italic>m</italic><sub>0</sub> in Eq. (##FORMU##39##4##), which is actually a function of the symmetry phase <italic>ϕ</italic>, alters the area ratio between up-magnetized and down-magnetized domains. Following Loehr et al.<sup>##REF##28703235##37##</sup>, we use here (therefore in square patterns <italic>m</italic><sub>0</sub> = 0) to ensure that the average magnetization in hexagonal patterns is very small, i.e.</p>", "<title>Magnetic field of the pattern</title>", "<p id=\"Par48\">To numerically compute the magnetic field of the pattern, <bold>H</bold><sub>p</sub>(<bold>r</bold>), at the desired position in action space we first discretize the pattern in a square grid with resolution 0.03<italic>a</italic> and compute the magnetization at the grid points via Eq. (##FORMU##39##4##). Next, we compute the magnetic field at the grid points by convolution of the magnetization with the Green’s-function of the system:Here <bold>r</bold><sub>⊥</sub> = (<italic>x</italic>, <italic>y</italic>) is the position coordinate in a plane parallel to the pattern. We calculate the magnetic field at an elevation above the pattern <italic>z</italic> = 0.5<italic>a</italic>, which is comparable to the experimental value. As usual, we perform the convolution in Fourier space.</p>", "<p id=\"Par49\">To calculate the magnetic field at a generic, off-grid, position we simply interpolate the magnetic field using bicubic splines.</p>", "<title>Pattern with a topological defect</title>", "<p id=\"Par50\">For the pattern with a topological defect shown in Fig. ##FIG##1##2##, the symmetry phase varies with the position <bold>r</bold><sub>⊥</sub> asand the global orientational phase is set to <italic>ψ</italic> = 0 in Eq. (##FORMU##41##6##). For our choice of wave vectors (see Eq. (##FORMU##41##6##) and Supplementary Fig. ##SUPPL##0##1##b), the symmetry phase modulation is simply . Here returns the four-quadrant inverse tangent of <italic>y</italic>/<italic>x</italic>. The symmetry phase varies therefore between <italic>ϕ</italic> = −<italic>π</italic>/3 and <italic>π</italic>/3 as we wind once around the origin. The topological charge of the defect located at the center of the pattern (<bold>r</bold><sub>⊥</sub> = 0) is <italic>q</italic> = Δ<italic>ϕ</italic>/(2<italic>π</italic>/<italic>p</italic>) = 1. Here Δ<italic>ϕ</italic> = 2<italic>π</italic>/3 is the angle that the director rotates if we wind once counter-clockwise around the defect, and <italic>p</italic> = 3 is the <italic>p</italic>-atic symmetry of the director field<sup>##UREF##23##74##</sup>. (The symmetry phase can be described with a 3-atic director field for which the local orientations are defined modulo <italic>π</italic>/3.) Varying the symmetry phase between −<italic>π</italic>/3 and <italic>π</italic>/3 also introduces a shift of the unit cell, cf. the unit cells for <italic>ϕ</italic> = <italic>π</italic>/3 and −<italic>π</italic>/3 in Supplementary Fig. ##SUPPL##0##1##c. To rectify this shift and avoid therefore discontinuities in the magnetization of the pattern, we need to use a local shift vector in Eq. (##FORMU##39##4##) given byThe shift vector can be understood as a Burgers vector since it corrects for the spatial distortion of the pattern around the defect.</p>", "<title>Symmetry phase modulated patterns</title>", "<p id=\"Par51\">To encode in the pattern the desired particle trajectories, we use the drawing software Krita<sup>##UREF##24##75##</sup>. We prescribe the stable trajectory on a square image with a side-length of 1000 pixels. In Krita, we draw the desired trajectory with a brush (thickness 1 pixel) that encodes the drawing direction in the hue of the colored pixels. The drawing direction directly translates into the transport direction that the particles will follow above the pattern. This procedure results in an image that is essentially empty except for the trajectory lines. We then map from hue to the symmetry phase <italic>ϕ</italic>. An example of the pattern at this stage is shown in Supplementary Fig. ##SUPPL##0##3##a. The mapping from hue to <italic>ϕ</italic> is simply a linear transformation.</p>", "<p id=\"Par52\">Next, we give a value to the symmetry phase everywhere in the pattern. To calculate the phase at a generic position <bold>r</bold><sub>⊥</sub> = (<italic>x</italic>, <italic>y</italic>) we average over all the prescribed phases along the trajectories. Each phase along the trajectory is weighted with a weight function proportional to , with <italic>r</italic><sub>d</sub> the distance between <bold>r</bold><sub>⊥</sub> and a point on the trajectory. Special care needs to be taken due to the periodicity of the symmetry phase<sup>##UREF##25##76##</sup>. We first transform the phases along the trajectories into unit vectors, next we average the vectors, and then transform back the averaged vector into a value of the symmetry phase. An illustration of the pattern after this stage is shown in Supplementary Fig. ##SUPPL##0##3##b. Finally, we use the value of the symmetry phase in the whole pattern to calculate the magnetization via Eq. (##FORMU##39##4##) (see Supplementary Fig. ##SUPPL##0##3##c).</p>" ]	[ "<title>Results</title>", "<p id=\"Par8\">The plane in which the particles move (action space) splits into allowed and forbidden regions. In the allowed (forbidden) regions the stationary points of the magnetic potential are minima (saddle points). The boundaries between allowed and forbidden regions in action space are the fences. The position of the fences in control space (a sphere that represents all possible orientations of the external field) depends on the symmetry of the pattern and it determines the loops that induce colloidal transport (see Fig. ##FIG##0##1##). An extended summary of the transport in periodic patterns<sup>##REF##28703235##37##</sup> is provided in Supplementary Note ##SUPPL##0##1## and Supplementary Figs. ##SUPPL##0##1## and ##SUPPL##0##2##.</p>", "<p id=\"Par9\">Here we focus on transport in inhomogeneous patterns. Sophisticated transport modes can be achieved by adding complexity to either the patterns, the loops, or to both of them. We see examples of each type in the following sections. Details about the experiments and computer simulations are given in the “Methods” section.</p>", "<title>Complex patterns and simple loops</title>", "<p id=\"Par10\">There is a full family of periodic hexagonal patterns characterized by the value of the symmetry phase <italic>ϕ</italic> (see the “Methods” section) and illustrative examples in Fig. ##FIG##0##1##b. We render the symmetry phase a continuous function of the position, which creates an inhomogeneous symmetry phase modulated pattern such as the example in Fig. ##FIG##0##1##b. For slow enough spatial changes of the symmetry phase, the cells of the modulated pattern deviate only weakly from the Wigner–Seitz cells of corresponding periodic patterns with fixed values of the symmetry phase. Hence, knowing how to control the transport in periodic patterns is enough to control the transport in inhomogeneous situations.</p>", "<p id=\"Par11\">We focus first on complex inhomogeneous patterns designed to achieve locally different transport for a single specific task. Most of the complexity of the transport is embedded in the pattern and therefore the modulation loops of the external field are simple.</p>", "<title>Topological defect in the symmetry phase</title>", "<p id=\"Par12\">We show in Fig. ##FIG##1##2## a symmetry phase modulated hexagonal pattern. The details to generate the pattern are given in the “Methods” section. Each time we wind around the center of the pattern we go through the full family of hexagonal patterns exactly once (including the inverse patterns with opposite magnetization) and return to the initial symmetry phase. This introduces a topological defect at the center of the pattern where the symmetry phase is not well defined.</p>", "<p id=\"Par13\">The symmetry phase is constant along radial directions and the modulation is weak everywhere except near the defect. To illustrate this, we have dissected the pattern into hexagonal cells in Fig. ##FIG##1##2##a. We also show enlarged Wigner Seitz cells of periodic patterns with a symmetry phase corresponding to that of the radial ray of the inhomogeneous pattern. The Wigner Seitz cells of the periodic patterns resemble closely the cells of the inhomogeneous pattern, even in the proximity of the central defect. It is therefore expected that the transport in the inhomogeneous pattern can be understood in terms of the transport in periodic patterns.</p>", "<p id=\"Par14\">The location of the fences in the control space varies substantially as we wind around the defect in the action space. (See the stereographic projections of control space for selected values of the symmetry phase in Fig. ##FIG##1##2##a and Supplementary Fig. ##SUPPL##0##1##.) Hence, it is possible to transport the microparticles into different directions depending on the sector of the pattern. In particular, we can construct modulation loops that use the central defect of the pattern as either an attractor or a repeller of colloidal particles.</p>", "<p id=\"Par15\">A stereographic projection of the modulation loop that attracts the particles towards the defect is shown in Fig. ##FIG##1##2##a next to each enlarged Wigner–Seitz cell. The loop is made of two subloops. Only one of the subloops is active (green) for each value of the symmetry phase <italic>ϕ</italic>. The subloop is active in the sense that it induces net transport for those particles located in sectors of the pattern with that value of <italic>ϕ</italic>. The other subloop is inactive (red) in the sense that after one complete subloop, the particle returns to its position and hence there is no net transport. Using two subloops we control simultaneously the transport direction in sectors of the pattern with opposite magnetization (different values of the symmetry phase). Note for example how the active subloop in regions with C<sub>6</sub> symmetry (<italic>ϕ</italic> = 0) becomes the inactive subloop in those regions with an inverse pattern (<italic>ϕ</italic> = ± <italic>π</italic>/3) and vice versa (see Fig. ##FIG##1##2##a). To induce transport a subloop must wind around at least three bifurcation points of the fences in control space , as explained in the Supplementary Note ##SUPPL##0##1##. Recall that control space is simply the surface of a sphere in which each point corresponds to one orientation of the external magnetic field. The bifurcation points are the points in which two segments of the fences meet in , see examples in Supplementary Fig. ##SUPPL##0##2##.</p>", "<p id=\"Par16\">The complete attractor loop, made of two subloops, induces four different transport directions (along ±<bold>a</bold><sub>1</sub> and along ±<bold>a</bold><sub>3</sub>) depending on the value of the symmetry phase (see Fig. ##FIG##1##2##a). Here, <bold>a</bold><sub><italic>i</italic></sub>, <italic>i</italic> = 1, 2, 3 are three lattice vectors of the periodic hexagonal pattern (see Fig. ##FIG##1##2## and the “Methods” section). The transition between the different transport directions, e.g. from +<bold>a</bold><sub>3</sub> to −<bold>a</bold><sub>1</sub>, occurs at specific values of the symmetry phase that can be adjusted with the loop. See the transition lines (dashed-black lines) in Fig. ##FIG##1##2##a.</p>", "<p id=\"Par17\">By controlling the location of the transition lines we fix whether the defect acts as an attractor or a repeller of particles (see Fig. ##FIG##1##2##b). In both cases, the particles wind clockwise around the defect. Instead of changing the position of the transition lines, we could also control whether the defect attracts or repels microparticles by reversing the direction of the transport. However, this requires a complete redesign of the modulation loop. Simply reversing the direction of the modulation loop does not reverse in general the transport direction in the whole pattern due to the occurrence of non-time reversal ratchets in hexagonal patterns<sup>##REF##28703235##37##,##REF##27249049##39##</sup>.</p>", "<p id=\"Par18\">In Fig. ##FIG##2##3##a, b we show the trajectories of a colloidal particle located above the defect pattern according to Brownian dynamics simulations. The particle is randomly initialized above the pattern and then subjected to several repetitions of the attractor loop shown in Fig. ##FIG##1##2##. We also show the trajectory followed by the particle under the repetition of the repeller loop, depicted in Fig. ##FIG##2##3##c. The repeller and the attractor loops have similar shapes since they differ only in the values of <italic>ϕ</italic> at which the transport direction changes. The corresponding experimental trajectories are shown in Fig. ##FIG##2##3##d. In the experiments, there are several colloidal particles that are initially located above the pattern in random positions. If the attractor loop is repeated enough times, one colloidal particle will have reached the defect with almost certainty. Once a particle reaches the defect it stays there. In the experiments, further colloidal particles that try to enter the defect are repelled by the particle already occupying the center via dipolar repulsion. We can thus use the attractor loop to initialize one microparticle in the defect center. Whereas the location prior to the action of the attractor loop was unknown, it is known after the repeated application of the loop. The topological initialization is robust to thermal fluctuations. Brownian dynamics simulations of colloidal particles at higher temperatures still initialize the location of the defect. We briefly discuss the effect of finite temperature in the “Methods” section and Supplementary Fig. ##SUPPL##0##4##.</p>", "<title>Encoding complex trajectories in the pattern</title>", "<p id=\"Par19\">Patterns with spatial modulation of the symmetry phase can be used to encode arbitrarily complex particle trajectories. The patterns are designed to induce the desired trajectory when the particles are subjected to the repetition of a simple modulation loop of the orientation of the external field. The modulation loop transports particles along all possible directions in hexagonal patterns, i.e. along ±<bold>a</bold><sub><italic>i</italic></sub> with <italic>i</italic> = 1, 2, 3, but in a way that only one direction is active for a given value of the symmetry phase. For example, particles on top of regions with C<sub>6</sub> symmetry are transported towards −<bold>a</bold><sub>3</sub>. The transport direction changes at specific values of the symmetry phase determined by the modulation loop. In Fig. ##FIG##3##4##a we show the modulation loop together with the representative fences and the resulting transport direction for each value of the symmetry phase.</p>", "<p id=\"Par20\">The detailed procedure to generate the patterns is described in the “Methods” section and Supplementary Fig. ##SUPPL##0##3##. In essence, we first draw the trajectories that the particles should follow by hand. Then, at each position along the trajectory, we encode the transport direction using the value of the symmetry phase. Finally, the value of the symmetry phase at each point in the complete pattern is calculated as a spatially resolved weighted average of the symmetry phase along the trajectory. As a result, the symmetry phase varies smoothly across the pattern except for the occurrence of string-like topological defects in the symmetry phase.</p>", "<p id=\"Par21\">Figure ##FIG##3##4##b shows a symmetry phase modulated pattern together with the corresponding simulated particle trajectories. The value of the symmetry phase is color-coded (see color bar). The pattern is designed to transport the particles along one stable trajectory that forms a closed loop resembling the letter “B”. In Fig. ##FIG##3##4##b we have highlighted the stable trajectory with a thick green line. Most particles above the pattern either enter the stable trajectory or leave the pattern. Occasionally one particle gets stuck in specific regions of the pattern. This can potentially be avoided by the introduction of random fluctuations in the modulation loop. In the presence of strong Brownian motion, the stable trajectories broaden to a width of a few unit cells, and additional stable trajectories might occur.</p>", "<p id=\"Par22\">Corresponding experimental trajectories are shown in Fig. ##FIG##3##4##c. Even though the agreement is not perfect, the experimental trajectories follow closely the prescribed letter “B”, demonstrating, therefore, the potential of the method. Small variations in the position of the fences due to the imperfections of the pattern are likely the reason behind the deviations shown in the experiments. Fine-tuning the modulation loop and the height of the particles above the pattern would likely improve the results.</p>", "<title>Simple patterns and complex loops</title>", "<p id=\"Par23\">We follow now the opposite approach by encoding the complexity in the modulation loop. We create simple inhomogeneous patterns by concatenating large patches of periodic square patterns. The patches differ in the global orientation of the lattice vectors given by a global phase <italic>ψ</italic> (see the “Methods” section). Each (simple) patch allows for a rich variety of transport tasks. The task in each patch can be controlled individually and simultaneously using rather complex modulation loops in control space.</p>", "<p id=\"Par24\">The fences of the C<sub>4</sub> square pattern are four equidistant points on the equator (see Supplementary Note ##SUPPL##0##1##). The four fence points in correspond to external fields pointing along the positive and negative directions of the lattice vectors<sup>##REF##28703235##37##,##UREF##11##44##</sup>, i.e. along ±<bold>a</bold><sub>1</sub> and ±<bold>a</bold><sub>2</sub>. Therefore, rotating the lattice vectors also rotates the position of the fences in control space. Thus, it is possible to construct loops that wind around different fences in , and hence induce different transport directions, depending on the orientation of the pattern <italic>ψ</italic>. An illustration is shown in Fig. ##FIG##4##5##a.</p>", "<p id=\"Par25\">Since the fences are points in it is in principle possible to concatenate an arbitrarily large number of patches with different orientations and control the motion in each of them independently. In practice, limiting factors might appear due to e.g. imperfections in the patterns that effectively make the fences in extended regions, the angular resolution with which the orientation of the external field can be controlled, and the presence of Brownian motion. Due to the limiting factors, two patterns can be resolved independently if they are rotated by an angle of at least Δ<italic>ψ</italic>. Hence, the maximum number of patches that can be controlled independently is (<italic>π</italic>/2)/Δ<italic>ψ</italic> since after a rotation of <italic>π</italic>/2 a C<sub>4</sub> pattern repeats itself (and so do the fences).</p>", "<p id=\"Par26\">With a resolution Δ<italic>ψ</italic> = 5° it is then possible to control the motion in up to 18 patches independently. As an example we program a single loop in that writes the first eighteen letters of the alphabet simultaneously, (see Fig. ##FIG##4##5##b and Supplementary Movie ##SUPPL##3##3##). Note that the letters are rotated by an angle <italic>ψ</italic>. For simplicity, we have designed an algorithm to write custom trajectories in a square pattern with global orientation <italic>ψ</italic> = 0. Next, we apply a global rotation to the modulation loop to control the transport in patterns with a generic orientation <italic>ψ</italic>. As a result, the trajectories are also rotated.</p>", "<p id=\"Par27\">The loop that writes the first 18 letters of the alphabet contains 2086 simple commands. Each command is a small closed subloop that either transports a particle in one unit cell along the four possible directions of the square lattice or leaves the particle in the same position, similar to the loops in Fig. ##FIG##4##5##a. Even though an angular resolution of Δ<italic>ψ</italic> = 5° is achievable experimentally, the number of commands required by the complete loop exceeds our current experimental capabilities. Nevertheless, we show in Fig. ##FIG##4##5##c, the experimental trajectories of a simplified loop that writes low-resolution versions of the first four letters of the alphabet. The loop is made of 96 simple commands. The agreement with computer simulations is essentially perfect, as we demonstrate in a one-to-one comparison in Supplementary Movie ##SUPPL##6##4##.</p>", "<p id=\"Par28\">The simultaneous control of the transport in several patches of rotated square patterns is particularly simple due to the simplicity of the fences in . However, the same ideas apply to patterns with other symmetry classes.</p>", "<p id=\"Par29\">Here, we have initialized the particles in the desired positions within their respective patches. As we discuss now, it is possible to automatize this process by combining the patches with complex patterns.</p>", "<title>Complex patterns and complex loops</title>", "<p id=\"Par30\">Complete control over the colloidal transport is achieved by combining complex patterns and complex loops. In Fig. ##FIG##5##6## we combine three C<sub>4</sub> patches that differ in their global orientation <italic>ψ</italic> and three hexagonal patterns with a topological defect in the symmetry phase. The transition between both patterns occurs smoothly within a region of length equivalent to approximately five unit cells of the square patterns.</p>", "<p id=\"Par31\">We first make use of the patterns with a topological defect to move randomly placed particles toward the defects. We simply repeat the attractor modulation loop shown in Fig. ##FIG##1##2## several times such that the particles move and stay at the defects, see the blue trajectories of the particles in Fig. ##FIG##5##6##. Once this initialization stage is finished we know the precise position of the particles and can control them independently. Using two simple loops we transport the particles downwards from the defects to the square patches. We use one loop to move the particles in the defect pattern (orange trajectories) and another loop to move the particles in the transition region and the square patches (green trajectories). Then, a relatively complex loop controls the motion of the three particles independently. Each particle follows a complex trajectory drawing either a square, a triangle, or a cross depending on the value of the global orientation <italic>ψ</italic> (red trajectories). Experimentally we tested each part of the loop separately, as shown in the insets of Fig. ##FIG##5##6##. Again, the agreement between simulations and experiments is excellent. The small errors that occur in the experimental trajectories, likely due to imperfections in the pattern, do not affect the global shape of the trajectories. A movie of the whole process is shown in Supplementary Movie ##SUPPL##7##5##.</p>" ]	[ "<title>Discussion</title>", "<p id=\"Par32\">We have shown that the combination of a complex static magnetic field with a simple time-dependent uniform external field of varying orientation allows us to control the motion of several identical microparticles independently and simultaneously. The transport complexity can be broken down to a finite set of special orientations of the external field. A modulation loop that winds around one of those orientations induces transport along a known direction in a known region of the pattern. The motion is topologically protected since only the winding numbers of the modulation loop around the special orientations (topological invariant) are important. Hence, it is relatively simple to generate loops and patterns that induce arbitrarily complex trajectories. Our ideas might be transferable to other systems in which the transport is also based on topological protection. These include, solitons<sup>##REF##25157161##45##</sup>, nano-machines<sup>##REF##10991123##46##,##UREF##12##47##</sup>, sound waves<sup>##REF##26561580##48##,##REF##25839273##49##</sup>, photons<sup>##REF##25192126##50##,##UREF##13##51##</sup>, and quantum mechanical excitations<sup>##UREF##14##52##</sup>.</p>", "<p id=\"Par33\">The complexity of the transport is encoded in the magnetic potential which varies in space and in time via the magnetic patterns and the modulation loops, respectively. An alternative approach that encodes the transport in the particle shape has appeared recently<sup>##REF##37558849##53##</sup>. There, Sobolev et al. find the shape of the rigid body that traces the desired trajectory when rolling down a slope. We have restricted our study to identical isotropic paramagnetic particles. However, as discussed in the “Introduction” section, colloidal particles with different characteristics (e.g. diamagnetic and paramagnetic particles or particles with different shapes) might belong to different topological classes. The fences of particles belonging to different topological classes are located in different regions in . Above non-periodic patterns, the control space of particles belonging to different topological classes will also depend on the space coordinate. A precise control over the transport depending not only on the position but also on the particle characteristics is then possible. Therefore, beyond offering the possibility to control the transport of identical microparticles simultaneously, our work also opens a new route towards dynamical self-assembly in colloidal science. As an example, we have created a colloidal rod factory<sup>##UREF##15##54##</sup> in which identical isotropic particles are transported toward a reaction site in which they self-assemble. Only when they reach the desired aspect ratio, do the rods leave the polymerization site following the desired trajectory. The use of patchy colloids<sup>##REF##16610908##55##–##UREF##16##58##</sup> with, e.g. hybridization of complementary DNA strands<sup>##UREF##17##59##–##REF##37363931##61##</sup> and other shape-anisotropic particles<sup>##UREF##18##62##,##UREF##19##63##</sup> would offer more versatility to create complex functional structures.</p>", "<p id=\"Par34\">We have considered transport above patterns made of identical patches rotated with respect to each other. It is also possible to combine patches of patterns with different symmetries provided that their respective fences do not overlap in control space. Moreover, a combination of both, i.e. a pattern made of patches with different symmetries, e.g. C<sub>4</sub> and C<sub>6</sub>, that in addition are rotated with respect to each other would substantially increase the number of tasks that can be done simultaneously since their respective fences in control space do not overlap.</p>", "<p id=\"Par35\">In the experiments, the Brownian motion of the colloidal particles is negligible but it might play a role in other systems with smaller colloids and/or at higher temperatures. Since the transport is topologically protected, it is robust against perturbations such as the presence of Brownian motion<sup>##UREF##11##44##</sup>. If we make Brownian motion more prominent (e.g. by increasing the temperature or reducing the particle size) the particles start to deviate from the expected trajectories but overall the transport is robust. An example of Brownian dynamics simulations at different temperatures is shown in Supplementary Fig. ##SUPPL##0##4##. The topological protection will disappear due to Brownian motion at sufficiently high temperatures and for small enough particles. A possible solution would then be to increase the magnitude of either the pattern field or the external magnetic field such that the magnetic forces dominate again the transport.</p>", "<p id=\"Par36\">Our systems are very dilute and therefore direct interparticle interactions and hydrodynamic interactions do not play any role. However, it would be interesting to look at the effect of both superadiabatic forces<sup>##UREF##20##64##</sup> and long-range hydrodynamic interactions<sup>##REF##35675407##65##</sup> in denser systems.</p>" ]	[]	[ "<p id=\"Par1\">Topological protection ensures stability of information and particle transport against perturbations. We explore experimentally and computationally the topologically protected transport of magnetic colloids above spatially inhomogeneous magnetic patterns, revealing that transport complexity can be encoded in both the driving loop and the pattern. Complex patterns support intricate transport modes when the microparticles are subjected to simple time-periodic loops of a uniform magnetic field. We design a pattern featuring a topological defect that functions as an attractor or a repeller of microparticles, as well as a pattern that directs microparticles along a prescribed complex trajectory. Using simple patterns and complex loops, we simultaneously and independently control the motion of several identical microparticles differing only in their positions above the pattern. Combining complex patterns and complex loops we transport microparticles from unknown locations to predefined positions and then force them to follow arbitrarily complex trajectories concurrently. Our findings pave the way for new avenues in transport control and dynamic self-assembly in colloidal science.</p>", "<p id=\"Par2\">External fields can control the motion of colloidal particles inducing different trajectories depending on for instance the particle size. The authors here use nonperiodic energy landscapes and topological protection to transport a collection of identical colloidal particles simultaneously and independently.</p>", "<title>Subject terms</title>" ]	[ "<title>Supplementary information</title>", "<p>\n\n\n\n\n\n\n\n\n</p>" ]	[ "<title>Supplementary information</title>", "<p>The online version contains supplementary material available at 10.1038/s41467-023-43390-0.</p>", "<title>Acknowledgements</title>", "<p>We thank Adrian Ernst for helping us to transfer the loops from the simulations to the experiment. We acknowledge funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under project numbers 440764520 (T.M.F. and D.d.l.H.) and 531559581 (D.d.l.H. and T.M.F.).</p>", "<title>Author contributions</title>", "<p>N.C.X.S. designed the modulation loops and performed the computer simulations. F.F. performed the experiments. N.C.X.S., F.F., T.M.F., and D.d.l.H. conceptualized the research. P.K., F.S., and M.U. produced the magnetic film. S.A. and Ar.E. performed the fabrication of the micromagnetic domain patterns within the magnetic thin film. N.C.X.S., T.M.F., and D.d.l.H. designed the patterns and wrote the manuscript. All authors contributed to the different revision stages of the manuscript.</p>", "<title>Peer review</title>", "<title>Peer review information</title>", "<p id=\"Par53\"><italic>Nature Communications</italic> thanks Pietro Tierno and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.</p>", "<title>Funding</title>", "<p>Open Access funding enabled and organized by Projekt DEAL.</p>", "<title>Data availability</title>", "<p>The code to simulate the system and to generate the modulation loops is available at Zenodo<sup>##UREF##21##67##</sup>. All other data supporting the findings are available from the corresponding author upon request.</p>", "<title>Code availability</title>", "<p>A code to perform the adaptive Brownian Dynamics simulations of the colloidal particles as well as to generate the modulation loops is available at Zenodo<sup>##UREF##21##67##</sup>.</p>", "<title>Competing interests</title>", "<p id=\"Par54\">The authors declare no competing interests.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><title>Periodic vs inhomogeneous patterns.</title><p><bold>a</bold> Periodic square pattern (a unit cell is highlighted in yellow), <bold>b</bold> hexagonal pattern in which the symmetry phase <italic>ϕ</italic> varies in space, and <bold>c</bold> a pattern made of two square patterns rotated by an angle of 45°. The patterns are made of regions with positive (black) and negative (white) magnetization normal to the pattern, see vertical arrows in (<bold>a</bold>). A polymer coating protects the patterns and acts as a spacer for the paramagnetic colloidal particles (orange) that are suspended in a solvent and move in a plane parallel to the pattern (action space). The motion is driven by a uniform external field (green arrow). The control space (gray spheres) represents all possible orientations of the external field. The orientation of the external field varies in time performing a loop (green curves). Loops that wind around special orientations induce particle transport. These special orientations are determined by the position of the fences and bifurcation points in control space which depend on the local symmetry of the pattern. Shown are the fences of square patterns for one (<bold>a</bold>) and two (<bold>c</bold>) different orientations, as well as those of four hexagonal patterns with different symmetry phases <italic>ϕ</italic> (<bold>b</bold>). We also indicate the bifurcation points (black circles) in (<bold>b</bold>) which are those points where two fence segments meet. Next to the fences, we show the corresponding unit cell of the pattern. In periodic patterns (<bold>a</bold>) all the particles move in the same direction (orange arrows), independently of their position above the pattern. In inhomogeneous patterns, a single modulation loop can induce transport in different directions depending on the position of the particle above the pattern. Complex particle trajectories can be generated using complex patterns and simple loops (<bold>b</bold>) or simple patterns and complex loops (<bold>c</bold>).</p></caption></fig>", "<fig id=\"Fig2\"><label>Fig. 2</label><caption><title>Pattern with a topological defect.</title><p><bold>a</bold> Magnetic pattern with a topological defect in the symmetry phase <italic>ϕ</italic>. The pattern is dissected into hexagonal cells (green hexagons). The central cell (yellow) contains the defect. Enlarged Wigner–Seitz cells of selected periodic hexagonal lattices with symmetry phase <italic>ϕ</italic> (see color bar) corresponding to their position in the pattern are shown. Next to each enlarged cell, we plot a stereographic projection of the corresponding control space and the modulation loop that attracts the particles toward the defect. Shown are the fences (blue), the equator (violet), and both the active (green) and the inactive (red) subloops. The loop winds as indicated by the circular black arrow. The two apparently open segments of the loop are actually joined at the south pole of the control space (not visible due to the projection). The transport direction (orange arrows) changes at the transition lines (black-dashed lines). <bold>b</bold> Illustrative configurations of the position of transition lines (black-dashed lines) that give rise to particle trajectories moving towards the defect (attractor) or away from it (repeller). The particle trajectories are illustrated in orange.</p></caption></fig>", "<fig id=\"Fig3\"><label>Fig. 3</label><caption><title>Attractor and repeller of particles.</title><p><bold>a</bold> Trajectory of a colloidal particle (randomly initialized) obtained with Brownian dynamics simulations above a pattern with a central topological defect in the symmetry phase. The blue (orange) trajectory is generated by the repetition of the attractor (repeller) modulation loop that moves particles towards (away from) the defect. The pattern is colored according to the value of the symmetry phase (color bar). The scale bar is 10<italic>a</italic>. <bold>b</bold> Close-up of the region indicated by a yellow square in (<bold>a</bold>) and the trajectories around the central defect. The background shows the local magnetization of the pattern. <bold>c</bold> Stereographic projection of the repeller loop (green) in . The equator (violet circle) and the fences of the C<sub>6</sub> and S<sub>6</sub> patterns as well as their inverse patterns, and , (dashed curves) are also depicted as a reference. The fences are colored according to the value of the symmetry phase. The two apparently open segments of the loop are actually joined at the south pole of the control space (not visible due to the projection). The loop is made of two subloops winding clockwise, as indicated by the circular arrows. <bold>d</bold> Experimental trajectories of several colloidal particles (labeled with a numbered circle) above the same pattern with a topological defect (yellow circle). The trajectories induced by the attractor (repeller) loop are colored in blue (orange). Blue and orange trajectories correspond to different experiments and have been superimposed in the figure. Note that under the microscope regions with negative magnetization appear darker than regions with positive magnetization, i.e. the opposite of our color choice in e.g. (<bold>b</bold>). The scale bar is 10<italic>a</italic> and the lattice constant of one cell is approx. 14 μm. Movies of the simulated and the experimental motion are provided in Supplementary Movie ##SUPPL##3##1##.</p></caption></fig>", "<fig id=\"Fig4\"><label>Fig. 4</label><caption><title>Symmetry phase modulated pattern.</title><p><bold>a</bold> Stereographic projection of control space showing the equator (violet circle), the closed modulation loop (green-solid curve), and the fences of patterns with C<sub>6</sub>, S<sub>6</sub>, and symmetries (dashed curves). The two apparently open segments of the loop are actually joined at the south pole of the control space (not visible due to the projection). The fences are colored according to the value of the symmetry phase (see the annular color bar). The transport directions induced by the loop (orange arrows) change at specific values of the symmetry phase <italic>ϕ</italic> as indicated by the transition lines (black-dashed lines). <bold>b</bold> Symmetry phase modulated pattern (the color indicates the value of the symmetry phase). A global rotation, <italic>ψ</italic> = <italic>π</italic>/2 in Eq. (##FORMU##41##6##), makes one transport direction (lattice vector <bold>a</bold><sub>3</sub>) parallel to the vertical axis. Particles above the pattern and subjected to the repetition of the modulation loop in (<bold>a</bold>) write the letter ''B''. Thin cyan lines show simulated particle trajectories for randomly initialized particles above the pattern. After several repetitions of the modulation loop, most particles enter the stable trajectory, highlighted with a thick green-solid line. <bold>c</bold> Experimental trajectories of colloidal particles above the pattern depicted in (<bold>b</bold>) and subjected to the modulation loop shown in (<bold>a</bold>). The region shown in the experiments (<bold>c</bold>) is smaller than that in simulations (<bold>b</bold>) due to the field of view of the microscope. The inset in (<bold>c</bold>) is a close view of the region indicated with a yellow circle in which we have altered the contrast of the image to better visualize the magnetization. Under the microscope regions with negative magnetization appear darker than those with positive magnetization. A colloidal particle (black dot) is also visible in the inset. A movie of the motion in simulations and experiments is provided in Supplementary Movie ##SUPPL##4##2##.</p></caption></fig>", "<fig id=\"Fig5\"><label>Fig. 5</label><caption><title>Simple patterns and complex loops.</title><p><bold>a</bold> Five square magnetic patterns (and their corresponding control spaces) with a different value of the global orientation <italic>ψ</italic>, as indicated. The fences in (blue circles) are four points located on the equator (violet circle). The position of the fences depends on the value of <italic>ψ</italic>. The modulation loop consists of four interconnected subloops that wind counterclockwise. A subloop is active (green) if it winds around a fence point (blue circles) and inactive (red) otherwise. The orange segments of the modulation loop simply connect the different subloops. Depending on the value of <italic>ψ</italic>, the modulation loop induces different transport directions (green arrows) or no transport at all. <bold>b</bold> A pattern made of 18 patches with square symmetry and different global orientation <italic>ψ</italic> (color bar). A modulation loop controls the trajectories of particles above each patch simultaneously and independently. The particle trajectories (black) write the first 18 letters of the alphabet. The length of the scale bar is 10<italic>a</italic>. A movie can be found in Supplementary Movie ##SUPPL##5##3##. <bold>c</bold> Experimental trajectories of colloidal particles above four square patches rotated with respect to each other. A schematic unit cell illustrating the global orientation is depicted in each patch. The length of the scale bar is 5<italic>a</italic> and in this case, we use patterns with <italic>a</italic> = 7 μm. A unique modulation loop transports the four colloidal particles simultaneously. The trajectories are colored according to the time evolution from blue (initial time) to red (final time). A movie showing the whole time evolution and a one-to-one comparison with computer simulations is available in Supplementary Movie ##SUPPL##6##4##.</p></caption></fig>", "<fig id=\"Fig6\"><label>Fig. 6</label><caption><title>Complex patterns and complex loops.</title><p>Brownian dynamics simulations of the transport of colloidal particles above a complex pattern made of three patches, each one with a topological defect in the symmetry phase (top) connected to three patches with square symmetry (down) rotated with respect to each other. The color of the patches with topological defects indicates the value of the symmetry phase <italic>ϕ</italic>. The color of the square patches indicates the global rotation <italic>ψ</italic>, illustrated with a sketch of the magnetization. A unique complex modulation loop made of four parts drives the transport in the whole system. In the first part, the repetition of the attractor loop moves the particles toward the defects (blue trajectories) and lets them wait there. The second part of the loop moves the particles downwards through the patterns with defects (orange trajectories). The third part of the loop moves the particles downwards in the square patterns (green trajectories). The last part of the loop writes a custom trajectory (square, triangle, and cross) depending on the global orientation <italic>ψ</italic> of the pattern (red trajectories). Insets show the corresponding experimental trajectories. The length of the scale bars (yellow) is 15<italic>a</italic>.</p></caption></fig>" ]	[]	[ "<inline-formula id=\"IEq1\"><alternatives><tex-math id=\"M1\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M2\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq2\"><alternatives><tex-math id=\"M3\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M4\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq3\"><alternatives><tex-math id=\"M5\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{\\,{{\\mbox{C}}}\\,{}_{6}{{\\mbox{}}}}$$\\end{document}</tex-math><mml:math id=\"M6\"><mml:mover accent=\"true\"><mml:mrow><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mstyle><mml:mtext>C</mml:mtext></mml:mstyle></mml:mrow><mml:mrow><mml:mn>6</mml:mn></mml:mrow></mml:msub><mml:mstyle><mml:mtext/></mml:mstyle></mml:mrow><mml:mo accent=\"true\">¯</mml:mo></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq4\"><alternatives><tex-math id=\"M7\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M8\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq5\"><alternatives><tex-math id=\"M9\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M10\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq6\"><alternatives><tex-math id=\"M11\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M12\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq7\"><alternatives><tex-math id=\"M13\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{\\,{{\\mbox{C}}}\\,{}_{6}{{\\mbox{}}}}$$\\end{document}</tex-math><mml:math id=\"M14\"><mml:mover accent=\"true\"><mml:mrow><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mstyle><mml:mtext>C</mml:mtext></mml:mstyle></mml:mrow><mml:mrow><mml:mn>6</mml:mn></mml:mrow></mml:msub><mml:mstyle><mml:mtext/></mml:mstyle></mml:mrow><mml:mo accent=\"true\">¯</mml:mo></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq8\"><alternatives><tex-math id=\"M15\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{\\,{{\\mbox{S}}}\\,{}_{6}{{\\mbox{}}}}$$\\end{document}</tex-math><mml:math id=\"M16\"><mml:mover accent=\"true\"><mml:mrow><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mstyle><mml:mtext>S</mml:mtext></mml:mstyle></mml:mrow><mml:mrow><mml:mn>6</mml:mn></mml:mrow></mml:msub><mml:mstyle><mml:mtext/></mml:mstyle></mml:mrow><mml:mo accent=\"true\">¯</mml:mo></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq9\"><alternatives><tex-math id=\"M17\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{\\,{{\\mbox{C}}}\\,{}_{6}{{\\mbox{}}}}$$\\end{document}</tex-math><mml:math id=\"M18\"><mml:mover accent=\"true\"><mml:mrow><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mstyle><mml:mtext>C</mml:mtext></mml:mstyle></mml:mrow><mml:mrow><mml:mn>6</mml:mn></mml:mrow></mml:msub><mml:mstyle><mml:mtext/></mml:mstyle></mml:mrow><mml:mo accent=\"true\">¯</mml:mo></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq10\"><alternatives><tex-math id=\"M19\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{\\,{{\\mbox{S}}}\\,{}_{6}{{\\mbox{}}}}$$\\end{document}</tex-math><mml:math id=\"M20\"><mml:mover accent=\"true\"><mml:mrow><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mstyle><mml:mtext>S</mml:mtext></mml:mstyle></mml:mrow><mml:mrow><mml:mn>6</mml:mn></mml:mrow></mml:msub><mml:mstyle><mml:mtext/></mml:mstyle></mml:mrow><mml:mo accent=\"true\">¯</mml:mo></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq11\"><alternatives><tex-math id=\"M21\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M22\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq12\"><alternatives><tex-math id=\"M23\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M24\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq13\"><alternatives><tex-math id=\"M25\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M26\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq14\"><alternatives><tex-math id=\"M27\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M28\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq15\"><alternatives><tex-math id=\"M29\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M30\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq16\"><alternatives><tex-math id=\"M31\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M32\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq17\"><alternatives><tex-math id=\"M33\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M34\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq18\"><alternatives><tex-math id=\"M35\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M36\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq19\"><alternatives><tex-math id=\"M37\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{A}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M38\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq20\"><alternatives><tex-math id=\"M39\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$+{m}_{{}_{{{{{{{{\\rm{p}}}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M40\"><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mrow/><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq21\"><alternatives><tex-math id=\"M41\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$-{m}_{{}_{{{{{{{{\\rm{p}}}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M42\"><mml:mo>−</mml:mo><mml:msub><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mrow/><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq22\"><alternatives><tex-math id=\"M43\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${V}_{{{{{{{{{\\rm{mag}}}}}}}}}}({{{{{{{{\\bf{r}}}}}}}}}_{{{{{{{{\\mathcal{A}}}}}}}}},t)$$\\end{document}</tex-math><mml:math id=\"M44\"><mml:msub><mml:mrow><mml:mi>V</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">mag</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq23\"><alternatives><tex-math id=\"M45\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{p}}}}}}}}}({{{{{{{{\\bf{r}}}}}}}}}_{{{{{{{{\\mathcal{A}}}}}}}}})$$\\end{document}</tex-math><mml:math id=\"M46\"><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq24\"><alternatives><tex-math id=\"M47\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{{\\bf{r}}}}}}}}}_{{{{{{{{\\mathcal{A}}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M48\"><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq25\"><alternatives><tex-math id=\"M49\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${H}_{{{{{{{{{\\rm{ext}}}}}}}}}}\\,\\gg \\,{H}_{{{{{{{{{\\rm{p}}}}}}}}}}({{{{{{{{\\bf{r}}}}}}}}}_{{{{{{{{\\mathcal{A}}}}}}}}})$$\\end{document}</tex-math><mml:math id=\"M50\"><mml:msub><mml:mrow><mml:mi>H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">ext</mml:mi></mml:mrow></mml:msub><mml:mspace width=\"0.25em\"/><mml:mo>≫</mml:mo><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mi>H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq26\"><alternatives><tex-math id=\"M51\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{A}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M52\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq27\"><alternatives><tex-math id=\"M53\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${V}_{{{{{{{{{\\rm{mag}}}}}}}}}}\\propto -({{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{ext}}}}}}}}}+{{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{p}}}}}}}}})\\cdot ({{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{ext}}}}}}}}}+{{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{p}}}}}}}}})$$\\end{document}</tex-math><mml:math id=\"M54\"><mml:msub><mml:mrow><mml:mi>V</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">mag</mml:mi></mml:mrow></mml:msub><mml:mo>∝</mml:mo><mml:mo>−</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">ext</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>⋅</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">ext</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ1\"><label>1</label><alternatives><tex-math id=\"M55\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${V}_{{{{{{{{{\\rm{mag}}}}}}}}}}({{{{{{{{\\bf{r}}}}}}}}}_{{{{{{{{\\mathcal{A}}}}}}}}},t)\\,\\approx -\\!{v}_{0}\\chi {\\mu }_{0}{{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{p}}}}}}}}}({{{{{{{{\\bf{r}}}}}}}}}_{{{{{{{{\\mathcal{A}}}}}}}}})\\cdot {{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{ext}}}}}}}}}(t).$$\\end{document}</tex-math><mml:math id=\"M56\"><mml:msub><mml:mrow><mml:mi>V</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">mag</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:mi>t</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mspace width=\"0.25em\"/><mml:mo>≈</mml:mo><mml:mo>−</mml:mo><mml:mspace width=\"0.3em\"/><mml:msub><mml:mrow><mml:mi>v</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mi>χ</mml:mi><mml:msub><mml:mrow><mml:mi>μ</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>⋅</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">ext</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq28\"><alternatives><tex-math id=\"M57\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${V}_{{}_{{{{{{{{\\rm{mag}}}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M58\"><mml:msub><mml:mrow><mml:mi>V</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mrow/><mml:mrow><mml:mi mathvariant=\"normal\">mag</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ2\"><label>2</label><alternatives><tex-math id=\"M59\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\gamma {\\dot{{{{{{{{\\bf{r}}}}}}}}}}_{{{{{{{{\\mathcal{A}}}}}}}}}=-\\!{\\nabla }_{{{{{{{{\\mathcal{A}}}}}}}}}{V}_{{{{{{{{\\rm{mag}}}}}}}}}+{{{{{{{\\boldsymbol{\\eta }}}}}}}},$$\\end{document}</tex-math><mml:math id=\"M60\"><mml:mi>γ</mml:mi><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>°</mml:mo></mml:mrow></mml:mover></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mo>−</mml:mo><mml:mspace width=\"0.3em\"/><mml:msub><mml:mrow><mml:mo>∇</mml:mo></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>V</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">mag</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mi mathvariant=\"bold-italic\">η</mml:mi><mml:mo>,</mml:mo></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq29\"><alternatives><tex-math id=\"M61\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\nabla }_{{{{{{{{\\mathcal{A}}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M62\"><mml:msub><mml:mrow><mml:mo>∇</mml:mo></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq30\"><alternatives><tex-math id=\"M63\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{{\\bf{r}}}}}}}}}_{{{{{{{{\\mathcal{A}}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M64\"><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">A</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq31\"><alternatives><tex-math id=\"M65\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M66\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq32\"><alternatives><tex-math id=\"M67\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M68\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq33\"><alternatives><tex-math id=\"M69\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M70\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq34\"><alternatives><tex-math id=\"M71\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M72\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq35\"><alternatives><tex-math id=\"M73\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\mathcal{C}}}}}}}}$$\\end{document}</tex-math><mml:math id=\"M74\"><mml:mi class=\"MJX-tex-caligraphic\" mathvariant=\"script\">C</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ3\"><label>3</label><alternatives><tex-math id=\"M75\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\bf{M}}}}}}}}({{{{{{{\\bf{r}}}}}}}})=M({{{{{{{{\\bf{r}}}}}}}}}_{\\perp })\\delta (z){\\hat{{{{{{{{\\bf{e}}}}}}}}}}_{z},$$\\end{document}</tex-math><mml:math id=\"M76\"><mml:mi mathvariant=\"bold\">M</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mi>M</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mi>δ</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>z</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi mathvariant=\"bold\">e</mml:mi></mml:mrow><mml:mrow><mml:mo>^</mml:mo></mml:mrow></mml:mover></mml:mrow><mml:mrow><mml:mi>z</mml:mi></mml:mrow></mml:msub><mml:mo>,</mml:mo></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq36\"><alternatives><tex-math id=\"M77\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\hat{{{{{{{{\\bf{e}}}}}}}}}}_{z}$$\\end{document}</tex-math><mml:math id=\"M78\"><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi mathvariant=\"bold\">e</mml:mi></mml:mrow><mml:mrow><mml:mo>^</mml:mo></mml:mrow></mml:mover></mml:mrow><mml:mrow><mml:mi>z</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ4\"><label>4</label><alternatives><tex-math id=\"M79\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$M({{{{{{{{\\bf{r}}}}}}}}}_{\\perp })={m}_{{\\rm {p}}}{{{{{{{\\rm{sign}}}}}}}}\\left(\\mathop{\\sum }\\nolimits_{i=1}^{N}\\cos ({{{{{{{{\\bf{q}}}}}}}}}_{i}\\cdot ({{{{{{{{\\bf{r}}}}}}}}}_{\\perp }-{{{{{{{\\bf{b}}}}}}}})-\\phi )+{m}_{0}(\\phi )\\right),$$\\end{document}</tex-math><mml:math id=\"M80\"><mml:mi>M</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub><mml:mi mathvariant=\"normal\">sign</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msubsup><mml:mrow><mml:mo>∑</mml:mo></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi>N</mml:mi></mml:mrow></mml:msubsup><mml:mi>cos</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">q</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>⋅</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:mi mathvariant=\"bold\">b</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>−</mml:mo><mml:mi>ϕ</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>ϕ</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:mfenced><mml:mo>,</mml:mo></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ5\"><label>5</label><alternatives><tex-math id=\"M81\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{{\\bf{q}}}}}}}}}_{i}={q}_{0}\\left(\\begin{array}{c}-\\!\\sin (\\pi i/2-\\psi )\\\\ \\cos (\\pi i/2-\\psi )\\end{array}\\right),\\quad i=1,2$$\\end{document}</tex-math><mml:math id=\"M82\"><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">q</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mi>q</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"center\"><mml:mo>−</mml:mo><mml:mspace width=\"0.3em\"/><mml:mi>sin</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>π</mml:mi><mml:mi>i</mml:mi><mml:mo>/</mml:mo><mml:mn>2</mml:mn><mml:mo>−</mml:mo><mml:mi>ψ</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"center\"><mml:mi>cos</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>π</mml:mi><mml:mi>i</mml:mi><mml:mo>/</mml:mo><mml:mn>2</mml:mn><mml:mo>−</mml:mo><mml:mi>ψ</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced><mml:mo>,</mml:mo><mml:mspace width=\"1.0em\"/><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ6\"><label>6</label><alternatives><tex-math id=\"M83\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{{\\bf{q}}}}}}}}}_{i}={q}_{0}\\left(\\begin{array}{c}-\\sin (2\\pi i/3-\\psi )\\\\ \\cos (2\\pi i/3-\\psi )\\end{array}\\right),\\quad i=1,2,3$$\\end{document}</tex-math><mml:math id=\"M84\"><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">q</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mi>q</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"center\"><mml:mo>−</mml:mo><mml:mi>sin</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mn>2</mml:mn><mml:mi>π</mml:mi><mml:mi>i</mml:mi><mml:mo>/</mml:mo><mml:mn>3</mml:mn><mml:mo>−</mml:mo><mml:mi>ψ</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"center\"><mml:mi>cos</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mn>2</mml:mn><mml:mi>π</mml:mi><mml:mi>i</mml:mi><mml:mo>/</mml:mo><mml:mn>3</mml:mn><mml:mo>−</mml:mo><mml:mi>ψ</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced><mml:mo>,</mml:mo><mml:mspace width=\"1.0em\"/><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn><mml:mo>,</mml:mo><mml:mn>3</mml:mn></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq37\"><alternatives><tex-math id=\"M85\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${q}_{0}=4\\pi /(a\\sqrt{3})$$\\end{document}</tex-math><mml:math id=\"M86\"><mml:msub><mml:mrow><mml:mi>q</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mn>4</mml:mn><mml:mi>π</mml:mi><mml:mo>/</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>a</mml:mi><mml:msqrt><mml:mrow><mml:mn>3</mml:mn></mml:mrow></mml:msqrt></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq38\"><alternatives><tex-math id=\"M87\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${m}_{0}(\\phi )=\\frac{1}{2}\\cos (3\\phi ){\\delta }_{N,3}$$\\end{document}</tex-math><mml:math id=\"M88\"><mml:msub><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>ϕ</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:mfrac><mml:mi>cos</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mn>3</mml:mn><mml:mi>ϕ</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi>δ</mml:mi></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:mn>3</mml:mn></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ7\"><label>7</label><alternatives><tex-math id=\"M89\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\int} M({{{{{{{{\\bf{r}}}}}}}}}_{\\perp }){\\rm {d}}{{{{{{{{\\bf{r}}}}}}}}}_{\\perp } \\, \\approx \\, 0.$$\\end{document}</tex-math><mml:math id=\"M90\"><mml:mo>∫</mml:mo><mml:mi>M</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mi mathvariant=\"normal\">d</mml:mi><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub><mml:mspace width=\"0.25em\"/><mml:mo>≈</mml:mo><mml:mspace width=\"0.25em\"/><mml:mn>0</mml:mn><mml:mo>.</mml:mo></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ8\"><label>8</label><alternatives><tex-math id=\"M91\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{p}}}}}}}}}({{{{{{{\\bf{r}}}}}}}})={{{{{{{{\\bf{H}}}}}}}}}_{{{{{{{{\\rm{p}}}}}}}}}({{{{{{{{\\bf{r}}}}}}}}}_{\\perp },z)=\\frac{1}{4\\pi }\\int{{{{{{{\\rm{d}}}}}}}}{{{{{{{{\\bf{r}}}}}}}}}_{\\perp }^{{\\prime} }\\frac{{{{{{{{{\\bf{r}}}}}}}}}_{\\perp }-{{{{{{{{\\bf{r}}}}}}}}}_{\\perp }^{{\\prime} }+z{\\hat{{{{{{{{\\bf{e}}}}}}}}}}_{z}}{\| {{{{{{{{\\bf{r}}}}}}}}}_{\\perp }-{{{{{{{{\\bf{r}}}}}}}}}_{\\perp }^{{\\prime} }+z{\\hat{{{{{{{{\\bf{e}}}}}}}}}}_{z}{\| }^{3}}M({{{{{{{{\\bf{r}}}}}}}}}_{\\perp }^{{\\prime} }).$$\\end{document}</tex-math><mml:math id=\"M92\"><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">H</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">p</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:mi>z</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>4</mml:mn><mml:mi>π</mml:mi></mml:mrow></mml:mfrac><mml:mo>∫</mml:mo><mml:mi mathvariant=\"normal\">d</mml:mi><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow><mml:mrow><mml:mo>′</mml:mo></mml:mrow></mml:msubsup><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow><mml:mrow><mml:mo>′</mml:mo></mml:mrow></mml:msubsup><mml:mo>+</mml:mo><mml:mi>z</mml:mi><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi mathvariant=\"bold\">e</mml:mi></mml:mrow><mml:mrow><mml:mo>^</mml:mo></mml:mrow></mml:mover></mml:mrow><mml:mrow><mml:mi>z</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:mo>∣</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow><mml:mrow><mml:mo>′</mml:mo></mml:mrow></mml:msubsup><mml:mo>+</mml:mo><mml:mi>z</mml:mi><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi mathvariant=\"bold\">e</mml:mi></mml:mrow><mml:mrow><mml:mo>^</mml:mo></mml:mrow></mml:mover></mml:mrow><mml:mrow><mml:mi>z</mml:mi></mml:mrow></mml:msub><mml:msup><mml:mrow><mml:mo>∣</mml:mo></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mi>M</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow><mml:mrow><mml:mo>′</mml:mo></mml:mrow></mml:msubsup></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ9\"><label>9</label><alternatives><tex-math id=\"M93\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\phi ({{{{{{{{\\bf{r}}}}}}}}}_{\\perp })=\\frac{1}{3}\\left(\\frac{\\pi }{2}-\\arctan \\left({{{{{{{{\\bf{q}}}}}}}}}_{3}\\cdot {{{{{{{{\\bf{r}}}}}}}}}_{\\perp },{\\hat{{{{{{{{\\bf{e}}}}}}}}}}_{z}\\cdot ({{{{{{{{\\bf{r}}}}}}}}}_{\\perp }\\times {{{{{{{{\\bf{q}}}}}}}}}_{3})\\right.\\right),$$\\end{document}</tex-math><mml:math id=\"M94\"><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow></mml:mfrac><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mfrac><mml:mrow><mml:mi>π</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:mfrac><mml:mo>−</mml:mo><mml:mi>arctan</mml:mi><mml:mfenced open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">q</mml:mi></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow></mml:msub><mml:mo>⋅</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi mathvariant=\"bold\">e</mml:mi></mml:mrow><mml:mrow><mml:mo>^</mml:mo></mml:mrow></mml:mover></mml:mrow><mml:mrow><mml:mi>z</mml:mi></mml:mrow></mml:msub><mml:mo>⋅</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">q</mml:mi></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:mfenced></mml:mrow></mml:mfenced><mml:mo>,</mml:mo></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq39\"><alternatives><tex-math id=\"M95\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\phi ({{{{{{{{\\bf{r}}}}}}}}}_{\\perp })=\\left(\\pi /2-\\arctan (x,y)\\right)/3$$\\end{document}</tex-math><mml:math id=\"M96\"><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>π</mml:mi><mml:mo>/</mml:mo><mml:mn>2</mml:mn><mml:mo>−</mml:mo><mml:mi>arctan</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>y</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:mfenced><mml:mo>/</mml:mo><mml:mn>3</mml:mn></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq40\"><alternatives><tex-math id=\"M97\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\arctan (y,x)$$\\end{document}</tex-math><mml:math id=\"M98\"><mml:mi>arctan</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>x</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ10\"><label>10</label><alternatives><tex-math id=\"M99\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{{{{{{\\bf{b}}}}}}}}({{{{{{{{\\bf{r}}}}}}}}}_{\\perp })=-({{{{{{{{\\bf{a}}}}}}}}}_{1}+{{{{{{{{\\bf{a}}}}}}}}}_{2})\\frac{\\phi ({{{{{{{{\\bf{r}}}}}}}}}_{\\perp })}{2\\pi }.$$\\end{document}</tex-math><mml:math id=\"M100\"><mml:mi mathvariant=\"bold\">b</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mo>−</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">a</mml:mi></mml:mrow><mml:mrow><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">a</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold\">r</mml:mi></mml:mrow><mml:mrow><mml:mo>⊥</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mi>π</mml:mi></mml:mrow></mml:mfrac><mml:mo>.</mml:mo></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq41\"><alternatives><tex-math id=\"M101\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$1/{r}_{{\\rm {d}}}^{2}$$\\end{document}</tex-math><mml:math id=\"M102\"><mml:mn>1</mml:mn><mml:mo>/</mml:mo><mml:msubsup><mml:mrow><mml:mi>r</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">d</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msubsup></mml:math></alternatives></inline-formula>" ]	[]	[]	[]	[]	[ "<supplementary-material content-type=\"local-data\" id=\"MOESM1\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM2\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM3\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM4\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM5\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM6\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM7\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM8\"></supplementary-material>" ]	[ "<fn-group><fn><p><bold>Publisher’s note</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group>" ]	[ "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq1.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Fig1_HTML\" id=\"d32e394\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq2.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Fig2_HTML\" id=\"d32e507\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq3.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq4.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq5.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq6.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq7.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq8.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Fig3_HTML\" id=\"d32e757\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq9.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq10.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Fig4_HTML\" id=\"d32e883\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq11.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq12.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq13.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Fig5_HTML\" id=\"d32e1013\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq14.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq15.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq16.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq17.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Fig6_HTML\" id=\"d32e1142\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq18.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq19.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq20.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq21.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq22.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq23.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq24.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq25.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq26.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq27.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ1.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq28.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ2.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq29.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq30.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq31.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq32.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq33.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq34.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq35.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ3.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq36.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ4.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ5.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ6.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq37.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq38.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ7.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ8.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ9.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq39.gif\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq40.gif\"/>", "<graphic xlink:href=\"41467_2023_43390_Article_Equ10.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"41467_2023_43390_Article_IEq41.gif\"/>" ]	[ "<media xlink:href=\"41467_2023_43390_MOESM1_ESM.pdf\"><caption><p>Supplementary Information</p></caption></media>", "<media xlink:href=\"41467_2023_43390_MOESM2_ESM.pdf\"><caption><p>Peer Review File</p></caption></media>", "<media xlink:href=\"41467_2023_43390_MOESM3_ESM.pdf\"><caption><p>Description of Additional Supplementary Files</p></caption></media>", "<media xlink:href=\"41467_2023_43390_MOESM4_ESM.webm\"><caption><p>Supplementary Movie 1</p></caption></media>", "<media xlink:href=\"41467_2023_43390_MOESM5_ESM.webm\"><caption><p>Supplementary Movie 2</p></caption></media>", "<media xlink:href=\"41467_2023_43390_MOESM6_ESM.webm\"><caption><p>Supplementary Movie 3</p></caption></media>", "<media xlink:href=\"41467_2023_43390_MOESM7_ESM.webm\"><caption><p>Supplementary Movie 4</p></caption></media>", "<media xlink:href=\"41467_2023_43390_MOESM8_ESM.webm\"><caption><p>Supplementary Movie 5</p></caption></media>" ]	[{"label": ["2."], "surname": ["Yang", "Alexandridis"], "given-names": ["L", "P"], "article-title": ["Physicochemical aspects of drug delivery and release from polymer-based colloids"], "source": ["Curr. Opin. Colloid Interface Sci."], "year": ["2000"], "volume": ["5"], "fpage": ["132"], "lpage": ["143"]}, {"label": ["3."], "surname": ["Boyd"], "given-names": ["BJ"], "article-title": ["Past and future evolution in colloidal drug delivery systems"], "source": ["Expert Opin. Drug Deliv."], "year": ["2007"], "volume": ["5"], "fpage": ["69"], "lpage": ["85"]}, {"label": ["5."], "surname": ["McGorty", "Fung", "Kaz", "Manoharan"], "given-names": ["R", "J", "D", "VN"], "article-title": ["Colloidal self-assembly at an interface"], "source": ["Mater. Today"], "year": ["2010"], "volume": ["13"], "fpage": ["34"], "lpage": ["42"]}, {"label": ["9."], "surname": ["Holzinger", "Lengemann", "G\u00f6llner", "Engel", "Ehresmann"], "given-names": ["D", "D", "F", "D", "A"], "article-title": ["Controlled movement of superparamagnetic bead rows for microfluid mixing"], "source": ["Appl. Phys. Lett."], "year": ["2012"], "volume": ["100"], "fpage": ["153504"]}, {"label": ["12."], "surname": ["Shin"], "given-names": ["S"], "article-title": ["Diffusiophoretic separation of colloids in microfluidic flows"], "source": ["Phys. Fluids"], "year": ["2020"], "volume": ["32"], "fpage": ["101302"]}, {"label": ["17."], "surname": ["L\u00f6wen"], "given-names": ["H"], "article-title": ["Colloidal soft matter under external control"], "source": ["J. Phys.: Condens. Matter"], "year": ["2001"], "volume": ["13"], "fpage": ["R415"], "lpage": ["R432"]}, {"label": ["18."], "surname": ["Erbe", "Zientara", "Baraban", "Kreidler", "Leiderer"], "given-names": ["A", "M", "L", "C", "P"], "article-title": ["Various driving mechanisms for generating motion of colloidal particles"], "source": ["J. Phys.: Condens. Matter"], "year": ["2008"], "volume": ["20"], "fpage": ["404215"]}, {"label": ["21."], "surname": ["Vissers"], "given-names": ["T"], "article-title": ["Lane formation in driven mixtures of oppositely charged colloids"], "source": ["Soft Matter"], "year": ["2011"], "volume": ["7"], "fpage": ["2352"], "lpage": ["2356"]}, {"label": ["28."], "surname": ["H\u00e4nggi", "Marchesoni"], "given-names": ["P", "F"], "article-title": ["Artificial Brownian motors: controlling transport on the nanoscale"], "source": ["Rev. Mod. Phys."], "year": ["2009"], "volume": ["81"], "fpage": ["387"], "lpage": ["442"]}, {"label": ["32."], "surname": ["Anderluh", "Hemmelmayr", "Nolz"], "given-names": ["A", "VC", "PC"], "article-title": ["Synchronizing vans and cargo bikes in a city distribution network"], "source": ["Cent. Eur. J. Oper. Res."], "year": ["2016"], "volume": ["25"], "fpage": ["345"], "lpage": ["376"]}, {"label": ["35."], "surname": ["Ladavac", "Kasza", "Grier"], "given-names": ["K", "K", "DG"], "article-title": ["Sorting mesoscopic objects with periodic potential landscapes: optical fractionation"], "source": ["Phys. Rev. E"], "year": ["2004"], "volume": ["70"], "fpage": ["010901"]}, {"label": ["44."], "surname": ["de las Heras", "Loehr", "Loenne", "Fischer"], "given-names": ["D", "J", "M", "TM"], "article-title": ["Topologically protected colloidal transport above a square magnetic lattice"], "source": ["New. J. Phys."], "year": ["2016"], "volume": ["18"], "fpage": ["105009"]}, {"label": ["47."], "surname": ["Popov"], "given-names": ["VL"], "article-title": ["Nanomachines: methods to induce a directed motion at nanoscale"], "source": ["Phys. Rev. E"], "year": ["2003"], "volume": ["68"], "fpage": ["026608"]}, {"label": ["51."], "surname": ["Ningyuan", "Owens", "Sommer", "Schuster", "Simon"], "given-names": ["J", "C", "A", "D", "J"], "article-title": ["Time- and site-resolved dynamics in a topological circuit"], "source": ["Phys. Rev. X"], "year": ["2015"], "volume": ["5"], "fpage": ["021031"]}, {"label": ["52."], "surname": ["Hasan", "Kane"], "given-names": ["MZ", "CL"], "article-title": ["Colloquium: topological insulators"], "source": ["Rev. Mod. Phys."], "year": ["2010"], "volume": ["82"], "fpage": ["3045"], "lpage": ["3067"]}, {"label": ["54."], "mixed-citation": ["Elschner, J. et al. Topologically controlled synthesis of active colloidal bipeds (2023) (in preparation)."]}, {"label": ["58."], "surname": ["Kim", "Moon", "Hwang", "Kim", "Yi"], "given-names": ["Y-J", "J-B", "H", "YS", "G-R"], "article-title": ["Advances in colloidal building blocks: toward patchy colloidal clusters"], "source": ["Adv. Mater."], "year": ["2022"], "volume": ["35"], "fpage": ["2203045"]}, {"label": ["59."], "surname": ["Geerts", "Eiser"], "given-names": ["N", "E"], "article-title": ["DNA-functionalized colloids: physical properties and applications"], "source": ["Soft Matter"], "year": ["2010"], "volume": ["6"], "fpage": ["4647"], "lpage": ["4660"]}, {"label": ["62."], "surname": ["Hernandez", "Mason"], "given-names": ["CJ", "TG"], "article-title": ["Colloidal alphabet soup: monodisperse dispersions of shape-designed LithoParticles"], "source": ["J. Phys. Chem. C"], "year": ["2007"], "volume": ["111"], "fpage": ["4477"], "lpage": ["4480"]}, {"label": ["63."], "surname": ["Sacanna", "Pine", "Yi"], "given-names": ["S", "DJ", "G-R"], "article-title": ["Engineering shape: the novel geometries of colloidal self-assembly"], "source": ["Soft Matter"], "year": ["2013"], "volume": ["9"], "fpage": ["8096"], "lpage": ["8106"]}, {"label": ["64."], "surname": ["de las Heras", "Zimmermann", "Samm\u00fcller", "Hermann", "Schmidt"], "given-names": ["D", "T", "F", "S", "M"], "article-title": ["Perspective: how to overcome dynamical density functional theory"], "source": ["J. Phys.: Condens. Matter"], "year": ["2023"], "volume": ["35"], "fpage": ["271501"]}, {"label": ["67."], "mixed-citation": ["Stuhlm\u00fcller, N. C. X. Drawing with colloids. "], "italic": ["Zenod"]}, {"label": ["73."], "surname": ["Jarosz", "Holzinger", "Urbaniak", "Ehresmann", "Stobiecki"], "given-names": ["A", "D", "M", "A", "F"], "article-title": ["Manipulation of superparamagnetic beads on patterned Au/Co/Au multilayers with perpendicular magnetic anisotropy"], "source": ["J. Appl. Phys."], "year": ["2016"], "volume": ["120"], "fpage": ["084506"]}, {"label": ["74."], "surname": ["Bowick", "Giomi"], "given-names": ["MJ", "L"], "article-title": ["Two-dimensional matter: order, curvature and defects"], "source": ["Adv. Phys."], "year": ["2009"], "volume": ["58"], "fpage": ["449"], "lpage": ["563"]}, {"label": ["75."], "mixed-citation": ["Krita (Krita foundation, accessed June 2023) "], "ext-link": ["https://krita.org/"]}, {"label": ["76."], "mixed-citation": ["Olson, E. On computing the average orientation of vectors and lines. In "], "italic": ["2011 IEEE International Conference on Robotics and Automation"]}]	{ "acronym": [], "definition": [] }	76	CC BY	no	2024-01-13 23:36:42	Nat Commun. 2023 Nov 18; 14:7517	oa_package/1d/02/PMC10657436.tar.gz
PMC10673832	38001287	[ "<title>Introduction</title>", "<p id=\"Par2\">37.3 million adults in the U.S. have diabetes; 95% of those have T2D<sup>##UREF##0##1##</sup>. Another 96 million U.S. adults have prediabetes; 5–10% of that population becomes diabetic every year<sup>##REF##22683128##2##</sup>, and it is estimated that 70% of individuals with prediabetes will convert to T2D over their lifetime<sup>##REF##17327355##3##</sup>. The annual cost of diabetes in the USA is $327b. Individuals with diagnosed diabetes incur $16,752 in health care expenses per year, which is 2.3 times greater than individuals without diabetes<sup>##UREF##1##4##</sup>.</p>", "<p id=\"Par3\">Three major studies in the USA, Finland, and China have shown that lifestyle interventions, including dietary weight loss and physical activity, can prevent diabetes progression in high-risk individuals by 51–58% from 2.9 to 6 years after the original intervention<sup>##REF##11832527##5##–##REF##26377054##7##</sup>, with continued protection of 27–43% for up to 20 years<sup>##REF##26377054##7##–##REF##12413779##9##</sup>. Two additional prospective trials in India and Japan showed similar protection at 3–4 years post-intervention<sup>##REF##16391903##10##,##REF##21824948##11##</sup>.</p>", "<p id=\"Par4\">Cornerstone features of the highly successful Diabetes Prevention Program include: individual case managers or “lifestyle coaches”; frequent contact with participants; a structured, 16-session core-curriculum that teaches behavioral self-management strategies, followed by additional classes and one-on-one meetings by phone or in person at least once per month; self-monitoring of weight, dietary intake, and physical activity; supervised physical activity sessions; tailoring of materials and strategies to address ethnic diversity; and an extensive network of training, feedback, and clinical support<sup>##REF##12453955##12##</sup>. Due to its success, this approach has been widely adopted as the standard of care in individuals at risk for T2D. The interventions needed to implement this program, while cost effective, are resource-intensive and require contact with health care professionals/systems that may not be accessible to all, with reported participation rates as low as 2.6% due to lack of physician referrals and socioeconomic barriers<sup>##REF##30661888##13##</sup>. During the first 4 years of implementation of the National DPP effort, only 39% of participants were retained at 44 weeks, and only 35.5% achieved the 5% weight loss goal<sup>##REF##32616617##14##</sup>. Furthermore, while personalization is recommended, the current approaches offer no formal method by which to accomplish such personalization.</p>", "<p id=\"Par5\">The explosion of new technologies that enable continuous glucose monitoring and activity tracking, as well as the widespread use of smartphones (currently used by 85% of US adults)<sup>##UREF##2##15##</sup>, provides a unique opportunity to leverage these technologies to significantly enhance the efficacy and practicality of lifestyle interventions. Technology-enabled diabetes self-management approaches have gained traction as supplements to traditional diabetes self-management models and implementation of DPP-based diabetes prevention approaches. Phone-based apps allow users to log fingerstick<sup>##UREF##3##16##–##UREF##4##18##</sup> glucose values, body weight, food eaten, and physical activity, with some apps accessing large nutritional databases that allow patients to determine calories and carbohydrates consumed when the user enters food items or scans a barcode. Wearable devices log steps, minutes of activity, miles attained, and heart rate changes, as well as estimate calories burned<sup>##UREF##5##19##</sup>.</p>", "<p id=\"Par6\">Continuous glucose monitors (CGM) are wearables that, via alarm features and real-time feedback to the user about glucose trends, were initially shown to lower both hyper and hypoglycemia in T1D and multidose-insulin-treated T2D<sup>##REF##18779236##20##–##UREF##6##27##</sup>. Recently, significant but modest benefits (HbA1c −0.29% vs FSBG) were also shown in non-insulin-treated T2D<sup>##UREF##7##28##</sup>. There has been no formal evaluation of CGM as a tool for enhanced lifestyle modification as a method to treat or prevent T2D. Several small proof of concept studies have been published, showing that individuals with T2D using CGM chose lower glycemic index foods<sup>##UREF##8##29##</sup>, increased physical activity<sup>##REF##18304674##30##</sup>, decreased caloric intake, lost weight, and demonstrated decreased postprandial glucose levels<sup>##REF##18701183##31##</sup>. Among individuals with prediabetes, there is only one published study addressing the role of CGM in promoting behavior change, and, while it showed greater dietary self efficacy, neither weight nor glycemic measures were reported<sup>##REF##36673620##32##</sup>.</p>", "<p id=\"Par7\">The benefits of CGM as a behavior modification tool would be magnified if information relating food and activity choices were linked to glycemic responses and shared with the user, who could then learn from the combined data. Current technology, including wearable devices that simultaneously and continuously track multiple health metrics and mobile apps that can integrate data from wearable devices, have the potential to revolutionize behavioral approaches to diabetes treatment and prevention. While the current approaches to lifestyle management have proven successful, they are not tailored to individuals, who may respond differently to nutrients and activity. Indeed, several studies showed that glycemic responses between individuals differ following exposure to the same foods<sup>##REF##26590418##33##–##UREF##9##35##</sup>, which may reflect a variety of interindividual biologic differences such as microbiome<sup>##UREF##9##35##</sup>, genetics<sup>##REF##32528151##34##</sup>, and underlying physiology such as insulin resistance and beta cell function<sup>##UREF##9##35##</sup>. Adherence to diets and physical activity also varies between individuals due differences in personal preferences and environmental factors<sup>##UREF##10##36##</sup>.</p>", "<p id=\"Par8\">Here, we sought to determine if a novel digital technology-based program, in which millions of CGM and other health data points were used to provide individualized feedback and tailored recommendations based on a user’s personal data patterns could improve lifestyle choices and metabolic health. We hypothesized that this approach, by inducing behavior modification that included healthier eating and physical activity, and took into account personalized glycemic responses and preferences, would promote weight loss, increase physical activity, and reduce hyperglycemia, which are important for treating and preventing T2D as endorsed by the American Diabetes Association and European Association for the Study of Diabetes for treatment of T2D<sup>##REF##30288571##37##</sup>.</p>" ]	[ "<title>Methods</title>", "<p id=\"Par34\">The methods were performed in accordance with relevant guidelines and regulations and approved by the Advarra review board.</p>", "<title>Participants</title>", "<p id=\"Par35\">Individuals over the age of 18 years were eligible to participate. Those with a prior diagnosis of diabetes who were not taking insulin were eligible, as were those with prediabetes or no history of glucose abnormalities. There were no body weight or BMI restrictions. Only participants who signed a disclaimer to use deidentified data (DID) were included. An external review board (Advarra) confirmed that analysis of DID was exempt from requiring formal informed consent.</p>", "<title>The season of Me program for personalized metabolic health management</title>", "<p id=\"Par36\">The Season of Me (SoM) program was designed to leverage technologic advances to improve glucose time in range and weight loss in individuals with or at risk for T2D. Participants paid to use a mobile-app (January AI) and wear a CGM (Freestyle Libre, Abbott) and HR monitor (Apple Watch or Fitbit) for 28 days (Fig. ##FIG##0##1##). The mobile app integrated CGM and HR data with user-entered diet and activity data, along with wearable-tracked HR. In addition to providing integrated data back to users, the program provided individualized recommendations based on data both logged by users and pulled from users’ wearable devices.</p>", "<p id=\"Par37\">The first 14 of 28 days consisted of an experimental phase, during which participants were monitored using a CGM and a HR monitor. The initial 4 days of this period served as a baseline, during which participants continued their regular diet and activities. On Day 3, participants undertook a glucose shot test. Commencing from Day 5, time-restricted feeding was introduced based on a schedule suggested by the app, and specific food experiments were initiated (e.g., ‘Low Glycemic Load first meal’ on Day 6).</p>", "<p id=\"Par38\">Upon completion of the 14-day experimental phase, participants received a personalized report. This report compiled health insights derived from the data collected during the experimental phase, and provided tailored recommendations aimed at improving glycemic control, focusing on the enhancement of TIR.</p>", "<p id=\"Par39\">Subsequent to the experimental phase, participants transitioned into a 15-day Time in Range Improvement Phase. During this period, daily tasks, structured as task cards within the mobile application, were assigned to participants. Each day involved the completion of 3–5 specific tasks, including mandatory reading of educational content (Fig. ##FIG##7##8##).</p>", "<p id=\"Par40\">For Days 1–14, tasks predominantly consist of adherence assignments (for example, “Wear your HR monitor for at least 23 h today”); food experimentation tasks; and time-restricted eating tasks. From Days 15–30, tasks were primarily centered on interventions to enhance TIR. These encompass strategies such as carbohydrate reduction, caloric restriction, exercise regimens, time-restricted eating protocols, and mindfulness practices.</p>", "<p id=\"Par41\">To facilitate participant learning throughout the 30-day journey, Insight Cards were provided via the app. These cards were categorized into Program-related Insight Cards and General Insight Cards. Program-related Insight Cards provided comparative analyses between different days and conditions (e.g., “Day 3 vs Day 4 vs Day 6”) to visualize the impacts of various interventions on blood glucose levels. General Insight Cards include Food Cards and Activity Cards, which illustrated the glucose and HR responses to a specific food item or physical activity, respectively.</p>", "<p id=\"Par42\">Following the initial 28 day phase, a 2-month optional second phase followed, during which participants implemented the learnings without the use of CGM or HR monitor, relying only on personalized recommendations generated by the mobile app. These recommendations centered around the following five levers (Fig. ##FIG##1##2##):</p>", "<p id=\"Par43\">1. Reducing spiking foods. Based on users’ food logs and CGM data, the app identified the foods that caused the largest increase in blood glucose, and offered alternative, lower-glycemic foods.</p>", "<p id=\"Par44\">2. Calorie restriction. The app gave users personalized total caloric recommendations based on age, weight, height, sex, and physical activity at baseline, with recommendations to stay below the caloric requirement for weight maintenance.</p>", "<p id=\"Par45\">3. Increasing fiber intake. After an observational period during which users’ baseline fiber intake was observed, the app suggested fiber-rich foods to increase daily fiber consumption to 21–25 and 30–35 g/day for females and males, respectively. The app not only identified users’ existing sources of fiber, but also suggested alternative foods with higher fiber content.</p>", "<p id=\"Par46\">4. Increasing activity. After an observational period during which users’ baseline physical activity level was observed, the app suggested activity, especially post-meal activity, with the goal of reducing postprandial glucose spikes.</p>", "<p id=\"Par47\">5. Increasing fasting period. The app recommended a 16-h fasting target to all users, tracking users’ fasting periods and comparing observed fasting activity against goal.</p>", "<title>Delivery of personalized food and activity recommendations</title>", "<p id=\"Par48\">Health goals were addressed by a proprietary mobile application that incorporates CGM and HR monitoring coupled with food and activity tracking, and generates glucose predictions for food and activity patterns.</p>", "<p id=\"Par49\">We utilized two blood glucose prediction models (“Continuous Glucose Prediction model”/“CGP model” and “Food Recommendation model”/“FR model”). The former utilizes a machine learning-based algorithm that takes into account the user’s previously recorded blood glucose, heart rate, and food logging information to output the user’s predicted blood glucose values in response to food and activity. The latter recommends to the user foods similar to those the user desires to eat, in order to allow the user to choose foods which cause comparatively lower spikes in glucose. Those models are described in detail below.</p>", "<title>Continuous Glucose Prediction (CGP) algorithm</title>", "<title>Overview</title>", "<p id=\"Par50\">The machine learning-based algorithm has a base of data that is collected from all users, comprising 46,655 days of data from 1978 users; based on an individual’s entered and captured data, the model is fit to their unique glycemic responses to food and exercise as captured by CGM, HR, and food logging data.</p>", "<p id=\"Par51\">The CGP model has two primary utilities. First, this model allows users to predict the glycemic impact of food 2 h into the future, and without consuming the food item(s) in question (“<bold>CGP</bold>”). Second, this model allows users to continuously estimate blood glucose values throughout the day, if provided information about food logging and heart rate alone (“Virtual CGM” or “<bold>VCGM</bold>”). This aspect of the algorithm allows for continued, personalized recommendations in-between CGM usage periods, thus lessening the user burden and cost associated with physical CGM devices.</p>", "<p id=\"Par52\">The CGP model requires a minimum of 5 days of complete data (12 h of HR and CGM data, in addition to logs of all calorie-containing food and beverage, constitute a day of “complete” data), but continues to fit itself to the individual if the individual continues wearing a CGM and heart rate monitor, and logging food.</p>", "<p id=\"Par53\">The CGP model was an RNN model. The RNN model consisted of a single LSTM layer followed by a dense layer with a sigmoid activation function. The LSTM layer allows the model to capture long-term dependencies in the input sequence. We tried both LSTM and GRU layers with different numbers of nodes and layers. Our evaluation of our model showed that, based on our data, LSTM was the best choice, giving us better RMSE and MAPE.</p>", "<p id=\"Par54\">We furthermore used a meta learning algorithm to optimize the hyperparameters of the RNN model. The meta learning algorithm uses a set of training tasks to learn the optimal hyperparameters for the RNN model. The training tasks consisted of subsets of the dataset. For each training user, the meta learning algorithm generated a set of hyperparameters that optimized the RNN model’s performance on the specific user.</p>", "<p id=\"Par55\">The error in these predictions is 13.4 mg/dl RMSE over the 2 h post-meal period. This error is on par with the best-published results, which do not report this high variance, post-meal period<sup>##REF##31383477##46##</sup> Notably, the 2-h, post-meal, glucose prediction error remained low at 14.8 mg/dl RMSE, even after participants stopped using their glucose monitors, suggesting that the app was able to learn an individual’s biology sufficiently well so as to predict their glucose response.</p>", "<title>Data and preprocessing</title>", "<p id=\"Par56\">Our dataset consisted of participant-derived continuous glucose measurements, heart rate readings, physical activity, time stamps, and dietary constituents. This resulted in a time-series database for each variable, offering a rich, multi-modal representation of individual physiological profiles.</p>", "<p id=\"Par57\">Initial preprocessing was conducted to assure the suitability of data for machine learning algorithms. This process comprised the removal of aberrant or incomplete data entries and the standardization of all input features to maintain consistency across the dataset. Additional features were engineered from the raw data to enhance the predictive power of the model. For example, time of day was represented as sin and cos functions to ensure temporal continuity. The preprocessed dataset was bifurcated into a training subset for model learning; and a testing subset for subsequent model performance evaluation.</p>", "<title>Model architecture</title>", "<p id=\"Par58\">The model architecture consists of Long Short-Term Memory (LSTM) layers and Dense layers. The LSTM layers are designed to capture temporal dependencies in the time series data, while the Dense layers provide non-linear transformations and help in the final prediction. The input to the model at each time step includes the following features: continuous glucose values, heart rate, exercise, time of day, and food nutrients. These features are concatenated and fed as input to the model. To train the model, sequences of input data are created from the training set. Each sequence contains a fixed number of consecutive time steps and associated target values (e.g., the next glucose value). The sequences are created by sliding a window over the time series data. The model is trained using the generated sequences from the training set. During training, the model predicts the next step given the current input, and the previous prediction is fed back as an input for the next time step. This feedback loop helps the model learn from its own predictions. The model is trained by minimizing the loss function, log likelihood loss function was used, between the predicted values and the true target values. The ADAM optimizer was used to perform backpropagation and gradient descent algorithms. Hyperparameters, such as the number of LSTM and Dense layers, the size of each layer, learning rate, and batch size, were tuned to optimize the model’s performance. After training, the performance of the model was evaluated using the testing set. Various evaluation metrics, such as root mean squared error, correlation coefficient, and MAPE were computed to assess the accuracy and reliability of the predictions. Based on the evaluation results, further refinements may be made to the model. This could involve adjusting hyperparameters, modifying the architecture, or adding regularization techniques to improve generalization and prevent overfitting. Once the model is trained and evaluated, it can be used to make predictions on new, unseen data. Given a sequence of input features, the model can generate predictions for the next time step(s) of blood glucose values (Fig. ##FIG##8##9##).</p>", "<p id=\"Par59\">We also wished to determine the most significant inputs (among CGM, heart rate, etc.) to the performance of the CGP model. Ablation analysis was conducted (Fig. ##FIG##9##10A##), removing inputs to the model in sequence to examine the deleterious effects on the model. The difference in the RMSE as a result of ablating nutrient information versus activity information demonstrates that the macronutrients and their quantity consumed are far more important than activity, heart rate, and time of day to the model’s fidelity.</p>", "<p id=\"Par60\">This was followed by reverse ablation analysis (Fig. ##FIG##9##10B##). While ablation analysis removes inputs to determine which input is most important, reverse ablation analysis adds inputs. The reverse ablation analysis shows that, by adding activity, HR, and time of day information, our RMSE increases from 12.5 to 14. However, upon adding nutrient information, RMSE increases to 21. This demonstrates the dramatic effect that nutrition information has on the fidelity of the model.</p>", "<p id=\"Par61\">Overall, both analyses led us to conclude that, in order of descending importance, the significance of each input was as follows: nutrients, time of day, heart rate, activity.</p>", "<title>Evaluation of CGP model</title>", "<title>Data Collected</title>", "<p id=\"Par62\">DID was collected retrospectively from 2217 users over 28 days. Data points included body weight, CGM data, food and activity log data, and HR from an activity tracker. Nutritional breakdown included total caloric intake, macronutrient composition, and fiber intake, which was captured by participants’ self-reported food logs collected in the mobile application. Activity was quantified in minutes/day. Only participants with complete logging and data capture were included in the final analysis (see below). Among those included in the final analysis, adjustments were made to account for potential bias in nutrient intake as a result of differences in logging frequency over time: (1) nutrients were calculated only from “good” logging days, defined as a minimum of two logging events spread throughout waking hours spanning a 16 h range, and a total of ≥1600 calories logged, and (2) specific macronutrients and fiber were presented as grams as well as proportion of total calories (grams converted to calories) such that the changes in the proportion of these nutrients were not biased by residual differences in frequency of logging. Physical activity was adjusted for overall frequency of logging and expressed as adjusted minutes/day. HR data was collected continuously, as was CGM data, both from wearable devices, and did not rely on participant adherence with logging; thus, this data is not subject to logging bias. For CGM, the first day of use is known to be somewhat less accurate, and thus all glycemic measures excluded the first day of use in all participants. Further adjustments were made for days with loss of CGM signal, and this proportion of “lost time” was applied to all measures of event frequency. The average measures such as TIR and GMI did not require this adjustment. HR data capture was remarkably consistent and no gaps in signal were present.</p>", "<title>Requirements for Inclusion in data analysis</title>", "<p id=\"Par63\">In order to ensure that only individuals who had complete data capture and reasonably consistent data logging were included in the final analysis, the following requirements were designated. Analysis of outcomes included only those individuals who had a sufficient quantity of CGM data capture, consistent food logging, and regular body weight tracking and HR capture. Requirements for CGM data were at least 70% CGM coverage on at least half of the days at the beginning (days 1–5, excluding day 1) and the end (days 15–27) of the 28 day period. Requirements for meal logging were active logging of all meals during the first 7 days, as well as the last 14 days, and HR capture ≥20 h per day. For inclusion in data analysis, users must have logged at least two meals and 1600 kcal/day. Requirements for body weight data tracking were at least one body weight measurement in the first 7 days and in the last 14 days. Because fewer individuals tracked weight at day 28, the analysis of weight change was conducted only in the subset who had the baseline and end of study weight measurements.</p>", "<title>Statistical analysis</title>", "<p id=\"Par64\">Data was measured using paired-student <italic>t</italic>-tests for beginning vs. end of study for all measures, using Jupyter Notebooks, SciPy, Numpy, Pandas, Matplotlib, Seaborn, pickle, and datetime (the latter two are inbuilt Python packages). Beginning of study was defined as days 2–7 for glucose variables; and days 1–5 for activity and food logging variables. All variables were checked for normality and none needed log transformation for analyses. End of study was defined as days 14–28 for all measures. P < 0.05 was considered statistically significant. The performance of the CGP model was shown to be superior when compared to other models (Fig. ##FIG##10##11A##), with a high correlation coefficient of 0.833 when comparing actual BGL to predicted BGL (Fig. ##FIG##10##11B##). A visual depiction of CGP compared to actual curves shows that the actual curve lies within the error bound of the CGP model. Figure ##FIG##10##11C## shows a comparison of glucose prediction to its corresponding actual CGM curve within a 2-h window, while Fig. ##FIG##10##11D## shows a comparison of virtual CGM prediction to its corresponding actual CGM curve within a 24-h window. We also examined whether there was a correlation between user demographics and error, in order to determine whether users of certain demographics were more prone to higher error in BGL predictions, and found that higher weight correlates with higher percent error (p < 0.05), and higher age correlates with lower percent error (p < 0.05) (Fig. ##FIG##10##11E##). Furthermore, we compared error by disease type and gender, in order to determine whether male/female participants, or normoglycemic/prediabetes/T2D participants were more likely to experience higher error in BGL predictions. Our percent error and RMSE peak/point-by-point was lower for healthy users than for users with T2D and with pre-diabetes. Our percent error was also lower for male participants than for female participants, though there are participants whose percent error represents an outlier (Fig. ##FIG##10##11F##).</p>", "<title>Food recommendation algorithm</title>", "<p id=\"Par65\">Food recommendations utilize a separate food recommendation engine underpinned by the CGP model, which predicts the glycemic impact of selected foods based on their macronutrient composition and the individual’s prior responses to macronutrients. The food recommendation engine extrapolates nutritional information and macronutrients from known databases to recommend similar foods that are predicted to be less impactful on a user’s blood glucose, based on the individualized output of the CGP model. The food recommender engine follows four main processing stages, with the user input being a specific food, and the result being similar foods with lower glycemic impacts. The food recommender engine winnows down the food database to find more similar foods, then healthier foods within the set of similar foods (Fig. ##FIG##11##12A##). Similar, healthier foods are then displayed to the user in-app as “healthy recommendations” (Fig. ##FIG##11##12C##). The model interfaces with the application via a “FoodRec Client” interface (Fig. ##FIG##11##12B##).</p>", "<title>Reporting summary</title>", "<p id=\"Par66\">Further information on research design is available in the ##SUPPL##1##Nature Research Reporting Summary## linked to this article.</p>" ]	[ "<title>Results</title>", "<title>Data collection and Cohort</title>", "<p id=\"Par9\">To assess whether the combination of wearable and machine learning data can be used to provide effective and personalized lifestyle recommendations, we collated a dataset from a cohort of <italic>N</italic> = 2217 individuals. These individuals were participants who enrolled in the Season of Me program, and agreed to provide retrospective de-identified data. Need for informed consent was waived (Advarra Internal Review Board). The Season of Me program was designed to leverage technologic advances to improve glucose time in range and weight loss in individuals with, or at risk for, T2D. Participants used a mobile application (“January AI app”) and wore a CGM (Freestyle Libre, Abbott) and HR monitor (Apple Watch or Fitbit) for 28 days (Fig. ##FIG##0##1##).</p>", "<p id=\"Par10\">The January AI app integrated CGM and HR data with user-entered diet and activity data. In addition to providing integrated response data back to users so that they would learn how lifestyle choices influenced their glucose patterns (Fig. ##FIG##1##2##), the app provided AI-based individualized recommendations (Figs. ##FIG##0##1##, ##FIG##1##2##, Methods).</p>", "<p id=\"Par11\">Following the initial 4 weeks, an 8-week second phase followed, during which participants had the option to continue using the app without the use of CGM or HR monitor, relying only on personalized recommendations generated by the mobile app. Glucose analyses included 1066 participants who had a sufficient quantity of CGM data capture, consistent food logging, and regular body weight tracking.</p>", "<p id=\"Par12\">Requirements for sufficient CGM data capture were: At least 70% CGM coverage on at least half of the days at the beginning (days 3–7) and the end (last 14 days) of the 28 day period. Requirements for consistent meal logging were: Active logging of all meals during the first 7 days, as well as the last 14 days. Requirements for regular body weight data tracking were: At least one body weight measurement in the first 7 days, and at least one body weight measurement in the last 14 days. Heart rate (HR) data was available throughout the entire period on all participants. Weight data was analyzed for 567 participants who met weight tracking criteria for inclusion (Methods). Over 27 million data points were captured across participant logs, HR, and CGM data. The majority of the participants were either normoglycemic (<italic>n</italic> = 746) or had prediabetes (<italic>n</italic> = 206), and a smaller subgroup had non-insulin-treated T2D (<italic>n</italic> = 94). The cohort was 49% male and 51% female, with an average age of 49 ± 11.5 years. Ethnicity data was not collected.</p>", "<title>Suboptimal control individuals showed notable TIR improvements, most significantly in healthy nondiabetics</title>", "<p id=\"Par13\">Time in range (TIR) refers to time spent in the following glucose ranges according to previous recommendations: 70–180 mg/dL for those with T2D, and 70–140 mg/dL for those without T2D<sup>##REF##21722581##24##,##REF##22100963##25##,##REF##31127824##38##</sup>. TIR was compared between the end of the 28-day program (defined as days 14–28), versus baseline (defined as days 2–7, excluding day 1 due to known inaccuracies in CGM readings during the first 24 hs of use).</p>", "<p id=\"Par14\">The group as a whole (<italic>n</italic> = 1066) demonstrated relatively high baseline TIR, measuring 82% among T2D (70–180 mg/dL range) and 91% among those with prediabetes and healthy nondiabetics (70–140 mg/dL range), consistent with prior studies<sup>##REF##21722581##24##,##REF##22100963##25##,##REF##25927986##39##</sup>. We believe that 70–140 mg/dL is more appropriate for individuals with normoglyemia or prediabetes since a target range should represent a range that is not already attained by nearly all individuals. Furthermore, since CGM is currently only approved for diabetes there has not yet been an official target range established for these groups.</p>", "<p id=\"Par15\">TIR did not significantly improve for the group as a whole. However, individuals with suboptimal baseline control, defined as <90% TIR, showed notable improvements. When considering those with suboptimal control at baseline, defined as <90% TIR, those with T2D (<italic>n</italic> = 37) increased TIR by 9.8%, and individuals with prediabetes (<italic>n</italic> = 57) and healthy nondiabetics (<italic>n</italic> = 182) increased TIR by 6.2% and 9.6%, respectively (Fig. ##FIG##2##3##). For those with baseline TIR of <70%, improvement was even greater, ranging from 13.2% in T2D (<italic>n</italic> = 17), 9.6% in prediabetes (<italic>n</italic> = 9), and 22% in healthy nondiabetics (<italic>n</italic> = 51, <italic>p</italic> < 0.0001). Due to low numbers in these subgroups, only the healthy nondiabetic group reached statistical significance.</p>", "<title>Significant reductions in Glucose Management Indicator GMI, hyperglycemic events, and glycemic variability were observed across subgroups</title>", "<p id=\"Par16\">Glucose Management Indicator (GMI) is a metric that uses CGM data to estimate HbA1c (ADD REFERENCE). Like TIR, GMI changes were evaluated in those with suboptimal values at baseline, defined as either >6% or >7%, irrespective of glycemic category. Significant GMI reductions were observed among participants with suboptimal values at baseline. Among those with baseline GMI > 7% (<italic>n</italic> = 23), GMI decreased by a mean of 0.43% (<italic>p</italic> < 0.001) and among those with baseline BMI > 6% (<italic>n</italic> = 115) GMI decreased by a mean of 0.22% (<italic>p</italic> < 0.00001). GMI reductions were similar and statistically significant in all glycemic subgroups (healthy nondiabetic, prediabetes, T2D) for both analyses (Fig. ##FIG##2##3##).</p>", "<p id=\"Par17\">In addition, the mean number of hyperglycemic events per day decreased in the cohort as a whole (<italic>p</italic> < 0.001): decreases in hyperglycemic events >250 mg/dL, >180 mg/dL, and > 140 mg/dL were 42%, 38%, and 24%, respectively, with the largest percent decreases in the healthy and prediabetes subgroups (Fig. ##FIG##3##4##). Decreases were present in all subgroups for all hyperglycemic events, with the exception of events > 140 which were not decreased in the T2D subgroup. Hypoglycemic events <70 mg/dL also decreased in the cohort as a whole, reaching statistical significance in the healthy nondiabetic subgroup (Fig. ##FIG##3##4##). Lastly, glycemic variability, measured as coefficient of variation, decreased significantly in all subgroups by an average of 13.5% (Fig. ##FIG##4##5##).</p>", "<title>Season of Me program aided weight loss, especially in higher starting weights and T2D participants</title>", "<p id=\"Par18\">To determine whether Season of Me promoted weight loss, we compared the last body weight measurement during the final 2 weeks of the program with the first body weight measurement at the beginning of the program (<italic>n</italic> = 567). All groups of individuals within this cohort significantly decreased their body weight over 28 days (<italic>p</italic> < 0.0001, Fig. ##FIG##5##6##). Overall, 75.5% of the 567 participants lost weight over the first 28 days, with an average of 2.5 lbs among nondiabetic and prediabetic individuals, and 4.4 lbs among those with T2D. Those who continued the program for 12 weeks (<italic>n</italic> = 137) lost an average of 4.4 lbs, with 2.6 lbs lost in healthy nondiabetics (<italic>p</italic> < 0.0001), 6.8 lbs lost in those with prediabetes (<italic>p</italic> = 0.003), and 9.4 lbs lost in those with T2D (<italic>p</italic> = 0.0007) (Fig. ##FIG##6##7##). Individuals with higher starting body weights lost the most weight: those with baseline weight 250–300 lbs who continued logging weight through 3 months lost a mean of 11.3 and 18.9 lbs at 4 and 12 weeks, respectively, and individuals with starting body weight of 200–249 lbs lost a mean of 2.9 and 7.4 lbs at 4 and 12 weeks, respectively (Fig. ##FIG##6##7##, Supplemental Table ##SUPPL##0##S1##). Expressed as % loss from initial body weight, at 12 weeks, the % loss was 1.5, 2.3, and 5.1% in healthy nondiabetic, prediabetic and T2D participants, respectively; and was 2.0, 3.2, and 6.8% in those weighing 150–199, 200–249, and >250 lbs at baseline.</p>", "<title>Participants, especially healthy and prediabetic subgroups, significantly increased daily physical activity during the study</title>", "<p id=\"Par19\">Participants were instructed to log all meals and physical activity during the first 7 days, as well as the last 14 days. Actual logging use, defined as logging at least two activities of any type per day, was 81% during days 1–7, and 43% during days 14–28. Activity was recorded in minutes per event and added up to a daily total. To account for changes in logging frequency at the end versus beginning of the study, the total daily minutes of activity was adjusted for the number of times a participant interacted with the app. From the beginning to the end of the study, the adjusted minutes/day of physical activity increased from 49 to 97 min. By subgroups, the healthy and prediabetes participants approximately doubled their physical activity (50–109 min/day and 45–73 min/day, respectively), whereas those with T2D did not change their physical activity (45–46 min/day). There was no correlation between minutes/day of physical activity and change in TIR in the group as a whole or in any subgroups.</p>", "<title>Heart rate as an objective measure of physical activity</title>", "<p id=\"Par20\">HR data capture was 100% throughout the study. To objectively assess changes in physical activity, HR > 110 bpm quantified as min/day was assessed in the group as a whole (<italic>n</italic> = 1066) and among glycemic subgroups (healthy, prediabetes, T2D). Five individuals were excluded due to resting HR > 110 bpm which precluded using this measure to indicate physical activity. In the group as a whole, HR > 110 bpm increased from 28.8 to 32.2 min/day (<italic>p</italic> = 0.008). Among healthy normoglycemic individuals (<italic>n</italic> = 764) the increase was 2.9 min/day (<italic>p</italic> = 0.009), whereas in those with prediabetes (<italic>n</italic> = 204) it was 6.3 min/day (<italic>p</italic> = 0.02), and in those with T2D it was 0.40 min/day (<italic>p</italic> = 0.88). Detailed data are available in Supplemental Table ##SUPPL##0##S2##.</p>", "<title>Participants demonstrated decreased caloric, carbohydrate, and sugar intake, and increased protein and fiber consumption</title>", "<p id=\"Par21\">A key feature of the program was personalized food insights and recommendations based on integrating glycemic responses captured by CGM and food logged on the mobile app by the user. 526 of the 1066 participants logged foods during the specified time periods (the first 7 days for baseline, and the last 14 days for end-of-study data) and were included in the analysis. Although over 2200 participants began the program, many did not generate sufficient data to perform analysis, for example, non logging of food, HR, etc; these participants were excluded from analysis, leaving 1066 participants upon whom analysis was performed. To account for potential decrease in logging adherence, only days in which food was logged at least twice, and totaled at least 1600 calories, were included. Average daily calories and macronutrient intake (including sugar, fiber, and saturated fat subcategories) were calculated. Macronutrients were expressed as absolute values (grams), and as a percent of total calories. Participants across all subgroups demonstrated decreases in caloric intake, carbohydrate, sugar, and saturated fat intake, and increases in protein, total fat, and fiber intake (Table ##TAB##0##1## and Supplement Table ##SUPPL##0##S3##). Percent change in the relative intake from each macronutrient was decreased for carbohydrates (-2.6%), sugar (-12.3%), and saturated fat (-0.5%); and increased for protein (+3.45), total fat (+1.1%) and fiber (+7.9%), indicative of a dietary improvement.</p>" ]	[ "<title>Discussion</title>", "<p id=\"Par22\">This real-world study demonstrates that use of digital technology in combination with CGM can facilitate lifestyle interventions that yield improvement in glycemic measures, in the largest cohort to date.</p>", "<p id=\"Par23\">Three studies have previously examined the use of CGM for lifestyle change T2D<sup>##UREF##8##29##–##REF##18701183##31##</sup> Cox et al.<sup>##UREF##8##29##</sup> included only four patients and did not have a control group. Allen et al.<sup>##REF##18304674##30##</sup> utilized solely physical activity intervention. Yoo et al.<sup>##REF##18701183##31##</sup> randomized patients with poorly controlled T2D (baseline HbA1c of 9%) who were treated with insulin (60%) or noninsulin therapies (40%), to real-time CGM vs. self monitoring blood glucose (SMBG) and demonstrated significantly greater reduction in HbA1c (0.50%, <italic>p</italic> = 0.004) at 12 weeks in the CGM group, along with reduction in total daily calorie intake, greater weight loss, and increased physical activity. Wada et al.<sup>##UREF##7##28##</sup> examined individuals with non-insulin-treated T2D with baseline HbA1c of 7.8%; the researchers did not measure lifestyle changes, but showed that use of flash CGM as compared to SMBG resulted in a reduction in HbA1c at 24 weeks (0.29%, <italic>p</italic> = 0.02).</p>", "<p id=\"Par24\">Our results extend the prior studies by demonstrating that use of CGM with a digital app designed to enhance healthy lifestyle behaviors by informing users of the impact of food and activity choices on glycemic responses yields both behavior changes and glycemic improvement in individuals with prediabetes and even earlier stages of dysglycemia detected by CGM. Combination of CGM data with heart rate and activity information, as well as content and personalized insights, is a novel approach to management of metabolism, and yielded noteworthy results.</p>", "<p id=\"Par25\">Glycemic improvement was observed in the group as a whole, as was reduction in glycemic variability, but the greatest improvement was evident in those whose glucose was not within the optimal range at baseline, defined as 70–140 mg/dL for those without diabetes and 70–180 mg/dL for those with T2D. This is the first study to evaluate personalization of lifestyle recommendations based on previously observed glucose patterns from CGM. The use of digital technology for diabetes treatment and prevention has been previously studied, with applications ranging from remote coaching to dissemination of educational programs such as the DPP<sup>##UREF##11##40##</sup> Importantly, none of these studies have evaluated integration of CGM with lifestyle measures or coaching, especially in addition to presentations to subjects of the projected glucose impacts of specific foods/meals and/or activity patterns.</p>", "<p id=\"Par26\">Like prior digital health apps, the one used in this study served as a virtual coach, offering recommendations and reminders that addressed many components of medical nutrition therapy as recommended by the American Diabetes Association<sup>##UREF##12##41##</sup> These include choosing healthy foods, and tailoring recommendations to consider individual preferences and environmental constraints (access, budget, living situation). Most importantly, however, this technology system (CGM and mobile app) uniquely integrated glycemic excursions obtained from CGM with actual food consumed, which allowed for personalized rather than generic coaching. Consultation with a RD in order to develop an individualized eating plan is associated with HbA1c reductions of 0.3-2.0%<sup>##UREF##13##42##</sup> In the present study, which spanned only 28 days and did not include any live coaching, GMI decreased by 0.43% in those with baseline GMI > 7%, and by 0.22% in those with baseline GMI 6–6.9%. In addition, hyperglycemic events (glucose spikes), glucose variability, and TIR improved in all subgroups ranging from healthy nondiabetic to T2D, although the small T2D subgroup reached statistical significance only for glycemic variability. Hypoglycemic events <70 mg/dL also decreased in the group as a whole, although, in subgroup analyses, statistical significance was reached only in the healthy nondiabetic subgroup.</p>", "<p id=\"Par27\">Based on data collected, the observed glycemic improvements likely resulted from three lifestyle changes: (1) healthier food choices; (2) weight loss; (3) increased physical activity. While only 526 of the 1066 participants logged sufficiently to be included in the detailed dietary analysis, food log reviews showed a decrease not only in total calories, carbohydrates, sugar, and saturated fat, but also in the proportion of calories from carbohydrates, sugar, and saturated fat, with an increase in the proportion of calories from protein, healthy fats (fats other than saturated include mono and polyunsaturated), and fiber. Although we did not quantify changes in the intake of meals that led to glucose elevation, the observation that there were fewer hyperglycemic events and that TIR improved strongly suggests that glucose-elevating meals were decreased.</p>", "<p id=\"Par28\">Weight loss is a cornerstone of diabetes treatment and prevention. In the present study, use of the CGM and mobile app promoted weight loss in >75% of participants who continued to log weight. The amount of weight lost was greater in those with T2D and those with higher baseline starting weight, who at 12 weeks lost up to 10.4 and 18.9 lbs, respectively. At 12 weeks, the % loss from initial body weight was 1.5, 2.3, and 5.1% in healthy nondiabetic, prediabetic and T2D participants, respectively; and was 2.0, 3.2, and 6.8% in those weighing 150–199, 200–249, and >250 lbs at baseline. Because not all participants logged weight throughout the study, this may selectively represent those who were more successful in losing weight, who owned a personal scale, or who were more motivated in general. Thus, the weight loss benefits in those who did not continue to log weight is not known. Nonetheless, it appears very likely that use of the CGM with app and self-weighing at least once after baseline is associated with progressive weight loss for at least 12 weeks of use. Longer term studies will be needed to determine whether this is sustained.</p>", "<p id=\"Par29\">Physical activity also lowers glucose levels, and the participants in the SOM program demonstrated increased physical activity as measured both by self report (logging) and by an objective measure (HR > 110 bpm). Multiple previous studies have demonstrated that use of accelerometer or heart rate monitor increases physical activity<sup>##REF##33044175##43##,##REF##34283229##44##</sup> Thus, it is not discernible whether simply wearing the HR tracker/accelerometer or receiving personalized activity recommendations from the app contributed to the observed increase in physical activity. Further, the nature and intensity of the activity, as well as nuances in HR change that more specifically address intensity and conditioning, were not available for this analysis. Ultimately, the observation that the technology-based intervention as described leads to behavior modification and clinical benefits is important. It should be noted that participants in both the healthy and pre-diabetes cohorts already had relatively high levels of baseline activity, which could have skewed the data <italic>vis a vis</italic> their inclination toward performing additional exercise; nevertheless, significant increases in physical activity among both groups was observed.</p>", "<p id=\"Par30\">It is worth noting the significance of the glycemic improvements observed in the healthy nondiabetic group. That the observation group exhibited glycemic excursions that could be improved by diet might come as a surprise to many. CGM data on nondiabetics is scant in the literature. While the TIR is high in this group at baseline, in the current analysis, which is the largest cohort of nondiabetic individuals with published data on CGM, glycemia still improved in multiple metrics. Whether improved glycemia in this population prevents diabetes or improved health outcomes is not currently known, as diabetes prevention studies have been conducted in high risk individuals with prediabetes. The data presented in fact suggests that with the advent of CGM an even earlier stage of dysglycemic is detectable and can improve with lifestyle interventions. This is important as future studies should examine the long term health risks (T2D, cardiovascular disease) as well as the impact of diabetes prevention strategies in this group of individuals. Such studies, which will take years to conduct, will determine whether the improvements in glycemic profile would be beneficial to health and potentially reduce the risk for T2D.</p>", "<p id=\"Par31\">The current findings have several limitations inherent in real world studies. First, there was no control group—data presented are based on the change from baseline to end-of-program and thus could represent a “placebo” effect from simply being enrolled in a program. A future randomized trial with a comparator group would extend and confirm the present findings. Second, the requirement to use a CGM means that it is likely that the participants in this study demonstrated high levels of self-efficacy, and thus it is not clear that results would translate into less self-motivated individuals who were recommended by a health care provider to engage in a similar intervention. Third, some of the data captured depends on adherence to logging. It is possible that participants did not log all food or activity; thus, alternate metrics were used, such as the ratio of macronutrient to total calories and HR > 110 min, which generally supported the logged metrics. Logging weight is also subject to success bias and thus may only be interpreted to reflect the weight loss of those who weighed themselves at least once after starting the program. Fourth, ethnicity was not collected in this cohort. It is important to recommend ethnically and culturally appropriate lifestyle interventions, particularly with regard to dietary recommendations, and thus improvement of this application would include capture of ethnicity and ethnic/culturally-sensitive recommendations if desired by the user. Fifth, the duration of intervention was 28 days. Longer duration studies will be required to ascertain the durability of behavior changes and glycemic benefits. Finally, weight reporting in this study was not comprehensive as weight loss was not a specific goal of our study and therefore weight monitoring was optional. Weight logging was not required, nor were users reminded to log or enter their weight. It is not appropriate to compare our study to the DPP in terms of weight reporting, as our study’s focus was on logging food and activity and measuring glucose levels with CGM.</p>", "<p id=\"Par32\">In our participants without a diagnosis of T2D, we used thresholds for Time in Range (TIR) that were previously reported in the literature (70–140 mg/dL) or justifiable based on translation to Hemoglobin A1c (Glycemic Management Indicator (GMI)). Currently, there are no TIR thresholds for patients without diabetes, but we believe that they will be established in the future<sup>##REF##31127824##38##</sup> It is not clear whether glucose levels outside a prespecified range (eg 70–140 mg/dL) or above a given threshold (>180 mg/dL) in individuals who do not meet traditional criteria for diabetes lead to clinical consequences such as microvascular disease. It is also not clear whether glucose levels on CGM predict increased conversion rates to T2D in those who do not meet traditional OGTT criteria for prediabetes. Long-term studies will be required to ascertain these important questions. However, both mild glycemic excursions into prediabetic and diabetic range, and glycemic variability, which has been associated with increased risk for cardiovascular disease<sup>##REF##33097560##45##</sup> are more readily ascertained with CGM than with older methods of glucose measurement, and it is likely that future studies will reveal answers to the questions posed above regarding the prediction of clinical events according to specific CGM metrics in both T2D and earlier stages of dysglycemia.</p>", "<p id=\"Par33\">In summary, we demonstrate that an app-based platform that integrates food and physical activity logging with CGM and HR data, and provides personalized lifestyle recommendations based on user input enhances healthy lifestyle practices and improves metabolic health in individuals with and without T2D. This nee technology improves glucose profiles even in individuals who by current standards are normoglyemic, and promotes weight loss in overweight and obese individuals, highlighting its potential for early intervention. Importantly, the ability to offer intervention without human coaching (with or without AI-enabled personalization) enables affordable scaling to large numbers of people, including those who are underserved or living in remote areas––thus helping to reduce the continually increasing prevalence of prediabetes and diabetes. In this respect, it will be important to optimize user engagement, including customization to varied ethnicities and socioeconomic levels, and to consider the needs of different age groups, including the elderly who often have more difficulty accessing in-person health care services, and to youth and young adults, who tend to be less adherent to traditional models of diabetes prevention and may selectively benefit from technology-based models. Overall, this approach and similar technology-based approaches have the potential to improve metabolic health at early stages, and may increase the efficacy of current practices to prevent and treat T2D through lifestyle modification.</p>" ]	[]	[ "<p id=\"Par1\">The effectiveness of lifestyle interventions in reducing caloric intake and increasing physical activity for preventing Type 2 Diabetes (T2D) has been previously demonstrated. The use of modern technologies can potentially further improve the success of these interventions, promote metabolic health, and prevent T2D at scale. To test this concept, we built a remote program that uses continuous glucose monitoring (CGM) and wearables to make lifestyle recommendations that improve health. We enrolled 2,217 participants with varying degrees of glucose levels (normal range, and prediabetes and T2D ranges), using continuous glucose monitoring (CGM) over 28 days to capture glucose patterns. Participants logged food intake, physical activity, and body weight via a smartphone app that integrated wearables data and provided daily insights, including overlaying glucose patterns with activity and food intake, macronutrient breakdown, glycemic index (GI), glycemic load (GL), and activity measures. The app furthermore provided personalized recommendations based on users’ preferences, goals, and observed glycemic patterns. Users could interact with the app for an additional 2 months without CGM. Here we report significant improvements in hyperglycemia, glucose variability, and hypoglycemia, particularly in those who were not diabetic at baseline. Body weight decreased in all groups, especially those who were overweight or obese. Healthy eating habits improved significantly, with reduced daily caloric intake and carbohydrate-to-calorie ratio and increased intake of protein, fiber, and healthy fats relative to calories. These findings suggest that lifestyle recommendations, in addition to behavior logging and CGM data integration within a mobile app, can enhance the metabolic health of both nondiabetic and T2D individuals, leading to healthier lifestyle choices. This technology can be a valuable tool for T2D prevention and treatment.</p>", "<title>Subject terms</title>" ]	[ "<title>Supplementary information</title>", "<p>\n\n\n</p>" ]	[ "<title>Supplementary information</title>", "<p>The online version contains supplementary material available at 10.1038/s41746-023-00956-y.</p>", "<title>Acknowledgements</title>", "<p>The authors would like to thank the participants in the study, as well as the employees of January AI who helped with preparation and submission. This work was wholly funded by January AI.</p>", "<title>Author contributions</title>", "<p>A.D.Z. and T.M. contributed to overall study design and manuscript preparation. A.D.Z. contributed to development and implementation of machine learning models. A.D.Z., A.H., and S.A. contributed to data analysis. S.T. contributed to IRB approval. A.V. and J.R. contributed to figure design. N.H. and M.W. contributed to manuscript review. M.P.S. and A.V. contributed to manuscript writing, preparation, review, revision, and submission.</p>", "<title>Data availability</title>", "<p>The data that support the findings of this study are not publicly available due to privacy, commercialization, and/or ethical restrictions. However, data can be made available upon request from the corresponding author.</p>", "<title>Code availability</title>", "<p>The underlying code for this study is not publicly available for proprietary reasons.</p>", "<title>Competing interests</title>", "<p id=\"Par67\">The authors declare the following competing financial and non-financial interests: S.A., A.H., A.V., and A.D.Z. are employed by January AI. T.M., N.A., and M.P.S. serve as Scientific Advisors to January AI. N.H. and M.P.S. are co-founders of January AI.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><p>Season of Me Program Overview.</p></caption></fig>", "<fig id=\"Fig2\"><label>Fig. 2</label><caption><p>User experience with data synthesis, feedback, education, and personalized health recommendations based on previously recorded information.</p></caption></fig>", "<fig id=\"Fig3\"><label>Fig. 3</label><caption><title>Change in level of glycemia in individuals with suboptimal control at baseline.</title><p><bold>A, B</bold> Time in range for individuals starting with <90% TIR defined as 70–180 mg/dL for T2D (A) and 70–140 mg/dL for prediabetes and healthy (<bold>B</bold>, <bold>C</bold>, <bold>D</bold>): GMI in individuals starting with GMI > 6% (<bold>C</bold>) and >7% (<bold>D</bold>).</p></caption></fig>", "<fig id=\"Fig4\"><label>Fig. 4</label><caption><title>Change in hyperglycemic and hypoglycemic events/day.</title><p>(<bold>A</bold>) Events > 140 mg/dL; (<bold>B</bold>) Events > 180 mg/dL; (<bold>C</bold>) Events > 250 mg/dL; (<bold>D</bold>) Events < 70 mg/dL.</p></caption></fig>", "<fig id=\"Fig5\"><label>Fig. 5</label><caption><p>Change in glycemic variability measured as coefficient of variation.</p></caption></fig>", "<fig id=\"Fig6\"><label>Fig. 6</label><caption><p>Weight loss at 4 weeks in those who logged at least one weight after baseline weight.</p></caption></fig>", "<fig id=\"Fig7\"><label>Fig. 7</label><caption><title>Weight loss during Season of Me Program.</title><p>(<bold>A</bold>) Weight loss according to glycemic subgroup (<bold>B</bold>) Weight loss in those who continued to log weight over 12 weeks.</p></caption></fig>", "<fig id=\"Fig8\"><label>Fig. 8</label><caption><title>Example task card.</title><p>Such a task card would have been presented to participants in the Season of Me program via their mobile application. Users can indicate whether or not the task was performed by toggling the button indicated.</p></caption></fig>", "<fig id=\"Fig9\"><label>Fig. 9</label><caption><title>Overview of the Machine Learning Pipeline for Prediction of Blood Glucose Values.</title><p>This figure illustrates the machine learning pipeline designed for predicting future blood glucose levels based on various inputs, including continuous blood glucose measurements, food nutrients, heart rate, exercise, and time of day. The pipeline consists of several steps, starting with data preprocessing, followed by the utilization of a recurrent neural network (RNN) comprising LSTM (Long Short-Term Memory) and Dense layers. <bold>A</bold> The process begins by collecting and preparing the input data, which encompasses continuous blood glucose readings, food nutrient information, heart rate data, exercise data, and time of day. The collected data then undergoes preprocessing, where it is cleaned, normalized, and organized in a suitable format for the subsequent stages. <bold>B</bold> Next, the preprocessed data is fed into the RNN model, which is composed of LSTM and Dense layers. The LSTM layers are employed to capture temporal dependencies and patterns within the data, enabling the model to understand the sequential nature of blood glucose fluctuations over time. The Dense layers aid in learning complex relationships and extracting relevant features from the input data. <bold>C</bold> The RNN model is trained to predict the blood glucose level for the next time step. Once the initial prediction is made, it is fed back into the model as an input, allowing the model to generate subsequent predictions for future time steps. This feedback loop enables the model to iteratively refine its predictions and adapt to changing conditions. <bold>D</bold> The output of the pipeline is a sequence of predicted blood glucose values, which can be used for various applications, such as monitoring and managing blood glucose levels in individuals with diabetes or supporting personalized dietary and exercise recommendations. Overall, this machine learning pipeline offers a systematic approach for blood glucose prediction, leveraging data preprocessing and a recurrent neural network architecture with LSTM and Dense layers to provide accurate and timely forecasts of blood glucose levels.</p></caption></fig>", "<fig id=\"Fig10\"><label>Fig. 10</label><caption><title>Reliance.</title><p><bold>A</bold> Use of ablation analysis to determine feature importance. Starting from the left, the most important modality is removed and the model is retrained to measure the impact of the removed dataset. This analysis demonstrates in order of descending importance the significance of each input was as follows: nutrients, time of day, heart rate, activity. <bold>B</bold> Similar to (<bold>A</bold>) but in each iteration the least important dataset is removed.</p></caption></fig>", "<fig id=\"Fig11\"><label>Fig. 11</label><caption><title>Understanding the performance of the CGP model.</title><p><bold>A</bold> Evaluation of CGP model performance against that of comparable models (prediction of the glucose impact of certain foods, “CGP”; and prediction of a glucose curve when given consistent food logging and heart rate information, “VCGM”) to that of several other models. Across a number of dimensions, including RMSE Peak, RMSE point by point, RMSE point by point shifted, correlation, and percent error, we found that the CGP model outperformed each of its competitors. <bold>B</bold> Comparison of actual blood glucose values versus blood glucose values predicted by the CGP algorithm. The correlation coefficient is 0.83, and holds more strongly for non-outlier values (<200 mg/dL). The reasons for this are twofold: first, because BGL fluctuation for these users is generally high; second, because extreme outlier BGL values are rare, and thus appear far less frequently in our training set. <bold>C</bold> Comparison of CGP predicted blood glucose values versus actual blood glucose values. The CGP algorithm operates on a stochastic basis, generating at each 15-min time interval 100 different potential BGL values, along with the corresponding likelihood of each value occurring. The red line reflects CGP predicted BGL; the green line represents BGL values derived from CGM. The orange zone represents the range of BGL values between the 25th and 75th percentiles of the CGP predictions, by likelihood of occurrence; the blue zone represents the 10th and 90th percentiles. As shown, the CGM-derived curve falls within the confidence interval of the predicted curve. <bold>D</bold> Comparison of VCGM predicted blood glucose values versus actual blood glucose values over a 24-h period. The red line reflects CGP predicted BGL; the green line represents BGL values derived from CGM. The orange zone represents the range of BGL values between the 25th and 75th percentiles of the CGP predictions, by likelihood of occurrence; the blue zone represents the 10th and 90th percentiles. As shown, the CGM-derived curve falls within the confidence interval of the predicted curve. <bold>E</bold> Correlation between demographics and errors. We examined whether certain demographic information correlated with higher instances of error. We found that higher weight correlates with higher percent error (<italic>p</italic> < 0.05), and higher age correlates with lower percent error (<italic>p</italic> < 0.05). <bold>F</bold> Comparisons of error by gender and disease type. We found that percent error and RMSE peak/point-by-point were lower for healthy participants than for participants with prediabetes/T2D; and lower for males than for females.</p></caption></fig>", "<fig id=\"Fig12\"><label>Fig. 12</label><caption><title>Overview of the Food Recommender model.</title><p><bold>A</bold> Food Recommender processing stages. Conceptually, the Food Recommender can be organized as a sequence of 4 processing stages: Input food →(1) Personalized similarity food matching. Finding food items similar to the food item being searched by the user →(2) Blacklist foods removal. Removal of foods that the user has “blacklisted”, i.e. allergies, sensitivities →(3) Healthiness ranking. Ranking of foods according to a “healthiness” scale that takes into account carbohydrate and fiber composition →(4) Cleanup of recommendations list. Removal of substandard recommendations→ Recommendations for user. <bold>B</bold> Interface between app and Food Recommender. <bold>C</bold> Example in-app recommendations. Note the similarity between the food item being looked up, and the food item being recommended to the user.</p></caption></fig>" ]	[ "<table-wrap id=\"Tab1\"><label>Table 1</label><caption><p>Percent change in nutrient intake from beginning to end of the Season of Me program.</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th/><th>kcal</th><th>Carb: Total kcal</th><th>Sugar: Total kcal</th><th>Protein: Total kcal</th><th>Fat/ Total kcal</th><th>Sat. Fat: Total kcal</th><th>Fiber: Total kcal</th></tr></thead><tbody><tr><td><bold>All</bold></td><td>-21.8</td><td>-2.6</td><td>-12.3</td><td>3.5</td><td>1.1</td><td>-0.5</td><td>7.9</td></tr><tr><td><bold>Healthy</bold></td><td>-22.9</td><td>-2.2</td><td>-13.1</td><td>5.4</td><td>1.6</td><td>-0.7</td><td>10.0</td></tr><tr><td><bold>Pre</bold></td><td>-21.0</td><td>-4.7</td><td>-11.2</td><td>-4.0</td><td>2.8</td><td>-2.8</td><td>7.9</td></tr><tr><td><bold>T2D</bold></td><td>-11.9</td><td>-4.8</td><td>-7.3</td><td>1.0</td><td>-3.5</td><td>-3.9</td><td>0.9</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[ "<supplementary-material content-type=\"local-data\" id=\"MOESM1\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM2\"></supplementary-material>" ]	[ "<table-wrap-foot><p>To account for potential bias due to decreased frequency of logging (min of two meals and 1600 kcal per day was required for inclusion), macronutrients are expressed as a proportion of total calories to demonstrate the relative intake of macronutrients which should be free of logging bias. absolute caloric and macronutrient intake is shown in supplemental data. Carbohydrate, sugar, and protein grams were multiplied by 4 to calculate calories, and fat and saturated fat grams were multiplied by 9 to calculate calories consumed for specific macronutrients. Fiber was expressed as grams:total calories.</p><p>Macronutrients expressed as macronutrient calories:total calories and fiber expressed as grams:total calories</p></table-wrap-foot>", "<fn-group><fn><p><bold>Publisher’s note</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn><fn><p><bold>Change history</bold></p><p>1/12/2024</p><p>A Correction to this paper has been published: 10.1038/s41746-024-00996-y</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"41746_2023_956_Fig1_HTML\" id=\"d32e385\"/>", "<graphic xlink:href=\"41746_2023_956_Fig2_HTML\" id=\"d32e403\"/>", "<graphic xlink:href=\"41746_2023_956_Fig3_HTML\" id=\"d32e498\"/>", "<graphic xlink:href=\"41746_2023_956_Fig4_HTML\" id=\"d32e552\"/>", "<graphic xlink:href=\"41746_2023_956_Fig5_HTML\" id=\"d32e559\"/>", "<graphic xlink:href=\"41746_2023_956_Fig6_HTML\" id=\"d32e601\"/>", "<graphic xlink:href=\"41746_2023_956_Fig7_HTML\" id=\"d32e617\"/>", "<graphic xlink:href=\"41746_2023_956_Fig8_HTML\" id=\"d32e890\"/>", "<graphic xlink:href=\"41746_2023_956_Fig9_HTML\" id=\"d32e976\"/>", "<graphic xlink:href=\"41746_2023_956_Fig10_HTML\" id=\"d32e998\"/>", "<graphic xlink:href=\"41746_2023_956_Fig11_HTML\" id=\"d32e1074\"/>", "<graphic xlink:href=\"41746_2023_956_Fig12_HTML\" id=\"d32e1104\"/>" ]	[ "<media xlink:href=\"41746_2023_956_MOESM1_ESM.pdf\"><caption><p>Supplementary Tables (PDF)</p></caption></media>", "<media xlink:href=\"41746_2023_956_MOESM2_ESM.pdf\"><caption><p>reporting summary</p></caption></media>" ]	[{"label": ["1."], "mixed-citation": ["Centers for Disease Control and Prevention. "], "italic": ["National Diabetes Statistics Report Website"], "ext-link": ["https://www.cdc.gov/diabetes/data/statistics-report/index.html"]}, {"label": ["4."], "mixed-citation": ["American Diabetes Association. Economic costs of diabetes in the U.S. in 2017. "], "italic": ["Diabetes Care"], "bold": ["41"]}, {"label": ["15."], "mixed-citation": ["Lashbrook, J. 85% of US adults own a smartphone. "], "italic": ["Marketing Charts"], "ext-link": ["https://www.marketingcharts.com/digital/mobile-phone-117548"]}, {"label": ["16."], "mixed-citation": ["Rao, Anoop, et al. \u201cEvolution of data management tools for managing self-monitoring of blood glucose results: a survey of iPhone applications.\u201d "], "italic": ["J. Diabetes Sci. Technol."], "bold": ["44"]}, {"label": ["18."], "surname": ["Joseph", "Rosanna", "John"], "given-names": ["T", "T", "R"], "article-title": ["White; smartphone-based glucose monitors and applications in the management of diabetes: an overview of 10 salient \u201capps\u201d and a novel smartphone-connected blood glucose monitor"], "source": ["Clin. Diabetes"], "year": ["2012"], "volume": ["30"], "fpage": ["173"], "lpage": ["178"], "pub-id": ["10.2337/diaclin.30.4.173"]}, {"label": ["19."], "surname": ["Iqbal"], "given-names": ["SMA"], "article-title": ["Advances in healthcare wearable devices"], "source": ["Npj Flex. Electron"], "year": ["2021"], "volume": ["5"], "fpage": ["9"], "pub-id": ["10.1038/s41528-021-00107-x"]}, {"label": ["27."], "surname": ["Ajjan"], "given-names": ["RA"], "article-title": ["Sensor and software use for the glycaemic management of insulin-treated type 1 and type 2 diabetes patients"], "source": ["Diabetes Vasc. Dis. Res."], "year": ["2016"], "volume": ["13"], "fpage": ["211"], "lpage": ["219"], "pub-id": ["10.1177/1479164115624680"]}, {"label": ["28."], "mixed-citation": ["Wada, E., et al. Flash glucose monitoring helps achieve better glycemic control than conventional self-monitoring of blood glucose in non-insulin-treated type 2 diabetes: a randomized controlled trial. "], "italic": ["BMJ Open Diabetes Res. Care"], "bold": ["8"]}, {"label": ["29."], "surname": ["Cox"], "given-names": ["DJ"], "article-title": ["Continuous glucose monitoring in the self-management of type 2 diabetes: a paradigm shift"], "source": ["Diabetes Care"], "year": ["2016"], "volume": ["39"], "fpage": ["71"], "lpage": ["73"], "pub-id": ["10.2337/dc15-2836"]}, {"label": ["35."], "mixed-citation": ["Hall, H., et al. Glucotypes reveal new patterns of glucose dysregulation. "], "italic": ["PLoS Biol."], "bold": ["16"]}, {"label": ["36."], "surname": ["Mendes-Soares"], "given-names": ["H"], "article-title": ["Assessment of a personalized approach to predicting postprandial glycemic responses to food among individuals without diabetes"], "source": ["JAMA Netw. Open"], "year": ["2019"], "volume": ["2"], "fpage": ["2"], "pub-id": ["10.1001/jamanetworkopen.2018.8102"]}, {"label": ["40."], "surname": ["Gershkowitz", "Hillert", "Crotty"], "given-names": ["BD", "CJ", "BH"], "article-title": ["Digital coaching strategies to facilitate behavioral change in type 2 diabetes: a systematic review"], "source": ["J. Clin. Endocrinol. Metab."], "year": ["2021"], "volume": ["106"], "fpage": ["1513"], "lpage": ["1520"], "pub-id": ["10.1210/clinem/dgaa850"]}, {"label": ["41."], "collab": ["American Diabetes Professional Practice Committee."], "article-title": ["Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes\u20142022"], "source": ["Diabetes Care"], "year": ["2022"], "volume": ["45"], "fpage": ["60"], "lpage": ["82"], "pub-id": ["10.2337/dc22-S005"]}, {"label": ["42."], "surname": ["Franz"], "given-names": ["MJ"], "article-title": ["Academy of nutrition and dietetics nutrition practice guideline for type 1 and type 2 diabetes in adults: systematic review of evidence for medical nutrition therapy effectiveness and recommendations for integration into the nutrition care process"], "source": ["J. Acad. Nutr. Dietet."], "year": ["2017"], "volume": ["117"], "fpage": ["1659"], "lpage": ["1679"], "pub-id": ["10.1016/j.jand.2017.03.022"]}]	{ "acronym": [], "definition": [] }	46	CC BY	no	2024-01-13 23:36:42	NPJ Digit Med. 2023 Nov 25; 6:216	oa_package/7c/8f/PMC10673832.tar.gz
PMC10681350	37295959	[ "<title>I. INTRODUCTION</title>", "<p>Whether and how the law can take account of interpersonal influences on decision making is an issue that has exercised law-makers, practitioners, and scholars for several years. What is sometimes lacking in these debates, however, is empirical evidence. Covering the first 12 years after the Mental Capacity Act (MCA 2005) was implemented, we outline the results of a qualitative content analysis of Court of Protection cases and other legal cases in England and Wales, shedding light on three key questions:</p>", "<p>What are the common characteristics of mental capacity court cases where interpersonal influence problems are a concern?</p>", "<p>What are the different categories of interpersonal influence problems on decision-making capacity?</p>", "<p>How do the courts discuss interpersonal influence problems using the language of the functional test in the MCA 2005?</p>" ]	[ "<title>III. METHODS</title>", "<title>A. Search criteria</title>", "<p>The search strategy was adapted from the criteria used in a previous, large-scale review of capacity judgments in the Court of Protection (CoP).<xref rid=\"fwad017-FN23\" ref-type=\"fn\"><sup>23</sup></xref> This study identified all published judgments from England’s CoP or Court of Appeal [Civil Division] (CoA) cases on appeal from the CoP, available on Westlaw and BAILII databases as of 11 September 2018; a total of 407 CoP and 26 CoA judgments. From these, we selected adult cases (where P was over 18 years old)<xref rid=\"fwad017-FN24\" ref-type=\"fn\"><sup>24</sup></xref> that contained rationales for judgments of incapacity or intact capacity of P in relation to a specific decision; a total of 131 judgments—128 CoP and three CoA judgments. For the purposes of the present study, we carried out an update search of Westlaw on 4 November 2019, resulting in a further 16 CoP and one CoA judgments containing capacity rationales. This gave a total of 144 CoP and four CoA capacity judgments.</p>", "<p>As we were interested in all judgments considering both capacity and interpersonal influence problems, we then identified (via Westlaw) all published High Court (non-COP) judgments, as of 4 November 2019, which invoked the inherent jurisdiction, using the search terms ‘coercion’, ‘undue influence’, and ‘inherent jurisdiction’. This search returned 15 published judgments. From these, we selected judgments for which the capacity of P was considered; a total of Four High Court (non-COP) judgments.</p>", "<p>The 152 selected judgments were screened for references to interpersonal influence as impairing or not impairing P’s decision making in relation to the capacity issue before the court, and cases without such references were excluded. We considered only descriptions of actual influence by a named influencer, not P’s hypothetical vulnerability to influence, because we wanted to examine <italic toggle=\"yes\">how</italic> the courts approached P’s ability to make actual decisions (for instance, contact with the influencer). Nor did we address situations in which the court did not, in fact, reach a conclusion as to P’s capacity. A final sample of 20 judgments (15 CoP, two CoA, and three non-COP High Court cases) met these criteria.</p>", "<title>B. Data analysis</title>", "<p>All authors are researchers in the Mental Health and Justice (MHJ) project, which takes an interdisciplinary approach to understanding mental capacity. K.A. has a background in psychology and drew insights from social and cognitive psychology to understand interpersonal dynamics. N.K. is a practising psychiatrist with experience in analysing CoP judgments on capacity. A.R.K. is a practising barrister and legal academic. G.O. is an academic psychiatrist with a research focus on mental capacity.</p>", "<p>K.A. and N.K. managed the full dataset of cases using Nvivo 12. K.A. first coded cases for descriptive characteristics such as age and gender of P, the capacity issue before the court, P’s impairment of the mind or brain, and the judge’s determination on P’s capacity.</p>", "<p>Qualitative content analysis (QCA) was then used to analyse the sample through an iterative coding process.<xref rid=\"fwad017-FN25\" ref-type=\"fn\"><sup>25</sup></xref> QCA is inherently qualitative as codes are generated from the interpretation of the data and are then applied to the data via close reading. It also has a quantitative component as codes are counted in order to detect patterns in the data which might guide further interpretation. It has been argued that content analysis of court judgments is particularly useful to gain knowledge of how judicial decisions are justified.<xref rid=\"fwad017-FN26\" ref-type=\"fn\"><sup>26</sup></xref></p>", "<p>K.A. read through the sample of 20 judgments, independently coding references to interpersonal influence, from a named influencer, as impairing or not impairing P’s decision making in relation to the matter before the court. The independently coded references were then discussed by K.A. and N.K. to reach a consensus on whether they met the definition of interpersonal influence. Disagreements were resolved by appealing to G.O., who arbitrated and made the final decision. This resulted in a total of 54 references.</p>", "<p>These references were then read by K.A. and N.K. and a provisional coding scheme for <italic toggle=\"yes\">types of influence on decision making</italic> was developed. K.A. and N.K. then proceeded with an iterative coding process, independently applying these codes to the whole sample, and refining the codes and resolving key boundary issues through discussion, with final arbitration from G.O. to resolve remaining disagreements. This resulted in a final coding scheme consisting of five types of influence problems on decision making and a residual category called ‘no specific mechanism’. We then carried out a reliability check using a ‘fuzzy kappa’ statistic, which measures the degree of agreement between the two coders in applying the pre-established coding scheme to the dataset, and adjusts for the fact the categories are non-exclusive (ie, that more than one category could be applied to a piece of text). This resulted in an intercoder agreement statistic of 0.80 across the five types,<xref rid=\"fwad017-FN27\" ref-type=\"fn\"><sup>27</sup></xref> suggesting good interrater reliability for the typology categories.</p>", "<p>K.A. subsequently examined references for links to sections 2 and 3 of the MCA 2005,<xref rid=\"fwad017-FN28\" ref-type=\"fn\"><sup>28</sup></xref> including linkage to abilities (understanding, retaining, using or weighing, communicating) and to the causative nexus (inability to make a decision <italic toggle=\"yes\">because of</italic> an impairment of the mind or brain). Finally, we used the themes generated by our qualitative content analysis as a prompt for further case-based analysis.</p>" ]	[ "<title>IV. RESULTS</title>", "<title>A. Sample characteristics</title>", "<p>As outlined in ##TAB##0##Table 1##, our final sample included 20 court judgments, containing 54 statements pertaining to interpersonal influence problems on capacity from a named influencer. Most of these judgments were derived from either the CoP (16 cases) or the CoA following an appeal from the CoP (two cases). The remaining judgments were derived from the High Court exercising its inherent jurisdiction (three cases). Interestingly, only two cases in the sample were decided prior to <italic toggle=\"yes\">PC v NC v City of York Council.</italic><xref rid=\"fwad017-FN29\" ref-type=\"fn\"><sup>29</sup></xref></p>", "<p>A range of conditions were considered to be the material ‘impairment of mind or brain’ in these cases. P was diagnosed with an intellectual disability in almost a half of cases in our sample (10 cases), with the severity of learning difficulties varying from ‘mild’<xref rid=\"fwad017-FN30\" ref-type=\"fn\"><sup>30</sup></xref> to ‘moderate’,<xref rid=\"fwad017-FN31\" ref-type=\"fn\"><sup>31</sup></xref> but none recorded as meeting the criteria for ‘severe’. Otherwise, the sample included various psychiatric conditions (anxiety, schizophrenia, and personality disorder), neurodevelopmental conditions (autistic spectrum disorder and Asperger’s syndrome), and neurological conditions (dementia and brain injury). In two High Court cases, there was no clear report of any current impairment of mind or brain. P was described as a vulnerable adult in both cases,<xref rid=\"fwad017-FN32\" ref-type=\"fn\"><sup>32</sup></xref> and they were reported to have had capacity to take each decision.</p>", "<p>The most common decisions in question were capacity to take decisions regarding residential matters (12 cases), contact (13 cases), care arrangements (10 cases), medical treatment, and property or financial affairs (five cases each). Less frequently, P was assessed for capacity to take decisions around sexual relations or contractual matters/testamentary capacity (three cases each), social media use and general activities (two cases each), and contraception, resuming married life, and revoking a Lasting Power of Attorney (one case each).</p>", "<p>Of the 54 statements pertaining to interpersonal influence on capacity from a named influencer, most of the statements were used as a rationale for P not having capacity (24 statements, 44.44%) or did not explicitly state whether it was arguing for or against the person having capacity (20 statements, 37.04%). Other references were used as a rationale for P having capacity (five statements, 9.26%), or P having capacity except in specific situations (six statements, 11.11%).</p>", "<title>B. Types of interpersonal influence problems</title>", "<p>We found five main types of interpersonal influence problems from our sample.<xref rid=\"fwad017-FN33\" ref-type=\"fn\"><sup>33</sup></xref></p>", "<title>1. Inability to preserve independence and free will</title>", "<p>Fifteen references; eight cases:</p>", "<p>This was the most referenced theme. Some of these statements questioned whether P was able to preserve their individual autonomy when exposed to the influencer. The theme also included references to free will or an overwhelming of P’s ability to make true, autonomous, voluntary choices. There may have been a description of an overwhelming power dynamic or a comment that P was unable to resist or free themselves from the influence. Perhaps unsurprisingly, at least one reference was coded as such in each of the three non-COP inherent jurisdiction cases.</p>", "<p>One relevant case included <italic toggle=\"yes\">Derbyshire County Council v AC</italic>.<xref rid=\"fwad017-FN35\" ref-type=\"fn\"><sup>35</sup></xref> The subject of proceedings, AC, was a 22-year-old woman who had a ‘significant learning disability’,<xref rid=\"fwad017-FN36\" ref-type=\"fn\"><sup>36</sup></xref> with some preserved independent living skills but limited executive functioning<xref rid=\"fwad017-FN37\" ref-type=\"fn\"><sup>37</sup></xref> and comprehension. Partly considering her history of abusive relationships, the local authority raised concerns over her living occasionally with her boyfriend who had prior convictions for domestic violence. AC had appeared to fluctuate between wishing to live with her parents and her boyfriend, sometimes ‘within the course of the same conversation’.<xref rid=\"fwad017-FN38\" ref-type=\"fn\"><sup>38</sup></xref> In relation to AC’s capacity to take a decision on residential matters, the solicitor acting on behalf of the local authority submitted that ‘AC has “difficulty in sustaining an independent view” if she is exposed to someone who “is influential” such as her mother, or boyfriend’.<xref rid=\"fwad017-FN39\" ref-type=\"fn\"><sup>39</sup></xref> Cobb J decided, in the interim, that AC lacked capacity to take a decision regarding her residence until such a time in the future where her capacity would be re-assessed. It is unclear to what extent AC’s inability to preserve her independence and free will contributed to the finding that she lacked capacity, though Cobb J’s emphasis on future capacity assessments suggests that removing the alleged influencers could be key to AC’s prospects of regaining capacity.</p>", "<p>The issue of independence was also contested in <italic toggle=\"yes\">Southend-On-Sea Borough Council v Meyers</italic>.<xref rid=\"fwad017-FN40\" ref-type=\"fn\"><sup>40</sup></xref> Mr Meyers (who waived anonymity) was at the time of proceedings a 97-year-old care home resident. He had capacity to take a decision on his residence, though he was considered a vulnerable adult due to his blindness and the conduct of his son and carer, KF. The issues raised in relation to KF concerned his alleged neglect and abuse of Mr Meyers and a history of intimidating behaviour towards social care services. The local authority had made several prior attempts to support Mr Meyers with his care needs over a 2-year period, with very limited success. It became clear that Mr Meyers’ physical health was deteriorating amid reports that his house was severely lacking in basic amenities. Mr Meyers himself was malnourished and required hospital treatment, to the point where his life was at risk. After feeling that they had met their legal obligations, the Local Authority sought an injunction.</p>", "<p>The relationship between Mr Meyers and KF was a key point during the discussion, which focused on Mr Meyers’ decision-making abilities and whether to invoke the inherent jurisdiction to safeguard him. At the time, Mr Meyers had wished to live with his son, despite having stated the opposite only months previously. The expert social worker submitted that Mr Meyers could ‘articulat[e] his wishes and feelings autonomously and not under influence or coercion’.<xref rid=\"fwad017-FN41\" ref-type=\"fn\"><sup>41</sup></xref> However, this did not convince Hayden J. His judgment referred to the ‘intensity of this relationship [which] occludes Mr Meyers’ ability to take rational and informed decisions’,<xref rid=\"fwad017-FN42\" ref-type=\"fn\"><sup>42</sup></xref> and that the consequence of this influence ‘is to disable Mr Meyers from making a truly informed decision’.<xref rid=\"fwad017-FN43\" ref-type=\"fn\"><sup>43</sup></xref> On this basis, and due to the physical risks to Mr Meyers, Hayden J exercised the inherent jurisdiction to allow Mr Meyers to return home as he wished, but prevent his son from residing with him.</p>", "<title>2. Influence restricting P’s perspective</title>", "<p>Twelve references; seven cases:</p>", "<p>In this situation, the influencer or the relationship with the influencer impaired P’s decision-making process due to confusion/anxiety or restricted P’s ability to consider abstract options or future possibilities. P’s perspective was therefore narrowed because of the influence.</p>", "<p>Considering future possibilities was a prominent theme in <italic toggle=\"yes\">PCT v P & Ors</italic>.<xref rid=\"fwad017-FN45\" ref-type=\"fn\"><sup>45</sup></xref> P was a young man who had been diagnosed with severe epilepsy and a ‘lower end of mild’ learning disability,<xref rid=\"fwad017-FN46\" ref-type=\"fn\"><sup>46</sup></xref> both of which were considered to impact his functioning. His mother, AH, had cared for P for 18 years until recently, when concerns were raised about their decision for P to discontinue his epilepsy medication, as well as the subsequent deterioration in P’s condition and daily living skills. On assessment, P was found to lack capacity to take a range of decisions relating to his health, contact and welfare. Hedley J appeared to refer heavily to the alleged impact of AH on P’s ability to use abstraction in the decision-making process, using terms such as ‘think about his future’ and ‘visualise any prospect’ as justification of P’s functional inability.<xref rid=\"fwad017-FN47\" ref-type=\"fn\"><sup>47</sup></xref> Hedley J was, however, keen to stress that these factors only led P to lack capacity when considered in addition to his impairments and their effects on his functional ability.</p>", "<p>In other cases, the influence was described as having introduced confusion or otherwise complicating the decision-making process. There were some notable examples of confusion triggering court proceedings, even when P was considered to be above the threshold of capacity at the beginning of proceedings. For example, in <italic toggle=\"yes\">London Borough of Redbridge v G & Ors</italic>,<xref rid=\"fwad017-FN48\" ref-type=\"fn\"><sup>48</sup></xref> the local authority initially advanced proceedings to protect a 94-year-old woman (G) under the inherent jurisdiction, as they considered her to have capacity to take decisions regarding her contact, residence and property, and affairs. The reason for the injunction was due to concerns that her carers, C and F, were financially exploiting her and compromising her ability to make informed decisions. On G’s part, she did not wish to lose the independence of living in her own home and feared that without C and F or anyone else to care for her, she would be placed in a care home against her wishes. The local authority had made previous attempts to communicate that they would provide sufficient support for G to remain in her own home, but suspected that C and F were withholding this information from G and exaggerating the risk of G’s removal so as to increase her dependency on them.<xref rid=\"fwad017-FN49\" ref-type=\"fn\"><sup>49</sup></xref></p>", "<p>Despite the initial finding of G having capacity, the court sought evidence from independent experts, which led to a ruling that G did not have capacity. The expert evidence is of interest partly because of the different reasons provided for G not having capacity. The social worker argued that this was because of the undue influence, whereas the psychiatrist acknowledged the influence as undermining capacity but considered P to lack capacity because of a mild-to-moderate dementia. Ultimately, the judge preferred the evidence of the psychiatrist, partly on the basis that the psychiatrist was qualified to recognize mental impairments. Nonetheless, the judge described the influence of C and F as having ‘compromised’ decision making, rendering it ‘even more difficult for G’ and that she was ‘at times almost paralysed by the threats regarding her removal to a care-home or to have F take over her personal and intimate care’.<xref rid=\"fwad017-FN50\" ref-type=\"fn\"><sup>50</sup></xref> It is important to consider that, while it was not contested that P was both vulnerable and subject to extreme social pressure, the course of proceedings depended entirely on whether P had a formal impairment of mind or brain.<xref rid=\"fwad017-FN51\" ref-type=\"fn\"><sup>51</sup></xref></p>", "<title>3. Valuing or being dependent on the relationship</title>", "<p>Twelve references; nine cases:</p>", "<p>In these statements, the influence was considered to show itself through the value P placed on the relationship with the influencer, which resulted in P placing particular weight on the perceived views of the influencer or acting to preserve the relationship at all costs. Unlike the following theme, suggestibility, the evidence here focused on factors that were specific to the relationship between P and the influencer. This took place in either a marriage, familial or caring context. In all these cases, there were clear tensions between the duty to protect and the freedom to make (capacitous) unwise decisions, as well as the right to respect for one’s private and family life under Article 8 of the European Convention on Human Rights.</p>", "<p>Some statements emphasized that it is common for close relations to have a strong input into one’s decisions. For example, in <italic toggle=\"yes\">London Borough of Croydon v KR & Anor</italic>,<xref rid=\"fwad017-FN54\" ref-type=\"fn\"><sup>54</sup></xref> a man was assessed to have capacity to take a decision as to where he lived and whom he lived with. Because there was no dispute that KR had capacity, he did not fall within the scope of any protections under the MCA 2005. In the light of concerns that he was being unduly influenced by his wife, the only safeguarding option would have been to invoke the inherent jurisdiction of the High Court. KR responded to those concerns by stating that he considered this to be ‘normal, as she is my wife’.<xref rid=\"fwad017-FN55\" ref-type=\"fn\"><sup>55</sup></xref> The judge decided not to intervene on this basis, having argued that:</p>", "<p>This echoed a similar argument in <italic toggle=\"yes\">London Borough of Hackney v SJF & Anor</italic>,<xref rid=\"fwad017-FN57\" ref-type=\"fn\"><sup>57</sup></xref> which involved a woman with mild learning disability. When asked to consider how SJF’s relationship with her son may impact her capacity to take a decision as to where to live, SJF’s solicitor opined that her ‘clearly stated wishes simply give greater weigh[t] to her family life and her wish to be with her son, in her own home of many years’,<xref rid=\"fwad017-FN58\" ref-type=\"fn\"><sup>58</sup></xref> despite her son’s challenging behaviour towards her. However, this argument did not persuade Senior Judge Hilder to find that SJF had capacity. Instead, she preferred the evidence of the consultant psychiatrist, who argued that it was SJF’s learning disability that led her to be unable to understand, retain, or use or weigh information about her treatment needs and risks to returning home with her son.</p>", "<p>On the other hand, some statements seemed to suggest an unequal relationship between P and the alleged influencer. P’s dependence on this person could then be reasoned to affect their capacity. In <italic toggle=\"yes\">Re MRJ</italic>,<xref rid=\"fwad017-FN59\" ref-type=\"fn\"><sup>59</sup></xref> the CoP heard an application with respect to an 82-year-old woman with dementia, amid concerns of emotional and financial abuse from her daughter and grandson. When providing evidence as to whether MRJ could revoke her existing Lasting Power of Attorney, the consultant psychiatrist successfully argued that MRJ was unable to use or weigh information relevant to the decision as her decision-making processes were ‘heavily influenced and distorted by her overwhelming sense of loyalty’ and ‘her need to retain these important relationships for her’.<xref rid=\"fwad017-FN60\" ref-type=\"fn\"><sup>60</sup></xref> Another example is <italic toggle=\"yes\">A Local Authority v WMA</italic>,<xref rid=\"fwad017-FN61\" ref-type=\"fn\"><sup>61</sup></xref> in which a 25-year-old man with autism spectrum disorder was alleged to have experienced long-term neglect. WMA was cared for by his mother, MA, and both opposed an increase in intervention from care services. The court ruled that WMA was unable to use or weigh information relevant to deciding where he should live, and Cardinal J’s observations on capacity focused heavily on WMA’s relationship with his mother, with whom WMA had an ‘unhealthy degree of interdependence’.<xref rid=\"fwad017-FN62\" ref-type=\"fn\"><sup>62</sup></xref> It is notable that in both cases the judges regarded the close family member(s) as having contributed to P’s social isolation and obstructed potential social support. Cardinal J went so far as to rule that it was in WMA’s best interests to move away from living with his mother, in part because this may reduce his dependence and allow him to form relationships with others.</p>", "<title>4. Suggestibility</title>", "<p>Six references; five cases:</p>", "<p>In these statements, the interpersonal influence was thought to be problematic through P’s tendency to align their decisions with the wishes of others. The underlying process has been described as suggestibility—a tendency to acquiesce, or an eagerness to please. Although our sampling frame selected cases that discussed influence from a named person, within these discussions of suggestibility we also found references to an abstract, or trait-like, suggestibility that was not specific to that named person. These references suggest a view that P’s decision making is too malleable because of their impairment of the mind or brain, as opposed to P only being made vulnerable from the deliberate actions of a specific person or being placed in an extreme environment. The implication was that a certain level of influence from anyone is more problematic for some people than others, in terms of their ability to make capacitous decisions.<xref rid=\"fwad017-FN64\" ref-type=\"fn\"><sup>64</sup></xref></p>", "<p>For example, <italic toggle=\"yes\">Re A</italic> concerned a 78-year-old woman with schizophrenia who was subject to a family dispute with regards to who should be appointed deputy for her property and affairs.<xref rid=\"fwad017-FN65\" ref-type=\"fn\"><sup>65</sup></xref> It is not clear whether A enjoyed positive relationships with all the family members involved. When concluding that A did not have capacity to manage her own affairs (and hence giving the court the jurisdiction to appoint a deputy to manage them on her behalf), the consultant psychiatrist appeared not to justify this with reference to factors specific to her family relationships. Instead, he pointed to past scenarios in which A was exploited by various third parties, and then to a hypothetical scenario in which he believed he could exert malign influence on A’s decision making that would lead her to lose all her assets. With reference to her diagnosis of schizophrenia, he argued that this rendered A widely vulnerable to being financially exploited by others <italic toggle=\"yes\">in general</italic>.<xref rid=\"fwad017-FN66\" ref-type=\"fn\"><sup>66</sup></xref></p>", "<p>We identified similar patterns in the other cases, such as <italic toggle=\"yes\">London Borough of Brent v NB</italic>.<xref rid=\"fwad017-FN67\" ref-type=\"fn\"><sup>67</sup></xref> These proceedings concerned a 22-year-old man, MB, who was diagnosed with a learning disability and an acquired brain injury, and he had a physical disability due to cerebral palsy. MB generally found it difficult to communicate his wishes, and although it was accepted that he did not wish to undergo a residential placement for additional support, his capacity to take various decisions was in question. The assessment was extensive, in part because of MB’s support needs and the role of his mother, NB, in his care. While the judgment focused primarily on the maternal relationship, which was described throughout as ‘enmeshed’<xref rid=\"fwad017-FN68\" ref-type=\"fn\"><sup>68</sup></xref> it was also discussed whether MB’s decision making could be compromised by non-specific third parties. For example, the expert clinical psychologist ‘noted that [MB’s] opinion changed rapidly and considered that he was vulnerable to the influence of others in making his decisions’.<xref rid=\"fwad017-FN69\" ref-type=\"fn\"><sup>69</sup></xref> This submission was used as evidence that MB did not have capacity to take a decision to appoint a case manager and who that case manager should be.</p>", "<title>5. Denial of facts about the influencer or the relationship</title>", "<p>Six references; three cases:</p>", "<p>In this, the least cited category, the rationale was that P did not have capacity because they denied negative facts about the influencer, or declined either to examine certain parts of the influencing relationship or to incorporate information relevant to those facts into their decision making where it was relevant to do so.</p>", "<p>Most of these statements derived from <italic toggle=\"yes\">Re B (Capacity: Social Media: Care and Contact)</italic> and the subsequent Court of Appeal decision in the same case, <italic toggle=\"yes\">B v A Local Authority</italic>.<xref rid=\"fwad017-FN71\" ref-type=\"fn\"><sup>71</sup></xref> This complex case concerned a 31-year-old woman with learning disabilities and arose in part due to safeguarding concerns with respect to a man she had met, Mr C, as well other men she had met on social media. The local authority was particularly concerned about the risk Mr C posed to her, given his history of sexual offences, his wish to marry Miss B, and recorded correspondence between them which suggested controlling behaviour. As outlined in the quote above, Cobb J concluded that Miss B could not use or weigh information relevant to deciding whom she should have contact with, in part because she seemed not to believe Mr C’s prior convictions or factor this into her decision. It was noted that the relevant information for the purposes of a decision to contact, includes ‘the positive and negative aspects of having contact with each person’,<xref rid=\"fwad017-FN72\" ref-type=\"fn\"><sup>72</sup></xref> and Theis J elaborated that ‘this will necessarily and inevitably be influenced by [P]’s evaluations. His evaluations will only be irrelevant if they are based on demonstrably false beliefs’.<xref rid=\"fwad017-FN73\" ref-type=\"fn\"><sup>73</sup></xref> In Miss B’s case, it would seem that her evaluation of the risk around Mr C, based on the apparent (false) belief that he had no prior convictions, rendered her unable to use or weigh the negative aspects of contact with him. No clear link was made in the judgment between her beliefs and her learning disability.<xref rid=\"fwad017-FN74\" ref-type=\"fn\"><sup>74</sup></xref></p>", "<p>Many of the same issues arose in another, earlier, case <italic toggle=\"yes\">PC v NC v City of York Council</italic>.<xref rid=\"fwad017-FN75\" ref-type=\"fn\"><sup>75</sup></xref> Here, PC was a 48-year-old woman with mild learning disabilities, who was cohabiting with her husband of 7 years (NC). NC had prior convictions for serious sexual offences and in anticipation of his release in 2011, the local authority asked whether PC had capacity take a decision to cohabit with her husband. On giving evidence, the consultant psychiatrist judged that PC was incapable of understanding or using or weighing with respect to her decision to have contact with NC, in large part because she ‘could not, or would not, accept the guilt, or even the possible guilt, of NC in respect of the matters of which he had been convicted’.<xref rid=\"fwad017-FN76\" ref-type=\"fn\"><sup>76</sup></xref></p>", "<p>Interestingly, although the first instance judge, Hedley J, agreed that the fact of NC’s guilt in relation to those offences was potentially highly relevant to PC’s capacity to take decisions in relation to his care, contact, and residence, he rejected the characterization of the issue as being whether she accepted NC’s guilt. By Hedley J’s reasoning, PC should have been entitled to make a potentially unwise judgment as to whether NC was guilty. Thus, Hedley J argued that the relevant issue was PC’s ‘learning disability, her unwillingness to examine the issue of his [NC’s] guilt, and her overwhelming desire to re-establish that relationship, and that that derives in significant part from her impairment’.<xref rid=\"fwad017-FN77\" ref-type=\"fn\"><sup>77</sup></xref> By doing so, Hedley J seemed to confirm that PC merely needed to engage with this information on some level to have capacity, and that she was unable to do so.</p>", "<p>Hedley J then ruled that it was in PC’s best interests to cohabit with NC, provided that the local authority could monitor their progress. This decision was made on the basis that PC had made a capacitous decision to marry NC, and that it would have been an intrusion upon their marital contract if they were forced to live apart. However, on PC’s appeal, the CoA overturned Hedley J’s judgment, as the psychiatrists’ evidence was considered insufficient to prove that PC’s learning disability had caused her to lack capacity. By doing so, the CoA appeared to suggest that the causative nexus argument should have been made based on PC’s learning disability alone, rather than in conjunction with PC’s examination of NC’s guilt, which was not considered to be relevant. The CoA instead acknowledged that NC was convicted and imprisoned when PC had taken a capacitous decision to marry him, and therefore their privacy should be respected as there was nothing to suggest that her impairment had worsened since then.</p>", "<title>C. Interpersonal influence: relation to functional abilities</title>", "<p>In total, 19 statements from 12 cases explicitly linked interpersonal influences to functional abilities (see ##TAB##1##Table 2##). These were most often made in reference to the ‘use or weigh’ criterion, followed by the understanding criterion. Only one statement made a clear reference to the presence of an influencer affecting P’s ability to retain information. The types of interpersonal influence constructed in these statements were spread relatively uniformly across the functional abilities, with two exceptions. We found evidence of ‘use or weigh’ but not understanding in the ‘inability to preserve independence and free will’ and in the ‘causative nexus’ categories. There were no clear mentions of interpersonal influence with respect to the ‘communication’ criterion: the ability to express a choice.</p>", "<title>D. How do judges use evidence of influence and impairments?</title>", "<p>Fifteen references; nine cases:</p>", "<p>Some judgments included nuanced discussion of how P’s ‘impairment of mind or brain’ was said to interact with interpersonal influence in a dynamic fashion; for example, through increasing anxiety in the subject, or through a learning disability rendering someone ‘eager to please’ others. Not all of these references explicitly used the term ‘causative nexus’ to describe this.<xref rid=\"fwad017-FN80\" ref-type=\"fn\"><sup>80</sup></xref></p>", "<p>The case-based analysis which follows seeks to organize the ways judges deal with evidence of influence and impairments in the more complex cases. We first consider two landmark cases, then proceed to examine two contrasting approaches taken by judges since then. To provide sufficient context to each case, we have included some quotes that were not part of the final sample of 54 references.</p>", "<title>1. Landmark cases</title>", "<p>The term ‘dynamic interaction’ is used in <italic toggle=\"yes\">A Local Authority v Mrs A</italic>,<xref rid=\"fwad017-FN81\" ref-type=\"fn\"><sup>81</sup></xref> in which P was a 29-year-old married woman with a learning disability. When providing evidence, the consultant psychiatrist implied that Mrs A’s capacity to take a decision to use contraception was a function of various interpersonal dynamics. The pressure applied from her husband, their joint relationship with services, and her own impairments were all considered part of a ‘dynamic interaction’ that was relevant to her decision-making abilities.<xref rid=\"fwad017-FN82\" ref-type=\"fn\"><sup>82</sup></xref> When making his final judgment, Bodey J seemed to accept the evidence that Mrs A had understood all necessary elements required to decide whether to take contraception. He was also ‘satisfied that her decision not to continue taking contraception is not the product of her own free will’.<xref rid=\"fwad017-FN83\" ref-type=\"fn\"><sup>83</sup></xref> Nonetheless, Bodey J controversially ruled that Mrs A did not have capacity to take this decision, on the basis that she could not use or weigh due to Mr A’s extreme pressure. The judgment as to whether contraception was in Mrs A’s best interests was then delayed until more meaningful engagement with Mrs A and her husband could take place. It should be noted that the decision (which predated that of the CoA in <italic toggle=\"yes\">PC v NC v City of York Council</italic>)<xref rid=\"fwad017-FN84\" ref-type=\"fn\"><sup>84</sup></xref> is, strictly, difficult to align with the MCA 2005 because it was not clear whether Bodey J found that Mrs A lacked capacity to take a decision regarding contraception because of the effect of her learning disability (ie, she lacked capacity applying the MCA 2005), or because of the influence of her husband (which would not satisfy the test under the MCA 2005). We revisit this point in the discussion below.</p>", "<p>The issue of dealing with influence was more adequately addressed, in MCA 2005 terms, in <italic toggle=\"yes\">PC v NC v City of York Council</italic>,<xref rid=\"fwad017-FN85\" ref-type=\"fn\"><sup>85</sup></xref> and which we discussed in Section IV.B.5 regarding the interpersonal aspect. On appeal, PC successfully contested the original ruling that she did not have capacity, partly on the basis that the previous judge had not adequately spelled out the causative nexus. The appeal judges were cautious to ensure that the causative nexus was not ‘watered down’<xref rid=\"fwad017-FN86\" ref-type=\"fn\"><sup>86</sup></xref> by accepting evidence that implied a weaker than causal relationship between the impairment and functional inability. To do so would, in their analysis, have led to an outcome-focused approach, which was incompatible with the MCA 2005. Given that PC was previously found to have capacity to marry NC, and that there was no evidence of any worsening of her learning disability since then, the CoA clearly did not consider itself to have the jurisdiction to infringe on either her decision to marry, or decisions closely related to it.</p>", "<title>2. Separating influence and impairment</title>", "<p>Since the decision in <italic toggle=\"yes\">PC</italic>,<xref rid=\"fwad017-FN87\" ref-type=\"fn\"><sup>87</sup></xref> judges have generally approached the causative nexus by viewing impairment and influence as distinct and separate, and clearly specifying which of the two caused P’s inability. This has been used to settle several disputes between expert witnesses. For example, in <italic toggle=\"yes\">NCC v PB and TB</italic>,<xref rid=\"fwad017-FN88\" ref-type=\"fn\"><sup>88</sup></xref> both witnesses referred to both the husband’s (TB’s) influence on PB and her anxiety affecting PB’s ability to make decisions with respect to her care, contact and residence (see the quote in Section IV.D below). While the second opinion psychiatrist had deliberated over whether TB’s influence had rendered PB incapacitous ‘all the time’, he ultimately argued that PB’s capacity was ‘finely balanced’.<xref rid=\"fwad017-FN89\" ref-type=\"fn\"><sup>89</sup></xref> Conversely, the treating psychiatrist ‘regarded PB and always has as clearly lacking capacity’.<xref rid=\"fwad017-FN90\" ref-type=\"fn\"><sup>90</sup></xref> In her judgment, Parker J sided with the latter evidence, and stayed loyal to the decision in <italic toggle=\"yes\">PC</italic> by regarding ‘PB’s condition as the cause of her inability to use or weigh’.<xref rid=\"fwad017-FN91\" ref-type=\"fn\"><sup>91</sup></xref> She held that PB met the threshold for lacking capacity as a result of her mental illness, with TB’s influence contributing to this even when he was not present.</p>", "<p>Similarly, in <italic toggle=\"yes\">London Borough of Redbridge v G</italic>,<xref rid=\"fwad017-FN92\" ref-type=\"fn\"><sup>92</sup></xref> a dispute took place regarding the role of the impairment and influence in relation to capacity (see Section IV.B.2 above). The psychiatrist argued that both dementia and influence were compromising G’s decision making, whereas the social worker argued that this inability was only caused by the influence and controlling behaviour of G’s carers. Russell J preferred the psychiatrists’ evidence and specified her detailed reasons as to why G’s dementia rendered her incapable of taking the relevant decisions.<xref rid=\"fwad017-FN93\" ref-type=\"fn\"><sup>93</sup></xref> Russell J accepted several of the social worker’s arguments on the influencing relationship; however, only the psychiatrist was instructed to give evidence on G’s impairment. In effect, once the influence and impairment had been separated, this meant that only the psychiatrist provided evidence on which to decide whether the MCA 2005 should apply.<xref rid=\"fwad017-FN94\" ref-type=\"fn\"><sup>94</sup></xref> Russell J went on to rule that G lacked capacity to take the relevant decisions and was also subject to undue influence by her carers, thus allowing jurisdiction under the MCA 2005.<xref rid=\"fwad017-FN95\" ref-type=\"fn\"><sup>95</sup></xref> Although Russell J made a clear case for a causal relationship between G’s impairment and inability, it is noteworthy that the published judgment did not cite <italic toggle=\"yes\">PC</italic>. Given the depth of evidence on both influence and impairment, one might consider Macfarlane LJ’s warnings over ‘watering down’<xref rid=\"fwad017-FN96\" ref-type=\"fn\"><sup>96</sup></xref> the causative nexus to be particularly relevant in this case.</p>", "<p>Several years later, in <italic toggle=\"yes\">Re B (Capacity: Social Media: Care and Contact)</italic>,<xref rid=\"fwad017-FN97\" ref-type=\"fn\"><sup>97</sup></xref> a young woman with a learning disability was considered to be at risk from a third party, Mr C (as discussed in Section IV.B.5 above). During his general observations on the causative nexus, Cobb J remarked, in very clear terms, that:</p>", "<p>In justifying his focus on the learning disability as separate to influence, he cited the precedent set by Parker J above.<xref rid=\"fwad017-FN99\" ref-type=\"fn\"><sup>99</sup></xref> Hence, Cobb J ruled that B could not use or weigh the relevant information to take a decision as to contact with Mr C, due to her learning disability.</p>", "<title>3. Mixing influence and impairment</title>", "<p>However, some judges explicitly spelled out the difficulty with separating the impairment from the influence. In <italic toggle=\"yes\">Newcastle Upon Tyne City Council v TP</italic>,<xref rid=\"fwad017-FN100\" ref-type=\"fn\"><sup>100</sup></xref> the CoP sought to determine whether TP, a woman with a learning disability as well as cerebral palsy, had capacity to take decisions regarding her social care, medical treatment, contact, and finances. TP had wished to live in the community, ideally with her partner (FW), who also had a learning disability. The local authority wished for TP to stay in residential care, and they had previously intervened with men she had befriended due to concerns that she was being financially exploited. During proceedings, the court heard evidence from the clinical psychologist that it was ‘difficult to tease out what is influencing TP’s decision making’.<xref rid=\"fwad017-FN101\" ref-type=\"fn\"><sup>101</sup></xref> Moir J also found it difficult to distinguish between the influence and capacity, particularly with regard to contact. Regarding capacity for contact, she remarked, for example, that ‘it is only because of TP’s learning disability that the coercion has been able to take such effective hold. Both exist together’.<xref rid=\"fwad017-FN102\" ref-type=\"fn\"><sup>102</sup></xref> The published judgment did not cite any of the influence landmark cases, though Moir J’s reasoning briefly focused on TP’s other relationships and functioning when FW was absent.<xref rid=\"fwad017-FN103\" ref-type=\"fn\"><sup>103</sup></xref> Moir J ultimately ruled that the evidence pointed towards TP having lacked capacity to take these decisions because of her learning disability.</p>", "<p>In the proceedings reported as <italic toggle=\"yes\">London Borough of Brent v NB</italic>,<xref rid=\"fwad017-FN104\" ref-type=\"fn\"><sup>104</sup></xref> Senior Judge Hilder cited <italic toggle=\"yes\">PC</italic>,<xref rid=\"fwad017-FN105\" ref-type=\"fn\"><sup>105</sup></xref> and reaffirmed that the court must be satisfied that the impairment itself causes an inability to take a decision, rather than other factors in the person’s life. However, the expert clinical psychologist considered that MB was vulnerable to influence and recommended that family therapy take place as a practicable step to potentially improve MB’s enmeshed maternal relationship and possibly regain his capacity. While ‘practicable steps’ usually target the inability caused by an impairment of mind or brain, here the therapeutic focus was MB’s relationship with his mother. Senior Judge Hilder’s decision to delay proceedings for this relational intervention, suggests the mixing of influence and impairment in the domain of decision-making support. If Senior Judge Hilder had decided to separate the influence and impairment during the initial proceedings, then she might have been satisfied (as she later ruled) that MB’s learning disability and brain injury caused his lack of capacity. Under such an approach, it would have been difficult to see how interventions to improve the influencing relationship could lead to MB regaining capacity, without targeting the impairments themselves.</p>", "<p>Following delays, MB received four sessions of family therapy, which did not produce any notable improvement. Interestingly, the family therapist submitted that intervening in enmeshed relationships ‘is not achievable in a few short weeks’.<xref rid=\"fwad017-FN106\" ref-type=\"fn\"><sup>106</sup></xref> There was some dispute, from MB’s father’s representative, as to whether MB had been provided with enough support, given that the therapy was unfinished and met with practical problems. Nonetheless, Senior Judge Hilder ruled that she was satisfied that the court had exhausted all practicable steps. She subsequently ruled that MB lacked capacity because of his brain injury and learning disability.<xref rid=\"fwad017-FN107\" ref-type=\"fn\"><sup>107</sup></xref></p>" ]	[ "<title>V. DISCUSSION</title>", "<title>A. Overview of main findings</title>", "<p>The role of influence, and when it becomes undue, is one that has exercised the courts and commentators for many years. However, traditionally, the focus has been upon examining the situation in retrospect, where the question is whether a particular action should be viewed as having been taken under the undue influence of another; for instance, whether a will should be accepted as valid, or whether a gift or contract should be set aside. There has been much less focus on how relational matters should be considered in ‘real time’, in circumstances where the question is about what is to be done to secure the interests of the person in question going forward. This is the first systematic content analysis of interpersonal influence problems in cases before the English courts where this issue has been the subject of consideration and determination.</p>", "<p>Our search returned 20 published cases for which influence from a named person was cited by the courts as relevant to P’s capacity. We then undertook a qualitative content analysis, during which we identified five main types of interpersonal influences towards P. Influence problems were construed as P having an inability to preserve their free will or independence, as restricting P’s perspective, as valuing or dependence on a relationship, as acting on a general suggestibility to influence, or as P denying facts about the relationship. Most of the statements were used as evidence of the person’s functional abilities and when discussing the causative nexus. Our results challenge perceptions of mental capacity as an individualized construct and show that the courts are attributing importance to relational factors across a range of decision-making situations and conditions.</p>", "<p>Out of the four functional abilities, interpersonal factors were most likely to be cited as justification that the person can or cannot ‘use or weigh’ relevant information. Our finding here is unsurprising, given that ‘using or weighing’ is the most contested part of the functional test, the broadest in scope, and overlaps conceptually with ‘understanding’.<xref rid=\"fwad017-FN108\" ref-type=\"fn\"><sup>108</sup></xref> This part of the analysis is important insofar as it shows that judges have had to explore how they considered interpersonal influence to be operative on the abilities set out in the MCA 2005, and did so at a granular level, rather than merely considering them in abstract. On this evidence, and perhaps contrary to the position sometimes advanced that the MCA 2005 is unable to take into account interpersonal factors,<xref rid=\"fwad017-FN109\" ref-type=\"fn\"><sup>109</sup></xref> the cases show that it is seems to be able to do so, albeit without always a clear mechanism being identified.</p>", "<p>Our third category, ‘valuing or dependence on the influencer or the relationship’, suggests that judges may look at the relational context to infer whether P is making an unwise decision, rather than an incapacitous one.<xref rid=\"fwad017-FN110\" ref-type=\"fn\"><sup>110</sup></xref> These statements show that interpersonal influence can go either way as a rationale for establishing whether P was unable, or simply unwilling, to use or weigh information relevant to the decision. P might be deemed unable to use or weigh because they are overvaluing a relationship on which they are dependent, as in <italic toggle=\"yes\">Re MRJ</italic>.<xref rid=\"fwad017-FN111\" ref-type=\"fn\"><sup>111</sup></xref> In another context, P might be deemed unwilling to use or weigh because of their strong family values, as in <italic toggle=\"yes\">London Borough of Croydon v KR</italic>.<xref rid=\"fwad017-FN112\" ref-type=\"fn\"><sup>112</sup></xref> One challenge for the CoP will be to demonstrate that it is able satisfactorily to be able to distinguish between these two scenarios and to justify how they are different.</p>", "<p>Although we only included cases with a named influencer, we should note that sometimes the courts widened their analysis to look at whether P was susceptible to problematic influences in a general sense. The statements within our ‘suggestibility’ category indicate that the idea of vulnerability has been used to argue that P lacks mental capacity, even though there is no mention of vulnerability or suggestibility within the MCA 2005. When used in the MCA 2005 context, it seems the courts partly see this vulnerability as inherent to P as opposed to only situational.<xref rid=\"fwad017-FN113\" ref-type=\"fn\"><sup>113</sup></xref> This framing has wide ranging implications. In one case, an expert witness explicitly stated that they could have negatively influenced a ‘suggestible’ person if they wanted to, which raises questions as to why influence problems only seem to be litigated when involving families, friends or carers.<xref rid=\"fwad017-FN114\" ref-type=\"fn\"><sup>114</sup></xref> The idea of labelling people as ‘suggestible’ is highly sensitive and could easily perceived as stigmatizing towards the person who has been subject to influence, particularly where this shades into abuse, and downplaying or taking responsibility away from those exerting the influence.<xref rid=\"fwad017-FN115\" ref-type=\"fn\"><sup>115</sup></xref> And in cases where the court is required to make decisions about P’s best interests, there are clearly implications as to the extent to which the court can or should take into account their wishes and feelings if those might, in fact, reflect the wishes and feelings of those around them.<xref rid=\"fwad017-FN116\" ref-type=\"fn\"><sup>116</sup></xref></p>", "<p>We were also able to identify how judges handled evidence of a possible interaction between P’s impairment and the interpersonal influence. <italic toggle=\"yes\">A Local Authority v Mrs A</italic> was the first case to do so and referred to this as the ‘dynamic interaction’.<xref rid=\"fwad017-FN117\" ref-type=\"fn\"><sup>117</sup></xref> However, this judgment is, with respect, legally incoherent because it did not, in fact, identify which was the material cause of Mrs A’s inability to make the decision in question: was it the impairment, or the influence of her husband, or some combination of the two?<xref rid=\"fwad017-FN118\" ref-type=\"fn\"><sup>118</sup></xref> The next case in our sample to address this, <italic toggle=\"yes\">PC v NC v City of York Council</italic>,<xref rid=\"fwad017-FN119\" ref-type=\"fn\"><sup>119</sup></xref> stressed that there must be a causal relationship between the impairment and the functional inability to find P as lacking capacity. Since then, judges have appeared to handle evidence of influence cautiously with respect to the causative nexus.</p>", "<p>Interestingly, these legal tensions have also manifested in Singapore, where in effect the same legislation is applied in a far more relational manner. For example, in <italic toggle=\"yes\">Re BKR</italic>,<xref rid=\"fwad017-FN120\" ref-type=\"fn\"><sup>120</sup></xref> the Singapore CoA came to the conclusion that the wording in section 1(4) of the MCA 2005 in Singapore:</p>", "<p>Instead, the CoA found her to lack capacity on the basis of <italic toggle=\"yes\">both</italic> her mental impairment <italic toggle=\"yes\">and</italic> the circumstances in which she lived, in circumstances where the Court accepted that it was unrealistic to imagine that BKR could simply be removed from those circumstances. The approach here seems to contrast to that which most judges explicitly take in the CoP, though, in our sample, most cases with similar disputes still found the person to lack capacity (see Section IV.D above).</p>", "<p>Nonetheless, we have found several examples in which the expert witness reasoned that the influence and the impairment had a multiplicative impact on the P’s functional abilities. It is also clear that several experts believe that extreme social pressure can have a substantial impact on a person’s decision-making ability in its own right. Judges are then tasked, on one view, with separating the influence from the impairment. This raises questions as to whether judges are well equipped to distinguish between these two factors, and whether the conclusions they reach are either overly inclusive (ie, ruling that a person lacks capacity to take a decision when, in reality, they are ‘merely’ under extreme pressure),<xref rid=\"fwad017-FN122\" ref-type=\"fn\"><sup>122</sup></xref> or under-inclusive (failing to identify that, taken together, the influence and the person’s impairment means that they cannot, in fact, make the decision in question for purposes of the MCA 2005). There are risks with either approach, but perhaps the greatest risk is that those concerned (from the judge downwards) are not clear about the basis upon which they are proceeding.</p>", "<p>Finally, the cases also shed light on how the criteria for certain decisions require some basic ability to engage with social information. For example, the information relevant to making decisions about care arrangements includes knowing that carers might not always provide the necessary support and that one can complain if this happens. Similarly, the legal test for making decisions about contact requires some ability to judge the positive and negative aspects of having contact with that particular person.<xref rid=\"fwad017-FN123\" ref-type=\"fn\"><sup>123</sup></xref> Arguably, such tests present an opportunity for the courts to consider relational factors within a capacity context. Also, if P makes an unwise decision, it can prove difficult to distinguish whether P’s apparent lack of engagement with social information is caused by their impairment, as opposed to their values or ambivalence. One way to introduce greater clarity and consistency may be to consider the psychological concept of theory of mind; the cognitive ability to consider the intentions, motivations, likely behaviours and perhaps even the competence of others.<xref rid=\"fwad017-FN124\" ref-type=\"fn\"><sup>124</sup></xref> The concept of theory of mind has been researched in people with various ‘impairments’, most notably autism.<xref rid=\"fwad017-FN125\" ref-type=\"fn\"><sup>125</sup></xref> Further investigation may help to identify those who have been <italic toggle=\"yes\">unable</italic> to process social information due to an impairment, as well as those who are able to, but might be considered at present to be disabled from doing so by third party influence. Both groups may be helped to have capacity through tailored practical supportive steps.</p>", "<title>B. Implications for clinical practice</title>", "<p>In this article we have highlighted several practical and policy considerations for professionals who assess capacity and added nuance to the concept of an ‘optimal’ capacity assessment. Our analysis shows that professionals are perceiving third party influence to be a problem, particularly for social care service users. A previous study has shown that many professionals tasked with capacity assessment are concerned about undue influence,<xref rid=\"fwad017-FN126\" ref-type=\"fn\"><sup>126</sup></xref> but it has been less clear how these concerns are dealt with. Some professionals appear to be struggling to resolve these concerns within their local safeguarding team and may therefore seek a legal solution by bringing these cases to court.<xref rid=\"fwad017-FN127\" ref-type=\"fn\"><sup>127</sup></xref> Leading up to this, professionals have often made unsuccessful attempts to engage with P and/or their family, friends, and carers, and they often have some suspicion that P is potentially at risk or vulnerable to exploitation, harm, abuse or neglect, either from that specific person or in general.<xref rid=\"fwad017-FN128\" ref-type=\"fn\"><sup>128</sup></xref> By proceeding with litigation, professionals may have sought to avoid making a determination which carries only risk for them; either of being seen to be grossly infringing on P’s private life or allowing them to remain in a dangerous situation<xref rid=\"fwad017-FN129\" ref-type=\"fn\"><sup>129</sup></xref> In any case, we have demonstrated that the courts are willing to scrutinize these concerns, both in terms of the MCA 2005 and the inherent jurisdiction.</p>", "<p>One key consideration from our study is that problematic influences have been constructed by the courts as interacting with and temporarily affecting P’s functional abilities. We argue that, in accordance with the MCA 2005’s principle of taking practicable steps to support P’s decision making,<xref rid=\"fwad017-FN130\" ref-type=\"fn\"><sup>130</sup></xref> the capacity assessment process should continue for as long as required for potentially problematic influences to be assessed. If appropriate, these should be mitigated during the assessment so as to support P to meet the requirements of each specific decision in question.<xref rid=\"fwad017-FN131\" ref-type=\"fn\"><sup>131</sup></xref> Capacity is, of course, time-specific and so it may be necessary to reach a capacity determination before this point. In this case, appropriate measures to provide support (either on the basis of informed consent or best interests, depending on the capacity outcome) might still be continued and these might form practicable steps down the line. As such, the determination should not be taken as holding indefinitely, but rather pending further—identified—work. Even in one case where P was determined to lack capacity, and best interests proceedings were initiated, the judge recommended that a repeat capacity assessment take place in the near future.<xref rid=\"fwad017-FN132\" ref-type=\"fn\"><sup>132</sup></xref></p>", "<p>In half of the cases in our study, P was diagnosed with an intellectual disability. This is a slightly higher proportion than in a sample of 170 personal welfare cases in the CoP (41.18%),<xref rid=\"fwad017-FN133\" ref-type=\"fn\"><sup>133</sup></xref> and higher than in another sample of published disputed capacity cases (37.50%).<xref rid=\"fwad017-FN134\" ref-type=\"fn\"><sup>134</sup></xref> This is consistent with evidence from a recent survey, which suggested that professionals are most concerned about undue influence when assessing capacity in people with intellectual disabilities, as well as people with dementia and older adults.<xref rid=\"fwad017-FN135\" ref-type=\"fn\"><sup>135</sup></xref> Professionals who work with these populations might thus particularly benefit from conceptualizing the different types of influence considered by the courts.</p>", "<p>Professional guidance on interpersonal factors during capacity assessments is largely scarce, with a few notable recent exceptions. The National Institute for Health and Care Excellence (NICE) guideline on decision-making capacity, for example, mentions that professionals should be aware of undue influence and coercion.<xref rid=\"fwad017-FN136\" ref-type=\"fn\"><sup>136</sup></xref> The British Psychological Society have issued guidance for clinical psychologists, which made brief references to ‘social influence’ during capacity assessments.<xref rid=\"fwad017-FN137\" ref-type=\"fn\"><sup>137</sup></xref> Although this is a positive shift, the mentions in both documents are brief and made with little to no supporting evidence, from either the case law or empirical research. The Social Care Institute of Excellence have also published a chapter advising social workers that both the MCA 2005 and inherent jurisdiction are available to safeguard adults.<xref rid=\"fwad017-FN138\" ref-type=\"fn\"><sup>138</sup></xref> This does not, however, provide any additional guidance on how to reach the capacity determination. Developments such as the revision of the MCA 2005 Code of Practice, albeit somewhat stalled at the time of writing, may present some opportunities to promote a better understanding towards the nuances of the relational context.<xref rid=\"fwad017-FN139\" ref-type=\"fn\"><sup>139</sup></xref></p>", "<title>C. How should the courts handle relational issues?</title>", "<p>Our typology provides clear evidence that the courts are developing an approach to the policy gap outlined by the Law Commission in 1993, which identified that some vulnerable adults would lie outside the scope of the MCA 2005 and other frameworks.<xref rid=\"fwad017-FN140\" ref-type=\"fn\"><sup>140</sup></xref> The MCA 2005 did not explicitly address these concerns, and some scholars have argued that a reformed MCA 2005 would provide for interpersonal issues, which causally affect the person’s ability to consent, to be considered within a capacity framework.<xref rid=\"fwad017-FN141\" ref-type=\"fn\"><sup>141</sup></xref> There is, at present, no immediate prospect of reform of the MCA 2005, but our study has shown that the courts are not waiting for reform and, instead, are grappling with these matters live. So far, there seem to have been two trends in the courts’ approach. First, judges may use an expansive approach to the causative nexus to infer that P does not have capacity when under the deleterious influence of another person. As we have demonstrated in Section IV.B. above, several experts have made the case that when an impairment of mind or brain <italic toggle=\"yes\">and</italic> an external influence are both present, they may act in tandem to worsen a person’s decision-making ability. This suggests that expert witnesses do not interpret the causative nexus as meaning that interpersonal problems are irrelevant to capacity determinations. On hearing this evidence, several judges have also found it difficult (or impossible) to separate the impairment from the influence. This would suggest that the Law Commission’s description of the functional test as a ‘cognitive test’ is being broadened and that their vague term ‘true choice’ is starting to gain greater specificity as influence cases get analysed in court.<xref rid=\"fwad017-FN142\" ref-type=\"fn\"><sup>142</sup></xref> An expansive approach could encourage judges against separating the impairment from influence in cases where such distinctions would prove arbitrary and decontextualizing. At present, the MCA 2005 does not expressly mention interpersonal factors, although as is evident in the case of Singapore (discussed in Section V.A. above) it does not prohibit their consideration.</p>", "<p>Secondly, judges may decide that to reach a determination of incapacity on the (partial) basis of interpersonal factors is either morally or legally unjustified. If they then find that the person has capacity, the only way to safeguard their interests is to use the inherent jurisdiction of the High Court. The bounds of the inherent jurisdiction are loosely defined, and the precise scope of what is, or is not, permissible when it comes to protection is unclear. To some, this may appear advantageous as it allows for protection beyond the MCA 2005 in exceptional circumstances, on a case-by-case basis.<xref rid=\"fwad017-FN143\" ref-type=\"fn\"><sup>143</sup></xref> To others, especially those who perceive the MCA 2005 as safeguarding autonomy, it may appear discomforting that such a framework can exist, untrammelled by statutory limits, and which can go against the wishes of people who have capacity.<xref rid=\"fwad017-FN144\" ref-type=\"fn\"><sup>144</sup></xref> It is also important to note that the inherent jurisdiction lacks the principled approach of the MCA 2005, including its straightforward provisions to provide support, as both practicable steps to maximize capacity and via a best interests process predicated on returning the person to autonomy. Indeed, some may argue that such extraneous factors might guide judges toward the MCA 2005 as a more workable framework.<xref rid=\"fwad017-FN145\" ref-type=\"fn\"><sup>145</sup></xref></p>", "<p>Ultimately, it may be thought that this is a question which can and should only be resolved by Parliament, because it represents a societal determination of how broadly the net of protection should be cast, and how fine-grained that net should be. In the meantime, some predict that more hard cases will test the limits of the MCA 2005,<xref rid=\"fwad017-FN146\" ref-type=\"fn\"><sup>146</sup></xref> which would likely include borderline capacity cases in which there is suspicion of coercion or undue influence. Perhaps the most important message from our study is the continued need for transparency during capacity assessments. It seems that the more granular the analysis, the more defensible the narrative as to whether P really lacks capacity under the MCA 2005, or is a capacitous, but vulnerable, adult.<xref rid=\"fwad017-FN147\" ref-type=\"fn\"><sup>147</sup></xref></p>", "<title>D. Future directions</title>", "<p>Future studies should explore the various ways in which interpersonal influence can be constructed using a larger sample of capacity assessments. Different methods may shed light on topics that are unlikely to arise in published court judgments, such as how interpersonal influence from health and social care professionals (as opposed to the ‘usual suspects’ of family members) is handled outside of litigation. Future studies should also consider interpersonal issues specific to different clinical populations, how to support people subjected to potentially problematic influences, and how these models of influence may vary between different cultures. Examples of study designs may include semi-structured interviews with persons whose capacity is being assessed or expert witnesses, surveys or case-based vignettes with professionals, or analyses of expert evidence submissions. The demographic data collection should be detailed enough to identify priority areas for these research interests.</p>", "<p>The work that has already started to conceptualize the place of relational influence within the MCA 2005 should be continued and tested.<xref rid=\"fwad017-FN148\" ref-type=\"fn\"><sup>148</sup></xref> Beyond legal analysis, it will also be critical to further explore the mechanisms by which interpersonal factors might be said to interact with various impairments to affect decision making; that is how influence operates on impairment and vice versa. Psychology and cognitive neuroscience studies can better elucidate these mechanisms and guide development of support. Finally, future studies will no doubt want to explore the extent to which the COVID-19 pandemic changed matters in relation to specific examples of interpersonal influence. While protection under the MCA 2005 requires that the person has an identified mental impairment, the recent and unprecedented challenges have made it clear that anyone (including those with only physical health problems)<xref rid=\"fwad017-FN149\" ref-type=\"fn\"><sup>149</sup></xref> may become vulnerable at any point.</p>", "<p>We also note that our work throws further light on a pressing debate. Human rights scholars have increasingly advocated for models of ‘supported decision making’ to replace ‘substituted decision making’ on the behalf of adults with impairments. This movement, rightly, seeks to implement policies that, insofar as possible, recognize a person’s legal capacity—their right to make decisions for themselves. However, support can easily shade into deleterious influence, and vice versa. This highlights the need for conceptual and societal clarity as to the markers for the points where that influence goes beyond acceptable limits. For example, those who require substantial support are generally more dependent on those providing it, which is a risk factor for undue influence.<xref rid=\"fwad017-FN150\" ref-type=\"fn\"><sup>150</sup></xref> Indeed, Article 12(4) of the United Nations Convention of the Rights of Persons with Disabilities (CRPD) states that ‘measures relating to the exercise of legal capacity respect the rights, will and preferences of the person [and] are free of conflict of interest and undue influence’<xref rid=\"fwad017-FN151\" ref-type=\"fn\"><sup>151</sup></xref> One challenge raised by our study is how to identify the line between support and undue influence.</p>", "<title>E. Limitations</title>", "<p>It will be noted that the search period pre-dated the coronavirus pandemic. This was not by design; the impact of pandemic-related demands upon the study team meant that it has not been possible to carry out a further review to bring the search closer to the present day. However, given the short gap between the end of the review period in November 2019 and the start of the pandemic in March 2020, the review serves to indicate how the courts were operating with the concepts of capacity and vulnerability before the additional extraneous challenges of the pandemic took effect.</p>", "<p>Given the complexity of the data, there were limitations to testing the reliability of the coding schemes. At a conceptual level, the themes were not completely distinct, so we decided to use relatively large blocks of text to preserve the full context in which the statement was made. As a result of our approach, we could not calculate a standard kappa statistic, which requires mutually exclusive categories.<xref rid=\"fwad017-FN152\" ref-type=\"fn\"><sup>152</sup></xref> Instead, we calculated intercoder agreement using an extension of the kappa statistic, which has been adjusted for holistic coding.<xref rid=\"fwad017-FN153\" ref-type=\"fn\"><sup>153</sup></xref> We argue that this is approach is more applicable for an ecologically valid coding scheme, and that the alternative would have overly condensed the references or the coding scheme and thereby risked oversimplifying the data.</p>", "<p>We only included published judgments from England and Wales within our sampling frame. Only a small number of CoP cases are selected by judges for publication, and it is not logistically possible to estimate the total number of unpublished capacity dispute cases over this period.<xref rid=\"fwad017-FN154\" ref-type=\"fn\"><sup>154</sup></xref> The content of each published judgment is also selected by the judge and the level of detail varies. Consequently, our results will reflect the more complex capacity cases likely to result in published judgments, and may not be representative, or exhaustive, of all the ways in which interpersonal influence problems have been construed to impact upon capacity, inside or outside the courts. For example, the majority of cases in the CoP are brought forward by professionals, so perhaps a reason why the courts do not construct professionals as being problematic influences is not because this does not take place, but rather that the courts have not provided an accessible route when P has such claims.<xref rid=\"fwad017-FN155\" ref-type=\"fn\"><sup>155</sup></xref> It is also difficult to escape the impression that cases involving the inherent jurisdiction are particularly driven by concerns as to the outcome of the decision(s) in issue since, in effect, its primary use in this context is to prevent a person from making a capacitous but unwise decision.</p>", "<p>While the authors of previous capacity case reviews have acknowledged concerns about bias, many have argued that dispute cases are broadly representative of unpublished case files.<xref rid=\"fwad017-FN156\" ref-type=\"fn\"><sup>156</sup></xref> Published judgments are especially informative as they tend to be selected based on precedent value to judges and normative value to practitioners.<xref rid=\"fwad017-FN157\" ref-type=\"fn\"><sup>157</sup></xref> Perhaps, one of the main strengths of our research is that it raises awareness of these complex issues around capacity and influence, as the courts consider them, and it provides a novel framework to assist with interpreting this. Arguably, a detailed consideration of interpersonal problems could be most useful where the line is most blurred between capacity and vulnerability. Some authors have demonstrated how such reviews lend themselves well to integrative methods, such as in-person observations, interviews and grey literature reviews, to produce complementary findings.<xref rid=\"fwad017-FN158\" ref-type=\"fn\"><sup>158</sup></xref> The depth of discussion within these cases should, therefore, provide a strong initial basis from which to evaluate the courts’ approach to dealing with concerns of problematic influences.</p>" ]	[ "<title>VI. CONCLUSION</title>", "<p>There is no detailed guidance to suggest how professionals in England and Wales should approach the question of interpersonal influence when assessing capacity. We have undertaken a content analysis to show that interpersonal influence problems are relevant to capacity judgments across a broad range of decisions and impairments. Our typology provides an early framework to begin conceptualizing the different ways in which interpersonal influence problems can be constructed by the courts. This has the potential to improve clarity around the most contested criteria within the functional model, and to better equip the courts to consider possible interactions between mental impairments and influence. Future research should supplement these findings by providing insights across different clinical groups and ethical positions.</p>" ]	[ "<title>Abstract</title>", "<p>For many purposes in England and Wales, the Court of Protection determines whether a person has or lacks capacity to make a decision, by applying the test within the Mental Capacity Act 2005. This test is regularly described as a cognitive test with cognitive processes discussed as internal characteristics. However, it is unclear how the courts have framed interpersonal influence as negatively impacting upon a person’s decision-making processes in a capacity assessment context. We reviewed published court judgments in England and Wales in which interpersonal problems were discussed as relevant to capacity. Through content analysis, we developed a typology that highlights five ways the courts considered influence to be problematic to capacity across these cases. Interpersonal influence problems were constructed as (i) P’s inability to preserve their free will or independence, (ii) restricting P’s perspective, (iii) valuing or dependence on a relationship, (iv) acting on a general suggestibility to influence, or (v) P denying facts about the relationship. These supposed mechanisms of interpersonal influence problems are poorly understood and clearly merit further consideration. Our typology and case discussion are a start towards more detailed practice guidelines, and raise questions as to whether mental capacity and influence should remain legally distinct.</p>" ]	[ "<title>II. BACKGROUND</title>", "<p>Many jurisdictions have established a legal framework to decide whether a person is capable of making specific decisions for themselves, based on the functional model of ‘decision-making capacity’. Simply put, these frameworks set out provisions focusing on two core ethical duties: to safeguard personal autonomy in making decisions and to protect vulnerable people from experiencing harm.<xref rid=\"fwad017-FN1\" ref-type=\"fn\"><sup>1</sup></xref> Under the functional model of capacity, the person assessing capacity must make careful inferences as to whether a person has the psychological abilities needed to make the decision, without discriminating against the person’s values and motivations, or imposing their own.<xref rid=\"fwad017-FN2\" ref-type=\"fn\"><sup>2</sup></xref> Capacity assessments can take place in any context, with a health or social care professional being the most likely to undertake a formal assessment.</p>", "<p>Applying such a model to more complex decisions can be difficult. In England and Wales, the MCA 2005 requires that the assessor (or the court) be satisfied that the person is unable to understand, retain, use, or weigh information relevant to a specific decision, or to communicate their decision.<xref rid=\"fwad017-FN3\" ref-type=\"fn\"><sup>3</sup></xref> This functional inability must be caused by the impairment of mind or brain, and the importance of identifying the ‘causative nexus’ between impairment and functional inability was made clear by the Court of Appeal in <italic toggle=\"yes\">PC v NC v City of York</italic>. <xref rid=\"fwad017-FN4\" ref-type=\"fn\"><sup>4</sup></xref> The Court noted that starting with impairment, as opposed to potential inability, gave rise to the danger that ‘the strength of the causative nexus between mental impairment and inability to decide is watered down’.<xref rid=\"fwad017-FN5\" ref-type=\"fn\"><sup>5</sup></xref> Emphasizing the need for a causative link, the Court identified that phrases, such as any inability being ‘referable to’ or ‘significantly relates to’ the impairment in question, were inadequate.<xref rid=\"fwad017-FN6\" ref-type=\"fn\"><sup>6</sup></xref></p>", "<p>One criticism of the functional model enshrined in the MCA 2005 is that these legal criteria encourage assessors to consider the test as a ‘cognitive’ one,<xref rid=\"fwad017-FN7\" ref-type=\"fn\"><sup>7</sup></xref> and to locate decision-making abilities (and in particular, inabilities) as purely internal characteristics. Models of relational autonomy reject this approach, by asserting that all aspects of self, and therefore autonomy, are shaped by interactions with others. For example, Camillia Kong has argued that the MCA 2005 has an overly individualistic focus on characteristics such as the person’s own values, wishes, preferences, and diagnosis or diagnoses.<xref rid=\"fwad017-FN8\" ref-type=\"fn\"><sup>8</sup></xref> While internal characteristics are important, several social psychology studies have demonstrated—under empirical conditions—that social stimuli are fundamental to the decision-making process.<xref rid=\"fwad017-FN9\" ref-type=\"fn\"><sup>9</sup></xref> Our emotions, cognitions, and behaviours are susceptible to information disclosed by other people (informational social influence), as well as to decisions that we witness other people making (normative social influence), particularly when we are feeling uncertain.<xref rid=\"fwad017-FN10\" ref-type=\"fn\"><sup>10</sup></xref> The <italic toggle=\"yes\">relative</italic> impact of these processes varies from person to person and are poorly understood in ‘vulnerable adults’, a term used by the courts among others.<xref rid=\"fwad017-FN11\" ref-type=\"fn\"><sup>11</sup></xref> Of course, it should not always be assumed that social influence is benign. So, if the MCA 2005 is, indeed, too individualistic, it may not adequately recognize the importance of freedom from duress and coercion in a person reaching an autonomous decision.<xref rid=\"fwad017-FN12\" ref-type=\"fn\"><sup>12</sup></xref> This would raise further questions as to how judges handle relational concepts within a capacity framework in the absence of any formal criteria or guidance.</p>", "<p>The relational aspect identified above is perhaps most evident where the person is in a situation where one or more other people appear to be exploiting or in some other way exposing them to harm. In such a situation, decision-making capacity as embodied in the MCA 2005 seems to be only part of the problem. The Law Commission, in its project leading to the MCA 2005, had grappled with the fact that such a situation could require a bespoke solution, having noted that:</p>", "<p>These concerns were not taken forward by the government when legislating, but judges have, however, crafted their own solution to the problem. In the absence of any statutory provision, these steps have been taken under the High Court’s inherent jurisdiction, described elegantly by Lord Donaldson as the ‘great safety net’ filling in the gaps of the statutory law.<xref rid=\"fwad017-FN14\" ref-type=\"fn\"><sup>14</sup></xref> Prior to the passage of the MCA 2005, this safety net was required to secure the interests both of those who would now be seen as lacking decision-making capacity, and those who <italic toggle=\"yes\">have</italic> such capacity but whose decision-making capacity is compromised by the actions of a third party.<xref rid=\"fwad017-FN15\" ref-type=\"fn\"><sup>15</sup></xref> Subsequent to the passage of the MCA 2005, there was some doubt as to whether the Act had entirely delineated the scope of those to whom the courts could afford protection.<xref rid=\"fwad017-FN16\" ref-type=\"fn\"><sup>16</sup></xref> However, in 2012, the Court of Appeal confirmed that the passage of the MCA 2005 did not entirely fill the gaps within the ‘great safety net’ described by Lord Donaldson, and therefore it would have been inappropriate to remove the ability of the High Court to take protective steps by using the inherent jurisdiction in relation to an adult even where they have decision-making capacity.<xref rid=\"fwad017-FN17\" ref-type=\"fn\"><sup>17</sup></xref></p>", "<p>Importantly, however, a High Court judge can only exercise this jurisdiction if the person in question <italic toggle=\"yes\">has</italic> capacity under the MCA 2005 to take the decision in question; for instance, whether to remain in contact with someone who appears to be abusing them. This means that they must first consider whether the person should be considered to lack capacity, thereby, directly applying the MCA 2005. The development of the inherent jurisdiction has been subject to academic criticism, not least because it is constrained by no governing statutory principles,<xref rid=\"fwad017-FN18\" ref-type=\"fn\"><sup>18</sup></xref> but its continuing growth seems to reflect a need experienced by health and social care professionals who are confronted by patients in situations at the margin of the MCA 2005.<xref rid=\"fwad017-FN19\" ref-type=\"fn\"><sup>19</sup></xref></p>", "<p>In a context where statutory reform did not take place to address the limitations identified by the Law Commission in the 1990s,<xref rid=\"fwad017-FN20\" ref-type=\"fn\"><sup>20</sup></xref> we sought to examine how judges have been approaching interpersonal factors when considering the concept of capacity as now defined within the MCA 2005. In approaching this question empirically, we aimed to provide a <italic toggle=\"yes\">psychological</italic> account of these relational processes as they are referred to in court judgments. Our account focuses on ‘interpersonal influence’, defining ‘interpersonal influence problems’ as any action or characteristic of another person that was constructed in legal submissions to have potentially had a deleterious effect on P’s decision-making capacity. We excluded cases where interpersonal influence was only constructed as positive, as this would have required a more complex search and the literature on supporting capacity is relatively better developed.<xref rid=\"fwad017-FN21\" ref-type=\"fn\"><sup>21</sup></xref> We chose to focus on ‘interpersonal influence’ rather than ‘undue influence’ as this better enabled us to explore in detail how the courts considered the relational context to be operative on decision-making capacity.</p>", "<p>Relational factors considered by the courts are not always described as ‘undue influence’, especially in cases where it is likely from the outset that P (the subject of proceedings before the court) lacks capacity and, therefore, would not require intervention under the inherent jurisdiction. By avoiding this technical term, we sought to make our search sensitive to a wider range of relevant evidence, as well as a wider range of discussion from judges on decision-making capacity. Furthermore, ‘undue influence’ presupposes that the relational context is one of harmful intentions, when the relational context may be better described as one of high interpersonal pressure, regardless of intentions. We were also aware that the term ‘undue influence’ has developed a life of its own in contexts less relevant to our study; for instance, in relation to looking back after the event to determine whether a gift was made voluntarily.<xref rid=\"fwad017-FN22\" ref-type=\"fn\"><sup>22</sup></xref></p>", "<p>To investigate interpersonal influence problems, we undertook a review and qualitative content analysis of Court of Protection cases and other legal cases in England and Wales in which both interpersonal influence problems and decision-making capacity were considered, and in which a determination was reached as to the individual’s decision-making capacity.</p>", "<title>Ethics</title>", "<p>All data are in the public domain and therefore we did not require ethical approval. Data files are available on reasonable request to the corresponding author.</p>" ]	[ "<title>Acknowledgements</title>", "<p>We would like to thank Anthony David and Scott Kim for contributing to discussions which led to the development of this work. Scott Kim also helped to collect the original dataset which this article is based upon.</p>", "<title>Funding</title>", "<p>All authors are part of the Mental Health and Justice Project, led by G.O., which is funded by a grant from the Wellcome Trust (203376/2/16/Z). N.K. is also supported by a grant from Mental Health Research UK and the Schizophrenia Research Fund.</p>", "<p>\n<italic toggle=\"yes\">Conflict of interest statement</italic>. None declared.</p>" ]	[]	[ "<table-wrap position=\"float\" id=\"fwad017-T1\"><label>Table 1.</label><caption><p>Characteristics of each judgment in the final sample</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"1\" colspan=\"1\">Name of the case</th><th rowspan=\"1\" colspan=\"1\">Neutral citation</th><th rowspan=\"1\" colspan=\"1\">MM/YY</th><th rowspan=\"1\" colspan=\"1\">Type of decision(s)</th><th rowspan=\"1\" colspan=\"1\">Material impairment or disturbance of mind or brain</th><th rowspan=\"1\" colspan=\"1\">Outcome(s)</th><th rowspan=\"1\" colspan=\"1\">N<xref rid=\"tblfn1\" ref-type=\"table-fn\"><sup>a</sup></xref></th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">PCT v P, AH, & A Local Authority</italic> [2009]</td><td rowspan=\"1\" colspan=\"1\">COPLR Con Vol 956</td><td rowspan=\"1\" colspan=\"1\">12/09</td><td rowspan=\"1\" colspan=\"1\">Care, contact, general activities, treatment</td><td rowspan=\"1\" colspan=\"1\">Intellectual disability</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take all decisions</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">A Local Authority v Mrs A and Mr A</italic> [2010]</td><td rowspan=\"1\" colspan=\"1\">EWHC 1549 (Fam)</td><td rowspan=\"1\" colspan=\"1\">06/10</td><td rowspan=\"1\" colspan=\"1\">Contraception</td><td rowspan=\"1\" colspan=\"1\">Intellectual disability</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take the decision</td><td rowspan=\"1\" colspan=\"1\">5</td></tr><tr><td rowspan=\"2\" colspan=\"1\">\n<italic toggle=\"yes\">D v R (Deputy of S) and S</italic> [2010]</td><td rowspan=\"2\" colspan=\"1\">EWHC 2405 (COP)</td><td rowspan=\"2\" colspan=\"1\">07/10</td><td rowspan=\"2\" colspan=\"1\">Contact, contract, property/finances</td><td rowspan=\"2\" colspan=\"1\">Dementia</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity: property/finances</td><td rowspan=\"2\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Unclear otherwise</td></tr><tr><td rowspan=\"2\" colspan=\"1\">\n<italic toggle=\"yes\">PC v NC v City of York Council</italic> [2013]</td><td rowspan=\"2\" colspan=\"1\">EWCA Civ 478</td><td rowspan=\"2\" colspan=\"1\">05/13</td><td rowspan=\"1\" colspan=\"1\">Contact</td><td rowspan=\"2\" colspan=\"1\">Intellectual disability</td><td rowspan=\"2\" colspan=\"1\">Appeal upheld</td><td rowspan=\"2\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Resumption of married life</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">LBX v K, L and M</italic> [2013]</td><td rowspan=\"1\" colspan=\"1\">EWHC 3230 (Fam)</td><td rowspan=\"1\" colspan=\"1\">06/13</td><td rowspan=\"1\" colspan=\"1\">Care, contact, residence</td><td rowspan=\"1\" colspan=\"1\">Intellectual disability</td><td rowspan=\"1\" colspan=\"1\">Had capacity to take all decisions</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">A Local Authority v WMA</italic> [2013]</td><td rowspan=\"1\" colspan=\"1\">EWHC 2580 (COP)</td><td rowspan=\"1\" colspan=\"1\">07/13</td><td rowspan=\"1\" colspan=\"1\">Care, contact, residence</td><td rowspan=\"1\" colspan=\"1\">Autistic Spectrum Disorder</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take all decisions</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">London Borough of Redbridge v G & Ors</italic> [2014]</td><td rowspan=\"1\" colspan=\"1\">EWCOP 485</td><td rowspan=\"1\" colspan=\"1\">02/14</td><td rowspan=\"1\" colspan=\"1\">Contact, residence, property/finances</td><td rowspan=\"1\" colspan=\"1\">Dementia</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take all decisions</td><td rowspan=\"1\" colspan=\"1\">4</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">NCC v PB and TB</italic> [2014]</td><td rowspan=\"1\" colspan=\"1\">EWCOP 14</td><td rowspan=\"1\" colspan=\"1\">03/14</td><td rowspan=\"1\" colspan=\"1\">Care, contact, residence</td><td rowspan=\"1\" colspan=\"1\">Anxiety</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take all decisions</td><td rowspan=\"1\" colspan=\"1\">7</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Re MRJ (Reconsideration of Order) [2014]</td><td rowspan=\"1\" colspan=\"1\">EWCOP B15</td><td rowspan=\"1\" colspan=\"1\">04/14</td><td rowspan=\"1\" colspan=\"1\">Revoke a lasting power of attorney</td><td rowspan=\"1\" colspan=\"1\">Dementia</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take the decision</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"2\" colspan=\"1\">\n<italic toggle=\"yes\">Derbyshire County Council v AC</italic> [2014]</td><td rowspan=\"2\" colspan=\"1\">EWCOP 38</td><td rowspan=\"2\" colspan=\"1\">10/14</td><td rowspan=\"1\" colspan=\"1\">Care, contact, residence</td><td rowspan=\"2\" colspan=\"1\">Intellectual disability</td><td rowspan=\"1\" colspan=\"1\">Had capacity: sexual relations</td><td rowspan=\"2\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Sexual relations</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity: care, contact, residence</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Re A</italic> [2016]</td><td rowspan=\"1\" colspan=\"1\">EWCOP 3</td><td rowspan=\"1\" colspan=\"1\">01/16</td><td rowspan=\"1\" colspan=\"1\">Contracts, property/finances</td><td rowspan=\"1\" colspan=\"1\">Schizophrenia</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take all decisions</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"2\" colspan=\"1\">\n<italic toggle=\"yes\">Newcastle Upon Tyne City Council v TP</italic> [2016]</td><td rowspan=\"2\" colspan=\"1\">EWCOP B4</td><td rowspan=\"2\" colspan=\"1\">11/16</td><td rowspan=\"1\" colspan=\"1\">Care, property/</td><td rowspan=\"2\" colspan=\"1\">Intellectual disability</td><td rowspan=\"2\" colspan=\"1\">Lacked capacity to take all decisions</td><td rowspan=\"2\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Finances, residence, treatment</td></tr><tr><td rowspan=\"2\" colspan=\"1\">\n<italic toggle=\"yes\">London Borough of Brent v NB</italic> [2017]</td><td rowspan=\"2\" colspan=\"1\">EWCOP 34</td><td rowspan=\"2\" colspan=\"1\">10/17</td><td rowspan=\"2\" colspan=\"1\">Care, contact, general activities, treatment</td><td rowspan=\"2\" colspan=\"1\">Intellectual disability, brain injury</td><td rowspan=\"1\" colspan=\"1\">Had capacity: general activities, contact</td><td rowspan=\"2\" colspan=\"1\">5</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Lacked capacity: care</td></tr><tr><td rowspan=\"2\" colspan=\"1\">\n<italic toggle=\"yes\">Re B</italic> (Capacity: Social media: Care and Contact) [2019]</td><td rowspan=\"2\" colspan=\"1\">EWCOP 3</td><td rowspan=\"2\" colspan=\"1\">02/19</td><td rowspan=\"2\" colspan=\"1\">Care, contact, property/finances, residence, sexual relations, social media</td><td rowspan=\"2\" colspan=\"1\">Intellectual disability</td><td rowspan=\"1\" colspan=\"1\">Had capacity: residence</td><td rowspan=\"2\" colspan=\"1\">5</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Lacked capacity: care, contact, property/finances, sexual relations, social media</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Southend-On-Sea Borough Council v Meyers</italic> [2019]</td><td rowspan=\"1\" colspan=\"1\">EWHC 399 (Fam)</td><td rowspan=\"1\" colspan=\"1\">02/19</td><td rowspan=\"1\" colspan=\"1\">Residence</td><td rowspan=\"1\" colspan=\"1\">None reported</td><td rowspan=\"1\" colspan=\"1\">Had capacity to take the decision</td><td rowspan=\"1\" colspan=\"1\">4</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">London Borough of Hackney v SJF & Anor</italic> [2019]</td><td rowspan=\"1\" colspan=\"1\">EWCOP 8</td><td rowspan=\"1\" colspan=\"1\">03/19</td><td rowspan=\"1\" colspan=\"1\">Care, contact, contracts, residence, treatment</td><td rowspan=\"1\" colspan=\"1\">Intellectual disability</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take all decisions</td><td rowspan=\"1\" colspan=\"1\">4</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">B v A Local Authority</italic> [2019]</td><td rowspan=\"1\" colspan=\"1\">EWCA Civ 913</td><td rowspan=\"1\" colspan=\"1\">06/19</td><td rowspan=\"1\" colspan=\"1\">Care, contact, residence, sexual relations, social media</td><td rowspan=\"1\" colspan=\"1\">Intellectual disability</td><td rowspan=\"1\" colspan=\"1\">Appeal dismissed</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">University Hospitals Bristol NHS Trust v RR</italic> [2019]</td><td rowspan=\"1\" colspan=\"1\">EWCOP 46</td><td rowspan=\"1\" colspan=\"1\">08/19</td><td rowspan=\"1\" colspan=\"1\">Treatment</td><td rowspan=\"1\" colspan=\"1\">Emotionally unstable personality disorder, Asperger’s syndrome</td><td rowspan=\"1\" colspan=\"1\">Lacked capacity to take the decision</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">London Borough of Croydon v KR & Anor</italic> [2019]</td><td rowspan=\"1\" colspan=\"1\">EWHC 2498 (Fam)</td><td rowspan=\"1\" colspan=\"1\">09/19</td><td rowspan=\"1\" colspan=\"1\">Residence</td><td rowspan=\"1\" colspan=\"1\">Brain injury</td><td rowspan=\"1\" colspan=\"1\">Had capacity to take the decision</td><td rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">Redcar & Cleveland Borough Council v PR</italic> (No 2) [2019]</td><td rowspan=\"1\" colspan=\"1\">EWHC 2800 (Fam)</td><td rowspan=\"1\" colspan=\"1\">09/19</td><td rowspan=\"1\" colspan=\"1\">Contact, residence</td><td rowspan=\"1\" colspan=\"1\">None reported (previous ‘mental health difficulties’ acknowledged)</td><td rowspan=\"1\" colspan=\"1\">Capacity to take all decisions</td><td rowspan=\"1\" colspan=\"1\">3</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"fwad017-T2\"><label>Table 2.</label><caption><p>Outlining how the courts link interpersonal influence to the language of the functional abilities in the MCA (2005)</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/><col valign=\"top\" align=\"center\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"1\" colspan=\"1\">Functional ability</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">Inability to preserve independence and free will</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">Restricting P’s perspective</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">Valuing or dependence</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">Suggestibility</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">Denial of facts</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">Causative Nexus</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">No mechanism</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">Total (inc. duplicates)</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Understanding</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">4</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Retaining</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Use or Weigh</td><td rowspan=\"1\" colspan=\"1\">3</td><td rowspan=\"1\" colspan=\"1\">6</td><td rowspan=\"1\" colspan=\"1\">4</td><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">22</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Total (inc. duplicates)</td><td rowspan=\"1\" colspan=\"1\">3</td><td rowspan=\"1\" colspan=\"1\">8</td><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">3</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">6</td><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\"/></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[ "<disp-quote content-type=\"extract\"><p>there are other people who are not incapable of taking their own decisions, but are also especially vulnerable to abuse or neglect from which they are unable to protect themselves. Some machinery is needed to protect them and the existing procedures outlined in this review already do so to some extent. However, they are widely believed to be unsatisfactory for this purpose.<xref rid=\"fwad017-FN13\" ref-type=\"fn\"><sup>13</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>I was advised that AC has ‘difficulty in sustaining an independent view’ if she is exposed to an alternative view from someone who ‘is influential’ such as her mother, or boyfriend.<xref rid=\"fwad017-FN34\" ref-type=\"fn\"><sup>34</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>the enmeshed relationship that he has with AH which severely restricts his perspective in terms of being able to think about his future.<xref rid=\"fwad017-FN44\" ref-type=\"fn\"><sup>44</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>Perhaps I do place more importance or weight on ST’s wishes and feelings but I think this is only normal, as she is my wife. I want to have the choice to live my life as I want.<xref rid=\"fwad017-FN52\" ref-type=\"fn\"><sup>52</sup></xref></p><p>‘She fails the third test of capacity because her decision making processes are heavily influenced and distorted by her overwhelming sense of loyalty to JT and KT and her need to retain these important relationships for her’.<xref rid=\"fwad017-FN53\" ref-type=\"fn\"><sup>53</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>it is important to be careful to distinguish between the entirely natural and common influence that one close family member will have over another, and the “undue influence” or “coercion” identified in SA and DL.<xref rid=\"fwad017-FN56\" ref-type=\"fn\"><sup>56</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>her inability to understand the actions of others (for example, fellow patients who stole from her or induced her to pay more than the real value of items) and her extreme suggestibility (I believe that I could have induced her to make over all her assets to me in return for helping her to meet with a celebrity), I consider that A is extremely vulnerable to exploitation and abuse.<xref rid=\"fwad017-FN63\" ref-type=\"fn\"><sup>63</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>she has shown herself to be unable to accept the fact of Mr C’s convictions (she has been told by five different professionals on seven separate occasions about these), and has been repeatedly dismissive of attempts to ‘educate’ her as to the convictions and their implications.<xref rid=\"fwad017-FN70\" ref-type=\"fn\"><sup>70</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>I agree that PB lacks capacity in certain situations, for example because of anxiety, mental disorder or influence. I don’t know if she has capacity in optimal circumstances, but I have not seen sufficient evidence that she lacks capacity then.<xref rid=\"fwad017-FN78\" ref-type=\"fn\"><sup>78</sup></xref></p><p>But also (and ‘in dynamic interaction’) so do emotional factors. Thus her capacity to weigh information: “… is further impeded by her ambivalence (mixed feelings, ‘confusion’) about her husband and the pressure he seems to place on her to have a family. The latter [pressure] is contributed to (a) by Mrs A’s personal characteristics, associated with both her learning disability and her personality, such as her eagerness to please, her suggestibility and her tendency to acquiescence and (b) by Mr A’s personal characteristics, including a suspicious and hostile stance in relation to support services, leading to his giving Mrs A mixed messages about what is in her interests, thereby ‘confusing her’ more and therefore incapacitating her further.<xref rid=\"fwad017-FN79\" ref-type=\"fn\"><sup>79</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>I am satisfied that influence is a factor, but I share the view of Dr. Rippon that it is not actually operative on her decision making and is in any event not more significant than the clearer evidence about impairment of the mind.<xref rid=\"fwad017-FN98\" ref-type=\"fn\"><sup>98</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>do[es] not suggest that there can be no other cause of P’s inability to make decisions besides mental impairment; we do not think that those words indicate that the MCA was intended to exclude situations in which the inability to decide was caused by both mental impairment and P’s actual circumstances.<xref rid=\"fwad017-FN121\" ref-type=\"fn\"><sup>121</sup></xref></p></disp-quote>" ]	[]	[]	[ "<table-wrap-foot><fn id=\"tblfn1\"><label>a</label><p>N is the number of statements that were coded to any category of interpersonal influence.</p></fn></table-wrap-foot>", "<fn-group><title>Footnotes</title><fn id=\"fwad017-FN1\"><label>1</label><p>T Grisso and PS Appelbaum, <italic toggle=\"yes\">Assessing Competence to Consent to Treatment: A Guide for Physicians and Other Health Professionals</italic>’ (OUP 1998) 131.</p></fn><fn id=\"fwad017-FN2\"><label>2</label><p>T Grisso and PS Applebaum, ‘Thinking about Competence’ (2003) 4 Crime: Critical Concepts in Sociology 25.</p></fn><fn id=\"fwad017-FN3\"><label>3</label><p>Mental Capacity Act 2005, s 3. Also, note that with the exception of the communication criteria, these reflect criteria originally endorsed at common law by the High Court, at that point exercising its inherent jurisdiction in <italic toggle=\"yes\">Re C (Refusal of Medical Treatment)</italic> [1994] 1 WLR 290. For a review of the history of the MCA 2005, see A Ruck Keene and others ‘Taking Capacity Seriously? Ten Years of Mental Capacity Disputes before England’s Court of Protection’ (2019) 62 International Journal of Law and Psychiatry 56.</p></fn><fn id=\"fwad017-FN4\"><label>4</label><p>See <italic toggle=\"yes\">PC v NC v City of York Council</italic> [2013] EWCA Civ 478 and, more recently (after the period covered by our review), in the Supreme Court judgment <italic toggle=\"yes\">Re JB</italic> [2021] UKSC 52, [78].</p></fn><fn id=\"fwad017-FN5\"><label>5</label><p>ibid [58].</p></fn><fn id=\"fwad017-FN6\"><label>6</label><p>ibid.</p></fn><fn id=\"fwad017-FN7\"><label>7</label><p>Law Commission, <italic toggle=\"yes\">Mentally Incapacitated and Other Vulnerable Adults: Public Law Protection</italic> (Law Comm No 130, 1993) <<ext-link xlink:href=\"https://www.lawcom.gov.uk/document/mentally-incapacitated-and-other-vulnerable-adults-public-law-protection/\" ext-link-type=\"uri\">https://www.lawcom.gov.uk/document/mentally-incapacitated-and-other-vulnerable-adults-public-law-protection/</ext-link>> accessed 29 April 2022, paras 2.18–2.19.</p></fn><fn id=\"fwad017-FN8\"><label>8</label><p>C Kong, ‘<italic toggle=\"yes\">Mental Capacity in Relationship: Decision-making, Dialogue, and Autonomy</italic>’ (CUP 2017) 3.</p></fn><fn id=\"fwad017-FN9\"><label>9</label><p>For a review of cogntive research on social influence, see W Wood and others, ‘Minority Influence: A Meta-analytic Review of Social Influence Processes’ (1994) 115 Psychological Bulletin 323.</p></fn><fn id=\"fwad017-FN10\"><label>10</label><p>See eg, U Toelch and RJ Dolan, <italic toggle=\"yes\">‘</italic>Informational and Normative Influences in Conformity from a Neurocomputational Perspective’ (2015) 19 Trends in Cognitive Sciences 579; E van der Plas and others, ‘Advice-taking as a Bridge between Decision Neuroscience and Mental Capacity’ (2019) 67 International Journal of Law and Psychiatry e101504.</p></fn><fn id=\"fwad017-FN11\"><label>11</label><p>See the Safeguarding Vulnerable Groups Act 2006, s 59, for the statutory definition of a vulnerable adult.</p></fn><fn id=\"fwad017-FN12\"><label>12</label><p>For similar critiques of whether relational issues should be framed as a ‘mental capacity’ issue, see eg, B Clough ‘What about Us? A Case for Legal Recognition of Interdependence in Informal Care Relationships’ (2015) 36 Journal of Social Welfare and Family Law 128; L Series ‘Relationships, Autonomy and Legal Capacity: Mental Capacity and Support Paradigms’ (2015) 40 International Journal of Law and Psychiatry 81.</p></fn><fn id=\"fwad017-FN13\"><label>13</label><p>Law Commission (n 7), para 1.6.</p></fn><fn id=\"fwad017-FN14\"><label>14</label><p>See <italic toggle=\"yes\">Re F (Mental Patient: Sterilisation)</italic> [1990] 2 AC 1, 13.</p></fn><fn id=\"fwad017-FN15\"><label>15</label><p>See <italic toggle=\"yes\">Re SA (Vulnerable adult with capacity: marriage)</italic> [2005] EWHC 2942 (Fam). The fact that the jurisdiction could be used in relation to both categories of individual—or even the same individual at different points—is illustrated by <italic toggle=\"yes\">Re G</italic> [2004] EWHC 2222. It also meant that there may not have been the same analytic clarity as to which category the person fell into. It is difficult, for instance, to be clear whether Ms T, in <italic toggle=\"yes\">Re T</italic> [1992] EWCA Civ 18, would be seen now as having or lacking the capacity to decide to accept or refuse the blood transfusion she required, as it was not necessary for the courts to disentangle the relative influence of the impact of the accident she had been in and the influence of her mother.</p></fn><fn id=\"fwad017-FN16\"><label>16</label><p>In addition to the above, see D Lock ‘Decision-making, Mental Capacity and Undue Influence’ (2015) 20 Judicial Review 1 for a more detailed overview of the pre- and post-MCA 2005 case law around the undue influence and the inherent jurisdiction.</p></fn><fn id=\"fwad017-FN17\"><label>17</label><p>See <italic toggle=\"yes\">DL v A Local Authority & Ors</italic> [2012] EWCA Civ 253.</p></fn><fn id=\"fwad017-FN18\"><label>18</label><p>It is beyond the scope of this article to provide a full summary of research on the high court’s inherent jurisdiction, but some relevant critiques of its use in undue influence cases include: MC Dunn and others, ‘To Empower or to Protect? Constructing the ‘Vulnerable Adult’ in English Law and Public Policy’ (2008) 28 Legal Studies 234; Ruck Keene and others (n 3); J Lewis, ‘Safeguarding Vulnerable Autonomy? Situational Vulnerability, the Inherent Jurisdiction, and Insights from Feminist Philosophy’ (2021) 29 Medical Law Review 306; P Skowron, ‘The Relationship between Autonomy and Adult Mental Capacity in the Law of England and Wales’ (2018) 27 Medical Law Review 32; J Craigie, ‘Conceptualising ‘Undue Influence’ in Decision-making Support for People with Mental Disabilities’ (2021) 29 Medical Law Review 48.</p></fn><fn id=\"fwad017-FN19\"><label>19</label><p>This has motivated the development of practical guidance, including: 39 Essex Chambers, ‘Using the Inhererent Jurisdiction in relation to adults’ (Guidance Notes, 9 November 2020). <<ext-link xlink:href=\"https://www.39essex.com/mental-capacity-guidance-note-inherent-jurisdiction/\" ext-link-type=\"uri\">https://www.39essex.com/mental-capacity-guidance-note-inherent-jurisdiction/</ext-link>> accessed 29 April 2022.</p></fn><fn id=\"fwad017-FN20\"><label>20</label><p>Although the recommendation was taken up in other jurisdictions, see, for instance, the Vulnerable Adults Act 2018 passed in Singapore, a jurisdiction which also has a Mental Capacity Act directly modelled on the MCA 2005.</p></fn><fn id=\"fwad017-FN21\"><label>21</label><p>There are numerous examples of research focusing explicitly on supporting capacity, including P Webb and others ‘Key Components of Supporting and Assessing Decision Making Ability’ (2020) 72 International Journal of Law and Psychiatry e101613; N Stanley and J Manthorpe, ‘Small Acts of Care: Exploring the Potential Impact of the Mental Capacity Act 2005 on Day-to-day Support’ (2009) 8 Social Policy and Society 37; Series (n 12).</p></fn><fn id=\"fwad017-FN22\"><label>22</label><p>See eg, <italic toggle=\"yes\">Evans & Ors v Lloyd & Anor</italic> [2013] EWHC 1725.</p></fn><fn id=\"fwad017-FN23\"><label>23</label><p>Ruck Keene and others (n 3).</p></fn><fn id=\"fwad017-FN24\"><label>24</label><p>Examples of cases thereby excluded are <italic toggle=\"yes\">The London Borough of Wandsworth v M & Ors</italic> [2017] EWHC 2435 (Fam) and <italic toggle=\"yes\">London Borough of Southwark v NP & Ors</italic> [2019] EWCOP 48, both decisions relating to 17-year-olds.</p></fn><fn id=\"fwad017-FN25\"><label>25</label><p>For a step-by-step overview of content analysis, see M Schreier, <italic toggle=\"yes\">Qualitative Content Analysis in Practice</italic> (Sage 2012) 41. For a more recent overview, including software and research examples, see P Mayring, <italic toggle=\"yes\">Qualitative Content Analysis: A Step-by-Step Guide</italic> (Sage 2021).</p></fn><fn id=\"fwad017-FN26\"><label>26</label><p>For a discussion regarding the benefits of content analysis for legal scholarship, see both RF Wright and MA Hall, <italic toggle=\"yes\">‘</italic>Systematic Content Analysis of Judicial Opinions’ (2008) 96 California Law Review 63; N Kane and others ‘Applying Decision-making Capacity Criteria in Practice: A Content Analysis of Court Judgments’ (2021) 16 Plos One e0246521</p></fn><fn id=\"fwad017-FN27\"><label>27</label><p>AP Kirilenko and S Stepchenkova, ‘Inter-coder Agreement in One-to-many Classification: Fuzzy Kappa’ (2016) 11 PloS One e0149787.</p></fn><fn id=\"fwad017-FN28\"><label>28</label><p>MCA 2005, ss 2 and 3.</p></fn><fn id=\"fwad017-FN29\"><label>29</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4).</p></fn><fn id=\"fwad017-FN30\"><label>30</label><p>An example of a ‘mild’ learning disability case is <italic toggle=\"yes\">London Borough of Hackney v SJF & Anor</italic> [2019] EWCOP 8, [6].</p></fn><fn id=\"fwad017-FN31\"><label>31</label><p>An example of a ‘moderate’ learning disability case is <italic toggle=\"yes\">A Local Authority v Mrs A and Mr A</italic> [2010] EWHC 1549 (Fam), [7].</p></fn><fn id=\"fwad017-FN32\"><label>32</label><p>In one case, P was considered to have been a vulnerable adult because of their unspecified mental health problem (<italic toggle=\"yes\">Redcar & Cleveland Borough Council v PR (No 2)</italic> [2019] EWHC 2305 (Fam)) and in the other, because of their physical health problems (<italic toggle=\"yes\">Southend-On-Sea Borough Council v Meyers</italic> [2019] EWHC 399 (Fam)).</p></fn><fn id=\"fwad017-FN33\"><label>33</label><p>Note that the remaining 12 references (from nine cases) did not point to a specific mechanism that was clearly classifiable.</p></fn><fn id=\"fwad017-FN34\"><label>34</label><p>\n<italic toggle=\"yes\">Derbyshire County Council v AC</italic> [2014] EWCOP 38, [44], <italic toggle=\"yes\">per</italic> Cobb J.</p></fn><fn id=\"fwad017-FN35\"><label>35</label><p>ibid.</p></fn><fn id=\"fwad017-FN36\"><label>36</label><p>ibid [8].</p></fn><fn id=\"fwad017-FN37\"><label>37</label><p>A term which broadly refers to complex mental processes that are necessary for goal-directed behaviour, such as attention, working memory, organization, and problem solving.</p></fn><fn id=\"fwad017-FN38\"><label>38</label><p>ibid [17].</p></fn><fn id=\"fwad017-FN39\"><label>39</label><p>ibid [44].</p></fn><fn id=\"fwad017-FN40\"><label>40</label><p>\n<italic toggle=\"yes\">Southend-On-Sea Borough Council v Meyers</italic> (n 32).</p></fn><fn id=\"fwad017-FN41\"><label>41</label><p>ibid [38].</p></fn><fn id=\"fwad017-FN42\"><label>42</label><p>ibid [40].</p></fn><fn id=\"fwad017-FN43\"><label>43</label><p>ibid [41].</p></fn><fn id=\"fwad017-FN44\"><label>44</label><p>\n<italic toggle=\"yes\">PCT v P, AH, & A Local Authority</italic> [2009] COPLR Con Vol 956, [37] <italic toggle=\"yes\">per</italic> Hedley J.</p></fn><fn id=\"fwad017-FN45\"><label>45</label><p>ibid.</p></fn><fn id=\"fwad017-FN46\"><label>46</label><p>ibid [37].</p></fn><fn id=\"fwad017-FN47\"><label>47</label><p>ibid.</p></fn><fn id=\"fwad017-FN48\"><label>48</label><p>\n<italic toggle=\"yes\">London Borough of Redbridge v G & Ors</italic> [2014] EWCOP 485.</p></fn><fn id=\"fwad017-FN49\"><label>49</label><p>See also ‘valuing or being dependent on the relationship’ below.</p></fn><fn id=\"fwad017-FN50\"><label>50</label><p>\n<italic toggle=\"yes\">PCT v P</italic> (46), [54], [79], <italic toggle=\"yes\">per</italic> Russell J.</p></fn><fn id=\"fwad017-FN51\"><label>51</label><p>Series (n 12) argued that <italic toggle=\"yes\">London Borough of Redbridge v G</italic> (n 48) was ‘as evidence that the courts treat mental capacity as being partially constituted by freedom from oppressive relationships’. She regarded this aim as a source of instability for judges, as it does not neatly fit into the idea of individual rationality. See Section IV.D.2, where we elaborate on how the courts constructed influence when referring to the causative nexus in our sample.</p></fn><fn id=\"fwad017-FN52\"><label>52</label><p>\n<italic toggle=\"yes\">London Borough of Croydon v KR & Anor</italic> [2019] EWHC 2498 (Fam), [26], <italic toggle=\"yes\">per</italic> KR.</p></fn><fn id=\"fwad017-FN53\"><label>53</label><p>\n<italic toggle=\"yes\">Re MRJ (Reconsideration of Order)</italic> [2014] EWCOP B15, [46] per Lush J.</p></fn><fn id=\"fwad017-FN54\"><label>54</label><p>\n<italic toggle=\"yes\">London Borough of Croydon v KR & Anor</italic> (n 52).</p></fn><fn id=\"fwad017-FN55\"><label>55</label><p>ibid [26].</p></fn><fn id=\"fwad017-FN56\"><label>56</label><p>ibid [60], referring to the cases in which the High Court’s inherent jurisdiction was developed and confirmed.</p></fn><fn id=\"fwad017-FN57\"><label>57</label><p>\n<italic toggle=\"yes\">London Borough of Hackney v SJF & Anor</italic> [2019] EWCOP 8.</p></fn><fn id=\"fwad017-FN58\"><label>58</label><p>ibid [60].</p></fn><fn id=\"fwad017-FN59\"><label>59</label><p>\n<italic toggle=\"yes\">Re MRJ (Reconsideration of Order)</italic> [2014] EWCOP B15.</p></fn><fn id=\"fwad017-FN60\"><label>60</label><p>ibid [46].</p></fn><fn id=\"fwad017-FN61\"><label>61</label><p>\n<italic toggle=\"yes\">A Local Authority v WMA</italic> [2013] EWHC 2580 (COP).</p></fn><fn id=\"fwad017-FN62\"><label>62</label><p>ibid [4].</p></fn><fn id=\"fwad017-FN63\"><label>63</label><p>Consultant Psychiatrist; <italic toggle=\"yes\">Re A</italic> [2016] EWCOP 3, para 20.</p></fn><fn id=\"fwad017-FN64\"><label>64</label><p>This framing has potentially wide-reaching implications around the idea of inherent vulnerability, which we briefly discuss in Section IV.A.</p></fn><fn id=\"fwad017-FN65\"><label>65</label><p>ibid.</p></fn><fn id=\"fwad017-FN66\"><label>66</label><p>ibid [20].</p></fn><fn id=\"fwad017-FN67\"><label>67</label><p>\n<italic toggle=\"yes\">London Borough of Brent v NB</italic> [2017] EWCOP 34.</p></fn><fn id=\"fwad017-FN68\"><label>68</label><p>ibid [51], [70]–[75], as examples.</p></fn><fn id=\"fwad017-FN69\"><label>69</label><p>ibid [72]. See Section IV.D.3 below, For a discussion on the causative nexus in relation to MB.</p></fn><fn id=\"fwad017-FN70\"><label>70</label><p>\n<italic toggle=\"yes\">B v A Local Authority</italic> [2019] EWCA Civ 913, [33], <italic toggle=\"yes\">per</italic> Cobb J.</p></fn><fn id=\"fwad017-FN71\"><label>71</label><p>ibid; <italic toggle=\"yes\">Re B (Capacity: Social Media: Care and Contact)</italic> [2019] EWCOP 3.</p></fn><fn id=\"fwad017-FN72\"><label>72</label><p>As per <italic toggle=\"yes\">LBX v K, L and M</italic> [2013] EWHC 3230 (Fam), [45] <italic toggle=\"yes\">per</italic> Theis J.</p></fn><fn id=\"fwad017-FN73\"><label>73</label><p>See n 71, [25].</p></fn><fn id=\"fwad017-FN74\"><label>74</label><p>We elaborate on the degree to which judges have been loyal to the causative nexus in Section IV.D below.</p></fn><fn id=\"fwad017-FN75\"><label>75</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4).</p></fn><fn id=\"fwad017-FN76\"><label>76</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4), [7].</p></fn><fn id=\"fwad017-FN77\"><label>77</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4), [8]. Quoted from <italic toggle=\"yes\">CYC v PC and NC</italic> [2012] MHLO 103 (COP), [12].</p></fn><fn id=\"fwad017-FN78\"><label>78</label><p>\n<italic toggle=\"yes\">NCC v PB and TB</italic> [2014] EWCOP 14, [67], <italic toggle=\"yes\">per</italic> Consultant Psychiatrist.</p></fn><fn id=\"fwad017-FN79\"><label>79</label><p>\n<italic toggle=\"yes\">A Local Authority v Mrs A and Mr A</italic> (n 31) <italic toggle=\"yes\">per</italic> Bodey J quoting Dr K.</p></fn><fn id=\"fwad017-FN80\"><label>80</label><p>Note that the term ‘causative nexus’ was only developed by the CoA in 2013 in <italic toggle=\"yes\">PC v NC</italic> (n 4).</p></fn><fn id=\"fwad017-FN81\"><label>81</label><p>See n 31.</p></fn><fn id=\"fwad017-FN82\"><label>82</label><p>ibid [51].</p></fn><fn id=\"fwad017-FN83\"><label>83</label><p>ibid [73].</p></fn><fn id=\"fwad017-FN84\"><label>84</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4).</p></fn><fn id=\"fwad017-FN85\"><label>85</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4).</p></fn><fn id=\"fwad017-FN86\"><label>86</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4), [58].</p></fn><fn id=\"fwad017-FN87\"><label>87</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4). Also see Lock (n 16) for an overview of these landmark cases, as well as pre-MCA 2005 case law.</p></fn><fn id=\"fwad017-FN88\"><label>88</label><p>See n 79.</p></fn><fn id=\"fwad017-FN89\"><label>89</label><p>ibid [63], [67], [69].</p></fn><fn id=\"fwad017-FN90\"><label>90</label><p>ibid [69].</p></fn><fn id=\"fwad017-FN91\"><label>91</label><p>ibid [92].</p></fn><fn id=\"fwad017-FN92\"><label>92</label><p>(n 48).</p></fn><fn id=\"fwad017-FN93\"><label>93</label><p>ibid [76]–[81].</p></fn><fn id=\"fwad017-FN94\"><label>94</label><p>Authors of other CoP reviews, such as Mary Donnelly, Paula Case and Jaime Lindsey, have expressed concerns over court deference to evidence from medical professionals over other professions: See M Donnelly, ‘Capacity Assessment under the Mental Capacity Act 2005: Delivering on the Functional Approach?’ (2009) 29 Legal Studies 464; P Case, ‘Negotiating the Domain of Mental Capacity: Clinical Judgement or Judicial Diagnosis?’ (2016) 16 Medical Law International 174; J Lindsey, ‘Competing Professional Knowledge Claims about Mental Capacity in the Court of Protection’ (2010) 28 Medical Law Review 1. Lindsey, for example, has argued that there is an implicit ‘hierarchy of professional evidence’ in capacity cases, favouring the perceived ‘objective’ expertise of psychiatrists over the ‘experiential’ social workers. In our analysis, G’s case highlights how such perceptions of expertise may affect which constructions of interpersonal influence are accepted by the courts.</p></fn><fn id=\"fwad017-FN95\"><label>95</label><p>In Section V.C below, we elaborate on the boundary issues between the MCA 2005 and the high court’s inherent jurisdiction in the context of capacity and relationships.</p></fn><fn id=\"fwad017-FN96\"><label>96</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4), [58].</p></fn><fn id=\"fwad017-FN97\"><label>97</label><p>See n 72.</p></fn><fn id=\"fwad017-FN98\"><label>98</label><p>ibid [19].</p></fn><fn id=\"fwad017-FN99\"><label>99</label><p>See n 79.</p></fn><fn id=\"fwad017-FN100\"><label>100</label><p>\n<italic toggle=\"yes\">Newcastle Upon Tyne City Council v TP</italic> [2016] EWCOP B4.</p></fn><fn id=\"fwad017-FN101\"><label>101</label><p>ibid [32].</p></fn><fn id=\"fwad017-FN102\"><label>102</label><p>ibid [37].</p></fn><fn id=\"fwad017-FN103\"><label>103</label><p>See relevant references to ‘suggestibility’ in Section IV.B.4 above.</p></fn><fn id=\"fwad017-FN104\"><label>104</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4), [58]. See Section IV.B.5. above for the background.</p></fn><fn id=\"fwad017-FN105\"><label>105</label><p>\n<italic toggle=\"yes\">PC v NC</italic> (n 4).</p></fn><fn id=\"fwad017-FN106\"><label>106</label><p>ibid [75].</p></fn><fn id=\"fwad017-FN107\"><label>107</label><p>Craigie (n 18), [70] cited the rulings in both <italic toggle=\"yes\">London Borough of Redbridge v G</italic> (n 48) and <italic toggle=\"yes\">London Borough of Brent v NB</italic> (n 68) as evidence of ‘fundamental ambivalence’ in the law, regarding how ‘the influence of others can impact on mental capacity’. One noteworthy difference is that, in the latter case, the psychologist’s evidence on influence delayed the judge’s decision on the causative nexus, whereas the social worker’s evidence did not. Perhaps, this indicates some desire for a more pragmatic approach to dealing with influence in a capacity context.</p></fn><fn id=\"fwad017-FN108\"><label>108</label><p>See n 3.</p></fn><fn id=\"fwad017-FN109\"><label>109</label><p>For an overview of the literature, including these arguments, see Series (n 12).</p></fn><fn id=\"fwad017-FN110\"><label>110</label><p>Note that a person cannot be found to lack capacity solely on the basis of an unwise decision under s 1(4) of the MCA 2005 (n 3).</p></fn><fn id=\"fwad017-FN111\"><label>111</label><p>See n 49.</p></fn><fn id=\"fwad017-FN112\"><label>112</label><p>\n<italic toggle=\"yes\">London Borough of Redbridge v G</italic> (n 48).</p></fn><fn id=\"fwad017-FN113\"><label>113</label><p>Dunn and others (n 18), offer an especially relevant analysis of how accounts of situational and inherent vulnerability have been used to justify interventions under the inherent jurisdiction, in cases shortly before the implementation of the MCA 2005. In their analysis of both <italic toggle=\"yes\">Re SA</italic> and <italic toggle=\"yes\">Re G</italic>, the court constructed P’s inherent vulnerability as automatically increasing the risk of circumstances in which P would be subject to malign intentions or influence. They concluded that narratives of inherent vulnerability risk ‘reawakening the ghost’ of a status-based approach to capacity [244].</p></fn><fn id=\"fwad017-FN114\"><label>114</label><p>\n<italic toggle=\"yes\">Re A</italic> (n 63), [20].</p></fn><fn id=\"fwad017-FN115\"><label>115</label><p>Lindsey’s review of CoP judgments and case files also found several references to P’s inherent vulnerability. She argued that such narratives contribute to a culture in which P is often excluded or limited from participating during proceedings: J Lindsey, ‘Testimonial Injustice and Vulnerability: A Qualitative Analysis of Participation in the Court of Protection’ (2018) 28 Social & Legal Studies 4.</p></fn><fn id=\"fwad017-FN116\"><label>116</label><p>Some cases focused on best interests may also be of note, as these were not in scope for the present study. For example, in <italic toggle=\"yes\">ADS v DSM</italic> [2017] EWCOP 8, [37], Charles J was critical of the best interests process which had not, in his view, given ‘consideration’ to the ‘possibility’ that P was ‘vulnerable to influence’ from others, or how influence might need to be ‘minimised’ to obtain P’s authentic will and preference.</p></fn><fn id=\"fwad017-FN117\"><label>117</label><p>See n 31, [51], <italic toggle=\"yes\">per</italic> Bodey J.</p></fn><fn id=\"fwad017-FN118\"><label>118</label><p>This might have been because this case was heard relatively early in the life of the CoP, at a time when at least some judges might still have been more familiar with the position pre-MCA 2005 when, as discussed in Section IV.D.1, they would not have had to identify which was the operative mechanism in determining whether to grant relief under the inherent jurisdiction.</p></fn><fn id=\"fwad017-FN119\"><label>119</label><p>See n 4.</p></fn><fn id=\"fwad017-FN120\"><label>120</label><p>\n<italic toggle=\"yes\">Re BKR</italic> [2015] SGCA 26.</p></fn><fn id=\"fwad017-FN121\"><label>121</label><p>ibid [87].</p></fn><fn id=\"fwad017-FN122\"><label>122</label><p>Donnelly (n 94) 145 has argued that treating undue influence as a mental capacity issue risks leading the courts to find a person to lack capacity simply based on the behaviour of third parties, thereby shifting the focus away from the real cause of the problem that could potentially be alleviated.</p></fn><fn id=\"fwad017-FN123\"><label>123</label><p>Both of these tests, for care arrangement and contact decisions, were specified by Theis J in <italic toggle=\"yes\">LBX v K & Ors</italic> (n 72).</p></fn><fn id=\"fwad017-FN124\"><label>124</label><p>See eg, CD Frith and U Frith, ‘Mechanisms of Social Cognition’ (2012) 63 Annual Review of Psychology 287; U Frith and CD Frith ‘Development and Neurophysiology of Mentalizing’ (2003) 358 Philosophical Transactions of the Royal Society of London Series B: Biological Sciences 459.</p></fn><fn id=\"fwad017-FN125\"><label>125</label><p>I Leudar and others, ‘Theory of Mind: A Critical Assessment’ (2004) 14 Theory & Psychology 571.</p></fn><fn id=\"fwad017-FN126\"><label>126</label><p>As shown in Section IV.D.3 above, <italic toggle=\"yes\">London Borough of Brent v NB</italic> (n 68) provides a useful example of a case in which a judge regarded mitigating influence as a practicable step to supporting capacity. See <italic toggle=\"yes\">London Borough of Hackney v SJF</italic> (n 30) [19] for another example.</p></fn><fn id=\"fwad017-FN127\"><label>127</label><p>As Lock notes (n 16), the role of P in influence cases has changed over time. Many pre-MCA 2005 cases invoking the inherent jurisdiction were brought forward by P, seeking to overturn their earlier decisions, rather than by third parties. More recently, public bodies have sought such orders to overturn P’s capacitous decisions, while P may actively defend their initial decision. This could be attributed, in part, to the broad criteria outlined in <italic toggle=\"yes\">Re SA</italic> (n 15).</p></fn><fn id=\"fwad017-FN128\"><label>128</label><p>This echoes a point made, by Margaret Isabel Hall, that a capacity assessment might be triggered by concerns about vulnerability, as opposed to only capacity per se: M Hall, ‘Mental Capacity in the (Civil) Law: Capacity, Autonomy, and Vulnerability’ (2012) 58 McGill Law Journal 61, 70.</p></fn><fn id=\"fwad017-FN129\"><label>129</label><p>For example, Dunn and others (n 18) have argued that recent abuse scandals in intellectual disability services have strengthened the drive, from health and social care services, to protect vulnerable adults using the inherent jurisdiction. Lock (n 16) has also speculated that local authorities could face more damages claims for failing to use such discretionary powers to protect vulnerable adults from abuse, as similar to cases of children with abusive parents.</p></fn><fn id=\"fwad017-FN130\"><label>130</label><p>Mental Capacity Act 2005 (n 3), s 1(3).</p></fn><fn id=\"fwad017-FN131\"><label>131</label><p>See n 126.</p></fn><fn id=\"fwad017-FN132\"><label>132</label><p>See <italic toggle=\"yes\">Derbyshire County Council v AC</italic> (n 34), [.</p></fn><fn id=\"fwad017-FN133\"><label>133</label><p>L Series and others, <italic toggle=\"yes\">Welfare Cases in the Court of Protection: A Statistical Overview</italic> (September 2017) <<ext-link xlink:href=\"https://orca.cardiff.ac.uk/118054/1/Series%20Fennell%20Doughty%202017%20Statistical%20overview%20of%20CoP.pdf\" ext-link-type=\"uri\">https://orca.cardiff.ac.uk/118054/1/Series%20Fennell%20Doughty%202017%20Statistical%20overview%20of%20CoP.pdf</ext-link>> 43, accessed 29 April 2022.</p></fn><fn id=\"fwad017-FN134\"><label>134</label><p>See n 3.</p></fn><fn id=\"fwad017-FN135\"><label>135</label><p>K Ariyo and others, ‘Experiences of Assessing Mental Capacity in England and Wales: A Large-scale Survey of Professionals’ (2021) 6 Wellcome Open Research 144.</p></fn><fn id=\"fwad017-FN136\"><label>136</label><p>National Institute for Health and Care Excellence (NICE), ‘Decision-making and Mental Capacity’ (NICE, 2018) <<ext-link xlink:href=\"https://www.nice.org.uk/guidance/ng108\" ext-link-type=\"uri\">https://www.nice.org.uk/guidance/ng108</ext-link>> paras 1.2.1, 1.2.4, 1.2.11, and 1.4, accessed 29 April 2022.</p></fn><fn id=\"fwad017-FN137\"><label>137</label><p>British Psychological Society (BPS), ‘What Makes a Good Assessment of Capacity<italic toggle=\"yes\">?</italic> (BPS, 2019) <<ext-link xlink:href=\"https://www.bps.org.uk/sites/www.bps.org.uk/files/Policy/Policy%20-%20Files/What%20makes%20a%20good%20assessment%20of%20capacity.pdf\" ext-link-type=\"uri\">https://www.bps.org.uk/sites/www.bps.org.uk/files/Policy/Policy%20-%20Files/What%20makes%20a%20good%20assessment%20of%20capacity.pdf</ext-link>> 30, accessed 29 April 2022.</p></fn><fn id=\"fwad017-FN138\"><label>138</label><p>Social Care Institute for Excellence (SCIE), ‘Gaining Access to an Adult Suspected to Be at Risk of Neglect or Abuse: A Guide for Social Workers and their Managers in England’ (SCIE, 2014) <<ext-link xlink:href=\"https://www.scie.org.uk/safeguarding/adults/practice/gaining-access\" ext-link-type=\"uri\">https://www.scie.org.uk/safeguarding/adults/practice/gaining-access</ext-link>> accessed 29 April 2022.</p></fn><fn id=\"fwad017-FN139\"><label>139</label><p>Note that the latest draft of the revised MCA 2005 Code of Practice advises professionals to go down the capacity route as long as the impairment can be demonstrated as ‘a cause’ of the inability, and uses the more specific term ‘real reason’ for influence. Compared to the status quo, this might be argued to more firmly discourage use of the inherent jurisdiction until the capacity question is exhausted—why? See Office of the Public Guardian, ‘<italic toggle=\"yes\">Mental Capacity Act 2005 Code of Practice Including the Liberty Protection Safeguards</italic> [draft]’ (Department for Health and Social Care 2022) <<ext-link xlink:href=\"https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1061499/draft-code-of-practice.pdf\" ext-link-type=\"uri\">https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1061499/draft-code-of-practice.pdf</ext-link>> paras 4.48–4.50, accessed 29 April 2022.</p></fn><fn id=\"fwad017-FN140\"><label>140</label><p>Law Commission (n 7), paras 2.18–2.19.</p></fn><fn id=\"fwad017-FN141\"><label>141</label><p>C Kong and A Ruck Keene, <italic toggle=\"yes\">Overcoming Challenges in the Mental Capacity Act 2005: Practical Guidance for Working with Complex Issues</italic> (Jessica Kingsley Publishers 2018) 140.</p></fn><fn id=\"fwad017-FN142\"><label>142</label><p>Law Commission (n 7), para 2.19.</p></fn><fn id=\"fwad017-FN143\"><label>143</label><p>Arguments in favour of this ‘safety net’ for vulnerable adults include those advanced by McFarlane LJ in <italic toggle=\"yes\">DL v A Local Authority</italic> (n 17), [53], as well as those made by Clough (n 12) and J Herring and J Wall, ‘Autonomy, Capacity and Vulnerable Adults: Filling the Gaps in the Mental Capacity Act’ (2015) 35 Legal Studies 698. Laura Pritchard-Jones has also tentatively argued that the inherent jurisdiction might be better suited than capacity law to promote autonomy in older adults, if implemented alongside effective advocacy and supported decision-making systems: L Pritchard-Jones ‘Ageism and Autonomy in Health Care: Explorations Through a Relational Lens’ (2017) 25 Health Care Analysis 73, 85.</p></fn><fn id=\"fwad017-FN144\"><label>144</label><p>For example, Dunn and others (n 18), [253] have argued that such measures ‘will not provide the adequate procedural and conceptual safeguards to guarantee that “vulnerable adults” are empowered, when protective interventions are deemed necessary’.</p></fn><fn id=\"fwad017-FN145\"><label>145</label><p>Similar arguments have been made in A Ruck Keene ‘The Inherent Jurisdiction: Where are We Now?’ (2013) Elder Law Journal 88. This also relates to Lindsey’s (n 95) conclusion that capacity law is used to deal with abuse concerns because of weaknesses in legal adult safeguarding frameworks, though this was not the focus of her paper.</p></fn><fn id=\"fwad017-FN146\"><label>146</label><p>N Kane and others, ‘Avoiding Hard Capacity Assessments Will Not Help’ (2020) 216 British Journal of Psychiatry 165.</p></fn><fn id=\"fwad017-FN147\"><label>147</label><p>Catriona Mackenzie raised the importance of finer grained analyses to distinguish between different sources of vulnerability, which makes it easier to separate between avoidable and unavoidable vulnerability: C Mackenzie ‘The Importance of Relational Autonomy and Capabilities for an Ethics of Vulnerability’ in C Mackenzie and others (eds), <italic toggle=\"yes\">New Essays in Ethics and Feminist Philosophy</italic> (OUP 2014). Jill Craigie has also concluded, in a similar review (n 18), that fine-grained analyses are needed to decide how appropriate such constructions of influence are to the context in which they are used.</p></fn><fn id=\"fwad017-FN148\"><label>148</label><p>See eg, C Kong and A Ruck Keene (n 141), the ‘modes of influence’ by Craigie (ibid) and the approaches to supporting legal capacity outlined by L Series (n 12).</p></fn><fn id=\"fwad017-FN149\"><label>149</label><p>As was the case in <italic toggle=\"yes\">Southend-On-Sea Borough Council v Meyers</italic> (n 32).</p></fn><fn id=\"fwad017-FN150\"><label>150</label><p>The boundaries between support and influence have been the focus of several articles, including J Craigie, ‘A Fine Balance: Reconsidering Patient Autonomy in Light of the UN Convention on the Rights of Persons with Disabilities’ (2015) 29 Bioethics 398; MJ Quinn ‘Undue Influence and Elder Abuse: Recognition and Intervention Strategies’ (2002) 23 Geriatric Nursing 11; S Wood and PJ Liu ‘Undue Influence and Financial Capacity: A Clinical Perspective’ (2012) 36 Generations 53.</p></fn><fn id=\"fwad017-FN151\"><label>151</label><p>See also Committee on the Rights of Persons with Disabilities, General Comment No 1, art 12: Equal recognition before the law (United Nations, 2014), para 37.</p></fn><fn id=\"fwad017-FN152\"><label>152</label><p>See US General Accounting Office, <italic toggle=\"yes\">Content Analysis: A Methodology for Structuring and Analyzing Written Material</italic> (General Accounting Office 1996) 20; JR Landis and GG Koch ‘An Application of Hierarchical Kappa-type Statistics in the Assessment of Majority Agreement among Multiple Observers’ (1977) 33 Biometrics 363.</p></fn><fn id=\"fwad017-FN153\"><label>153</label><p>See n 27.</p></fn><fn id=\"fwad017-FN154\"><label>154</label><p>As Series and others have noted, there have been several methodological obstacles to obtaining detailed and representative data from unpublished health and welfare case files (n 135), [26–37].</p></fn><fn id=\"fwad017-FN155\"><label>155</label><p>See also Ruck Keene and others (n 3), [69] where the authors mention that P was only an applicant to court for deprivation of liberty safeguard (DOLS) cases. This is noteworthy as DOLS have a specific mechanism to support people to apply. The authors also reference statistics by Series and others (n 135) which further supports this claim.</p></fn><fn id=\"fwad017-FN156\"><label>156</label><p>Following a comparative analysis with case files and one author’s experience as a CoP barrister, Ruck Keene and others also found that their cases were broadly representative (n 3). Case has also argued that there was no reason to believe the BAILII judgments were unrepresentative of the courts’ health and welfare caseload. She acknowledged, however, that CoP cases were grossly underreported in its early years, which hampers a historical understanding of the issues we have raised in this article (n 95).</p></fn><fn id=\"fwad017-FN157\"><label>157</label><p>This was noted by Ruck Keene and others (n 3). A key benefit of capacity case reviews is that they make disparate legal developments (including developments around judges handling of influence) accessible to a wider audience.</p></fn><fn id=\"fwad017-FN158\"><label>158</label><p>Lindsey has combined capacity case reviews alongside unpublished case files, in-depth interviews of social workers and observations of ongoing CoP proceedings (n 95 and 116). These integrative methods not only reduce selection bias concerns but may also offer insights into earlier, unpublished cases. Craigie’s review (n 18) similarly combined a web-based case search with insights from voluntary sector and public body organizations.</p></fn></fn-group>" ]	[]	[]	[]	{ "acronym": [], "definition": [] }	0	CC BY	no	2024-01-13 23:36:46	Med Law Rev. 2023 Jun 9; 31(4):564-593	oa_package/b7/b4/PMC10681350.tar.gz
PMC10681352	37253391	[ "<title>I. INTRODUCTION</title>", "<p>Time has a fundamental role in the regulation of abortion. It is used to draw lines delineating the boundaries of abortion, setting the dividing line between lawful and unlawful abortions.<xref rid=\"fwad015-FN1\" ref-type=\"fn\"><sup>1</sup></xref> The point in gestation at which those lines are drawn varies between jurisdictions, but in many jurisdictions the legal bright line adopted for that boundary is <italic toggle=\"yes\">viability</italic>, generally understood as the point at which the fetus could survive, albeit with medical assistance, outside the uterus.<xref rid=\"fwad015-FN2\" ref-type=\"fn\"><sup>2</sup></xref> A large body of philosophical literature critiques the moral relevance of viability as the point at which the fetus attains significance and should be protected.<xref rid=\"fwad015-FN3\" ref-type=\"fn\"><sup>3</sup></xref> However, there is much less literature that critiques the problems of enshrining a viability threshold in the law.<xref rid=\"fwad015-FN4\" ref-type=\"fn\"><sup>4</sup></xref> The focus of this article is upon the use of viability as a legal construct and the uncertainty that this creates.</p>", "<p>Viability as a concept was initially developed to determine the boundaries of acceptable treatment for extremely premature neonates,<xref rid=\"fwad015-FN5\" ref-type=\"fn\"><sup>5</sup></xref> a very different context to the termination of pregnancy. Nevertheless, since the mid-twentieth century, viability has become a central feature in abortion regulation, becoming a threshold beyond which a fetus can no longer be legally aborted, or when permissible grounds for a termination of pregnancy are severely restricted. However, viability is a difficult concept on which to base a law, or even professional guidance. The concept is ambiguous, complex, and difficult to apply in practice. It is a moveable threshold, determined by fetus-specific and external considerations, rather than a universal standard. Viability is innately fetus-specific, dependent upon a number of intersecting fetal characteristics such as sex and weight.<xref rid=\"fwad015-FN6\" ref-type=\"fn\"><sup>6</sup></xref> Furthermore, fetal outcomes cannot be divorced from external considerations like geography and, often relatedly, resources.<xref rid=\"fwad015-FN7\" ref-type=\"fn\"><sup>7</sup></xref> When discussed as a standard, viability is based on the ‘human interpretation of statistical probabilities’ applied to fetuses as a group without consideration of the contextual factors influencing the likelihood that any specific fetus could or would survive.<xref rid=\"fwad015-FN8\" ref-type=\"fn\"><sup>8</sup></xref> This makes viability as a concept ill-suited to laws determining the scope of criminal liability, where a person’s access to healthcare and a doctor’s liberty and licence to practice medicine are at stake. Moreover, the import of a medical concept designed to determine the appropriateness of treatment intended to preserve life in the case of extremely premature birth into the context of abortion, where, by its very nature, the fetus is not intended to survive, is a conceptually illegitimate ground on which to base abortion regulation. The two contexts are entirely distinct.</p>", "<p>The World Health Organization (WHO) specifically recommends ‘against laws and other regulations that prohibit abortion based on gestational age limits’ because such laws delay access to abortion (especially at later gestations) and are associated with higher incidences of unsafe abortion and maternal morbidity and mortality.<xref rid=\"fwad015-FN9\" ref-type=\"fn\"><sup>9</sup></xref> Despite the inherent uncertainty of gestational age limits, viability is often adopted as a threshold concept in laws regulating abortion. The regulatory models adopted in England and Wales and the Netherlands provide two particularly good examples of the centrality accorded to viability in the determination of the parameters of non-criminal abortion, restricting post-viability abortion to cases where the person’s life or health is at risk, or where the termination of pregnancy is based upon fetal anomaly (embryopathic) grounds. In both jurisdictions, there is significant concern that advances in perinatal medicine that enable neonates born at earlier gestations to survive might lead to a reduction in the time limit for abortion.<xref rid=\"fwad015-FN10\" ref-type=\"fn\"><sup>10</sup></xref> Our contribution to the literature is particularly timely in the light of the current review of the Dutch guideline on perinatal care in case of extremely premature birth.<xref rid=\"fwad015-FN11\" ref-type=\"fn\"><sup>11</sup></xref> The likely revision of the perinatal guidance, to recognize that preterm neonates can survive <italic toggle=\"yes\">prior</italic> to the 24th week of gestation, could lead to the lowering of the upper limit for lawful abortion.<xref rid=\"fwad015-FN12\" ref-type=\"fn\"><sup>12</sup></xref> This possibility thus necessitates an examination of the use of fetal viability to denote the boundaries of lawful abortion and the potential adoption of a single threshold for abortion <italic toggle=\"yes\">and</italic> the care of premature neonates.</p>", "<p>This article compares the regulation of abortion in England and Wales and the Netherlands, evaluating the role played by fetal viability in the law. While there are significant differences in the law relating to abortion in doctrinal terms, there is much commonality in the practice of abortion. Both jurisdictions are often viewed as examples of places with ‘liberal abortion laws’ in Europe.<xref rid=\"fwad015-FN13\" ref-type=\"fn\"><sup>13</sup></xref> This is a misconception. In both jurisdictions, the viability threshold acts as a significant barrier to accessing abortion services. Even before viability, access is limited by being contingent upon medical discretion, with doctors being placed in the position of gatekeepers to lawful abortion.<xref rid=\"fwad015-FN14\" ref-type=\"fn\"><sup>14</sup></xref><italic toggle=\"yes\">After</italic> viability, access is much more restricted, with abortion only being available on the basis of a ‘maternal health/life’, or embryopathic indication. While we make our arguments with specific reference to these jurisdictions, our conclusions about the impetus for the decriminalization of abortion and/or removal of gestational age limits from abortion regulation have broader applicability and provide support to calls from international actors, such as the WHO<xref rid=\"fwad015-FN15\" ref-type=\"fn\"><sup>15</sup></xref> and United Nations Special Rapporteurs,<xref rid=\"fwad015-FN16\" ref-type=\"fn\"><sup>16</sup></xref> for decriminalization.</p>", "<p>We begin the next Section II by considering the legal frameworks regulating abortion in England and Wales and the Netherlands. In Section III, we compare the legal frameworks and the role played by the concept of viability therein, analysing its impact upon the continued criminalization of abortion and the categorization of abortion as a medical matter, rather than the exercise of an individual’s autonomy. Finally, we argue that the concept of viability is misconceived in its application to abortion and that neonatal viability (relating to treatment of the premature infant) and fetal viability (related to the capacity to survive birth) must be distinguished to ensure better access to late-term abortion for those who need it (in Section IV). Moreover, we demonstrate that the use of viability as a threshold renders the law uncertain and that, by embedding this concept in the regulatory framework, the law fails to reflect the social context within which the law and practice of abortion operates.</p>" ]	[]	[]	[]	[ "<title>IV. CONCLUSION</title>", "<p>As Leah Eades has noted, the 24-week fetus can be located in multiple settings ‘within a womb, an incubator, or an abortion clinic.’<xref rid=\"fwad015-FN190\" ref-type=\"fn\"><sup>190</sup></xref> We argue that the distinctiveness of those settings is crucial, and that neonatal viability has no role to play in the abortion context. Inevitably, framing abortion as a medical matter allows medical concepts to ‘creep’ into regulation. Scientific and medical developments inform the law, but science takes no account of the relational context of pregnancy. Rather, it focuses upon the potential for survival of the fetus, while disregarding the impact continuance of the pregnancy will have upon the pregnant person’s life. By placing viability at the centre of abortion regulation, pregnant people’s rights and interests are disregarded; their emergency situation/personal circumstances are trumped by the biological status of the fetus.</p>", "<p>By continuing to anchor the regulation of abortion in the criminal law, both jurisdictions perpetuate the stigmatization of abortion, causing doctors to act cautiously around the threshold of viability for fear of prosecution. They stigmatize those who present later for abortion, leaving them to seek assistance abroad or online. The opportunity costs associated with regulating abortion in the context of criminal law are significant. Criminalized abortion restricts access to care and results in stigma, distress, anxiety, poor quality post-abortion care and a lack in continuity of care. In addition, criminalized abortion imposes financial costs and burdens upon those required to travel to access abortion and increases the workload of healthcare professionals required to submit their clinical decisions to external scrutiny to demonstrate compliance with the regulation.<xref rid=\"fwad015-FN191\" ref-type=\"fn\"><sup>191</sup></xref> The increasing ability to bypass controls intended to restrict abortion renders such control illusionary. Criminal regulation of abortion structured around fetal viability does little to protect fetal life but renders abortion less safe, posing a risk to pregnant people’s lives and health.</p>", "<p>As developments in perinatology continue to enhance the ability to support survival at ever earlier gestations, it is conceivable that one day even very early abortions would be banned if viability continues to operate as a threshold. We suggest that the time has come to recognize the impact of neonatal viability upon the unrelated medical termination of pregnancy, to decentre viability and to focus instead upon empowering people to make reproductive choices that reflect their own interests.</p>" ]	[ "<title>Abstract</title>", "<p>Time plays a fundamental role in abortion regulation. In this article, we compare the regulatory frameworks in England and Wales and the Netherlands as examples of the centrality accorded to viability in the determination of the parameters of non-criminal abortion, demonstrating that the use of viability as a threshold renders the law uncertain. We assess the role played by the concept of viability, analysing its impact upon the continued criminalization of abortion and categorization of abortion as a medical matter, rather than a reproductive choice. We conclude that viability is misconceived in its application to abortion and that neonatal viability (relating to treatment of the premature infant) and fetal viability (related to the capacity to survive birth) must be distinguished to better reflect the social context within which the law and practice of abortion operate. We show how viability thresholds endanger pregnant people.</p>" ]	[ "<title>II. LEGAL FRAMEWORKS</title>", "<title>A. England and Wales</title>", "<p>Abortion is a crime in England and Wales. Section 58 of the Offences Against the Person Act 1861 (OAPA) stipulates that any person who procures a pregnant person’s miscarriage ‘by any means whatsoever’ with the intent of procuring miscarriage is guilty of a criminal offence.<xref rid=\"fwad015-FN17\" ref-type=\"fn\"><sup>17</sup></xref> This offence can be committed throughout pregnancy<xref rid=\"fwad015-FN18\" ref-type=\"fn\"><sup>18</sup></xref> and carries a maximum sentence of life imprisonment. In addition, section 1 of the Infant Life (Preservation) Act 1929 (ILPA) criminalizes ‘child destruction’, committed when a person ‘with intent to destroy the life of a child capable of being born alive, by any wilful act causes a child to die before it has an existence independent of its mother’. The term capable of being born alive is not defined further in the 1929 Act, although it is noted that a fetus is to be <italic toggle=\"yes\">presumed</italic> ‘capable of being born alive’ from 28 weeks’ gestation.<xref rid=\"fwad015-FN19\" ref-type=\"fn\"><sup>19</sup></xref> Unlike the ‘unlawful procurement of miscarriage’ therefore, ‘child destruction’ can only be committed <italic toggle=\"yes\">after</italic> a fetus is ‘viable’ later in a pregnancy.<xref rid=\"fwad015-FN20\" ref-type=\"fn\"><sup>20</sup></xref></p>", "<title>1. Grounds for abortion</title>", "<p>The Abortion Act 1967 (AA) specifies the conditions in which <italic toggle=\"yes\">doctors</italic> will not be guilty of either of these criminal offences when performing or supervising termination of pregnancy. Termination of pregnancy is lawful where two doctors have formed the opinion, in good faith, that:</p>", "<p>the pregnancy has not exceeded 24 weeks and continuing the pregnancy is a greater risk than termination to either the pregnant person’s physical or mental health or to any existing children of their family; or</p>", "<p>termination is necessary to prevent ‘grave permanent injury’ to the pregnant person’s physical or mental health; or</p>", "<p>continuance of the pregnancy poses a greater risk to the pregnant person’s life than termination; or</p>", "<p>there is a ‘substantial risk’ that if the fetus is born it would ‘suffer from such physical or mental abnormalities as to be seriously handicapped’. <xref rid=\"fwad015-FN21\" ref-type=\"fn\"><sup>21</sup></xref></p>", "<p>When making a determination about a pregnant person’s physical or mental health, doctors should take into account their ‘actual and reasonably foreseeable circumstances’.<xref rid=\"fwad015-FN22\" ref-type=\"fn\"><sup>22</sup></xref> Consequently, the first ground—often referred to as the ‘social ground’ for abortion<xref rid=\"fwad015-FN23\" ref-type=\"fn\"><sup>23</sup></xref>—is read incredibly broadly, and in practical terms renders every early pregnancy legally terminable.<xref rid=\"fwad015-FN24\" ref-type=\"fn\"><sup>24</sup></xref> The risks of abortion (medical or surgical) early in a pregnancy will always be lesser than those associated with carrying a pregnancy to full-term and childbirth,<xref rid=\"fwad015-FN25\" ref-type=\"fn\"><sup>25</sup></xref> particularly before 13 weeks' gestation. It is often on this basis that the 1967 Act is praised for rendering abortion easily accessible.<xref rid=\"fwad015-FN26\" ref-type=\"fn\"><sup>26</sup></xref> Having said that, the Act does not enable ‘abortion on demand’,<xref rid=\"fwad015-FN27\" ref-type=\"fn\"><sup>27</sup></xref> or on ‘social grounds’. Although often described as a social indication, section 1(1)(a) is, in its construction, a socio-<italic toggle=\"yes\">medical</italic> indication requiring the abortion to be justified <italic toggle=\"yes\">in clinical terms</italic>, albeit considering a person’s social context and broader welfare.<xref rid=\"fwad015-FN28\" ref-type=\"fn\"><sup>28</sup></xref></p>", "<title>2. The centrality of viability</title>", "<p>The AA 1967 does not make any explicit reference to fetal viability, but it does instil a threshold <italic toggle=\"yes\">before</italic> which point access is <italic toggle=\"yes\">easier</italic>, and <italic toggle=\"yes\">after</italic> which point it is <italic toggle=\"yes\">more difficult</italic>. Before 24 weeks, section 1(1)(a) permits the socio-medical abortions described above. After 24 weeks, some proof of a danger to the pregnant person or the fetus is required.<xref rid=\"fwad015-FN29\" ref-type=\"fn\"><sup>29</sup></xref> This is harder to establish.<xref rid=\"fwad015-FN30\" ref-type=\"fn\"><sup>30</sup></xref> The 24-week threshold is not described in the Act itself as being the identified point <italic toggle=\"yes\">because</italic> it reflects the point at which a fetus might be deemed ‘viable’, but it correlates with the point in gestation at which viability is most often referenced,<xref rid=\"fwad015-FN31\" ref-type=\"fn\"><sup>31</sup></xref> and so instils ‘an implicit viability threshold’.<xref rid=\"fwad015-FN32\" ref-type=\"fn\"><sup>32</sup></xref></p>", "<p>The offence of ‘child destruction’ was introduced, via the 1929 Act, to fill the gap between abortion and homicide (which requires live birth) where a fetus is killed during birth.<xref rid=\"fwad015-FN33\" ref-type=\"fn\"><sup>33</sup></xref> The victim in this situation is recognized as a fetus ‘capable of being born alive’<xref rid=\"fwad015-FN34\" ref-type=\"fn\"><sup>34</sup></xref> and thus defined <italic toggle=\"yes\">directly by comparison to a newborn</italic>. As we have noted above, there is a statutory presumption that at 28 weeks’ gestation the fetus will constitute a ‘child capable of being born alive’ and this makes it clear that the offence of child destruction is <italic toggle=\"yes\">not</italic> limited to the fetus killed during birth. ‘Capable of being born alive’ can be interpreted in different ways, raising the question whether the capacity for live birth suffices, or is the capacity for survival required? It has been argued that the explicit viability threshold in English law—codified in the offence of child destruction—means ‘capable of being born alive and surviving for a time by breathing, rather than being born alive and surviving in the longer term’.<xref rid=\"fwad015-FN35\" ref-type=\"fn\"><sup>35</sup></xref> The purpose of the presumption is to relieve the prosecution of the need to prove that a fetus meets the criterion of being a child capable of being born alive from the 28th week of pregnancy onwards.<xref rid=\"fwad015-FN36\" ref-type=\"fn\"><sup>36</sup></xref></p>", "<p>Although prosecutions for child destruction generally relate to individuals who have assaulted the pregnant person (rather than the pregnant person themselves, or a doctor),<xref rid=\"fwad015-FN37\" ref-type=\"fn\"><sup>37</sup></xref> it has been recognized in case law that the offence might also be committed when a later-term abortion is conducted.<xref rid=\"fwad015-FN38\" ref-type=\"fn\"><sup>38</sup></xref> Few prosecutions of child destruction are brought every year, still fewer convictions are achieved due to the need to demonstrate intent to destroy life.<xref rid=\"fwad015-FN39\" ref-type=\"fn\"><sup>39</sup></xref> However, the convictions have all related to the destruction of life <italic toggle=\"yes\">after</italic> 28 weeks’ gestation.<xref rid=\"fwad015-FN40\" ref-type=\"fn\"><sup>40</sup></xref> Nevertheless, the presumption does not preclude a finding that a fetus or fetuses earlier in gestation can have the capacity to be born alive<xref rid=\"fwad015-FN41\" ref-type=\"fn\"><sup>41</sup></xref> and it is suggested that the 24-week time limit applied to socio-medical abortions lends support to the view that child destruction may be committed from <italic toggle=\"yes\">at least</italic> that point onwards.</p>", "<title>3. Post-viability abortion</title>", "<p>After 24 weeks’ gestation, access to abortion becomes much harder, requiring either a maternal indication or fetal anomaly (under sections 1(1)(b)–(d) of the AA 1967).</p>", "<title>a. Maternal indication</title>", "<p>Later in pregnancy, there is a defence to both child destruction (under the 1929 Act) and unlawful miscarriage (under the 1861 Act) where there is a risk to life, or a risk of grave, permanent injury to the pregnant person’s physical or mental health. Section 1(1)(c) establishes a comparative standard, requiring the risk to the person’s life be greater if the pregnancy were to continue than if it were terminated. There is no such stipulation where the abortion is <italic toggle=\"yes\">necessary</italic> to prevent ‘grave and permanent damage to health’,<xref rid=\"fwad015-FN42\" ref-type=\"fn\"><sup>42</sup></xref> but the threshold of risk is high and is limited to serious conditions, such as those that might lead to kidney, brain or heart damage.<xref rid=\"fwad015-FN43\" ref-type=\"fn\"><sup>43</sup></xref> These provisions are broad; terms like ‘grave’ and ‘permanent’ are undefined, to ensure that wide discretion is conferred upon clinicians. Furthermore, the requirement is that doctors form their opinion that the indication is satisfied in good faith, rather than that their opinion is correct and therefore, in practice, doctors are able to intervene to end later-term pregnancies to preserve a pregnant person’s life or health without fear of prosecution.</p>", "<title>b. Fetal anomaly</title>", "<p>There is no time limit for abortion where doctors, forming their opinion in good faith, believe that there is a ‘substantial risk’ that the fetus will be ‘seriously handicapped’.<xref rid=\"fwad015-FN44\" ref-type=\"fn\"><sup>44</sup></xref> Neither of these terms, however, are defined by statute or in case law, with the lacuna being left to be filled by professional guidance.<xref rid=\"fwad015-FN45\" ref-type=\"fn\"><sup>45</sup></xref> This ground has attracted considerable criticism for being too broad<xref rid=\"fwad015-FN46\" ref-type=\"fn\"><sup>46</sup></xref> and has resulted in judicial review challenges to decisions to allow abortion for conditions such as Down’s syndrome<xref rid=\"fwad015-FN47\" ref-type=\"fn\"><sup>47</sup></xref> and cleft palate<xref rid=\"fwad015-FN48\" ref-type=\"fn\"><sup>48</sup></xref> later in pregnancy. Clinical guidance from the Royal College of Obstetricians and Gynaecologists (RCOG) states that a serious handicap will be a non-trivial condition that is not readily correctable and causes significant suffering or inability to participate in society.<xref rid=\"fwad015-FN49\" ref-type=\"fn\"><sup>49</sup></xref> The RCOG working party guidance indicates that whether a risk is substantial is not merely a statistical calculation, but depends ‘upon factors such as the nature and severity of the condition and the timing of diagnosis, as well as the likelihood of the event occurring’.<xref rid=\"fwad015-FN50\" ref-type=\"fn\"><sup>50</sup></xref> This suggests that even a moderate risk of a severe condition may satisfy the criterion. Doctors are advised to seek advice from specialists to demonstrate that they formed their opinion about the risk or the severity of the fetal anomaly in good faith.<xref rid=\"fwad015-FN51\" ref-type=\"fn\"><sup>51</sup></xref> Notwithstanding the broad discretion afforded to clinicians, the challenges to clinical judgement evident in cases like <italic toggle=\"yes\">Jepson</italic> and <italic toggle=\"yes\">Crowter</italic> have left some doctors feeling vulnerable to prosecution, resulting in a preference to perform embryopathic abortions prior to the expiry of the 24 week time limit applied to section 1(1)(a) AA 1967.<xref rid=\"fwad015-FN52\" ref-type=\"fn\"><sup>52</sup></xref></p>", "<title>B. The Netherlands</title>", "<p>Abortion is regulated in the Netherlands by the Dutch Penal Code (WvS),<xref rid=\"fwad015-FN53\" ref-type=\"fn\"><sup>53</sup></xref> the Termination of Pregnancy Act 1981 (Wafz),<xref rid=\"fwad015-FN54\" ref-type=\"fn\"><sup>54</sup></xref> and the Termination of Pregnancy Decree 1984 (Bafz).<xref rid=\"fwad015-FN55\" ref-type=\"fn\"><sup>55</sup></xref> Situated directly after the section of the Penal Code relating to crimes against life, Article 296(1) of the WvS stipulates that:</p>", "<p>Setting out an exception to this provision, Article 296 (5) of the WvS provides that a termination of pregnancy will not be punishable if it is performed by a doctor in a licensed hospital, or clinic, in accordance with the Wafz.</p>", "<p>The Explanatory Memorandum to the Act sets out the legislation’s three broad aims: (i) to provide assistance to pregnant persons in an emergency situation because of an unwanted pregnancy; (ii) to protect unborn life; and (iii) to safeguard pregnant persons’ health, both in relation to the performance of the termination itself and through good aftercare.<xref rid=\"fwad015-FN56\" ref-type=\"fn\"><sup>56</sup></xref> Each aim is considered in turn below. As these aims make clear, the regulatory model adopted in the Netherlands emphasizes that the fetus is morally significant, albeit not a legal person and underscores the exceptionalism that characterizes abortion regulation—abortion is framed as neither a purely medical matter to be left to doctors to determine, nor simply a matter of choice for pregnant people.</p>", "<title>1. Assisting pregnant persons in an emergency situation because of unwanted pregnancy</title>", "<p>In the same way that the AA 1967 excludes criminal liability under the OAPA 1861 and the ILPA 1929, the Wafz excludes liability under Article 296 of the WvS, but it does so in broad terms, excluding liability where the pregnant person is in a state of emergency and the termination is performed in accordance with the requirements set out in the Act. As was common in legislation during the later part of the twentieth century, the Dutch law underlines the exceptionalism attributed to abortion, categorizing abortion as a measure to assist pregnant persons in an emergency situation as a result of an unwanted pregnancy, rather than recognizing a right to termination.</p>", "<p>The Act does not attempt to define what will constitute an emergency, adopting a general proposition and leaving the determination of whether the pregnant person is in a state of emergency to be determined by the individual and their doctor.<xref rid=\"fwad015-FN57\" ref-type=\"fn\"><sup>57</sup></xref> In practice, this provides wide access to abortion in the Netherlands as any unwanted pregnancy can be regarded as constituting an emergency situation for the individual. Nevertheless, it is unfortunate that the second review of the Wafz did not recommend that the Act be amended to recognize autonomy as the justification for abortion, rather than a ‘state of emergency’ as assessed by a third party. Moreover, as discussed below, the general state of emergency will only permit abortions performed <italic toggle=\"yes\">prior</italic> to viability; thereafter, the individual’s state of emergency as a result of unwanted pregnancy becomes irrelevant and protection of fetal life is prioritized absent a maternal or embryopathic indication.</p>", "<p>Unlike the AA 1967, the Wafz does not set out any indications that will justify an abortion, relying solely upon the pregnant person being in a state of emergency based upon an unwanted pregnancy. Neither medically indicated nor embryopathic abortions are provided for by the Wafz,<xref rid=\"fwad015-FN58\" ref-type=\"fn\"><sup>58</sup></xref> instead they are subject to the general prohibition of abortion,<xref rid=\"fwad015-FN59\" ref-type=\"fn\"><sup>59</sup></xref> leaving the doctor dependent upon the justification of necessity to escape criminal liability. As we now demonstrate, viability plays an essential role in these contexts.</p>", "<title>2. Protecting unborn life—the significance of viability</title>", "<p>The second aim set out in the Explanatory Memorandum is the protection of unborn life. By retaining the crime of abortion in the Penal Code,<xref rid=\"fwad015-FN60\" ref-type=\"fn\"><sup>60</sup></xref> albeit with an exemption from criminal liability for doctors performing an abortion to resolve a pregnant person’s state of emergency in accordance with the Wafz,<xref rid=\"fwad015-FN61\" ref-type=\"fn\"><sup>61</sup></xref> the legislature expressed the exceptionalism of abortion. Abortion is framed not merely as a medical procedure subject to the general law and professional guidance relating to medical treatment, but as an area of healthcare requiring additional regulation. The Wafz seeks to protect unborn life through a combination of substantive and procedural rules (the due care criteria) designed to ensure careful decision-making. It requires that:</p>", "<p>The explicit reference to the pregnant person’s responsibility for unborn life underlines the expectation that they should continue a pregnancy. Moreover, although there is stress laid upon abortion being the individual’s decision, the Act requires the doctor to be satisfied that there is no other way to resolve the pregnant person’s emergency situation than to terminate the pregnancy.<xref rid=\"fwad015-FN63\" ref-type=\"fn\"><sup>63</sup></xref> To this end, the doctor is required to discuss alternatives with the pregnant person,<xref rid=\"fwad015-FN64\" ref-type=\"fn\"><sup>64</sup></xref> and a mandatory reflection period is set out designed to ensure a well-considered decision.<xref rid=\"fwad015-FN65\" ref-type=\"fn\"><sup>65</sup></xref></p>", "<p>No time limit for permissible abortions is set out in the Wafz. However, the Explanatory Memorandum specifically states that termination of pregnancy in the case of a viable fetus will remain a criminal offence and constitute an instance of intentional deprivation of life according to Article 82a of the WvS, an amendment to the Penal Code introduced by the Wafz.<xref rid=\"fwad015-FN66\" ref-type=\"fn\"><sup>66</sup></xref> Therefore, the parameters of lawful abortion in the Netherlands are set by Article 82a of the WvS, which provides that ‘Taking the life of a person … shall include: the killing of a fetus that can reasonably be expected to have the ability to survive outside the mother’s body.’ If a fetus is born alive after a post-viability abortion, no offence will have been committed. However, if a fetus is stillborn, the abortion performed by a doctor will constitute a homicide,<xref rid=\"fwad015-FN67\" ref-type=\"fn\"><sup>67</sup></xref> concurrently with abortion,<xref rid=\"fwad015-FN68\" ref-type=\"fn\"><sup>68</sup></xref> as the exception set out in Article 296(5) of the WvS does not apply after viability.<xref rid=\"fwad015-FN69\" ref-type=\"fn\"><sup>69</sup></xref> Applied in this manner, the legality of abortion provision is tied to the potential for the fetus’ survival after birth.</p>", "<p>While the viability threshold is an external time limit, the provisions of the Wafz are construed in accordance with Article 82a of the WvS, thus excluding post-viability abortion from the scope of the Act. Notably, the provision does not specify when viability can reasonably be expected to occur, or even set up a statutory presumption of viability such as that found in the ILPA 1929. This is problematic as law, particularly criminal law, should be certain in scope and there are multiple definitions attributed to viability. Reflecting the scientific consensus of the time, the Explanatory Memorandum adopts 24 weeks as the viability threshold,<xref rid=\"fwad015-FN70\" ref-type=\"fn\"><sup>70</sup></xref> a position confirmed in 1991 by the Supreme Court (<italic toggle=\"yes\">Hoge Raad</italic>).<xref rid=\"fwad015-FN71\" ref-type=\"fn\"><sup>71</sup></xref> The court identified 24 weeks as the upper limit for abortion, noting that medical science would support a reasonable expectation of viability from that point and that all Article 82a of the WvS requires is an expectation that the fetus would survive birth, <italic toggle=\"yes\">even if only for a short time</italic>. Importantly, the Supreme Court stressed that, in practice, the upper limit for abortion would be significantly lower than 24 weeks, stating that a margin of inaccuracy of 4 weeks should be taken into account when dating a pregnancy, reduced to 2 weeks when more advanced diagnostic tools are used.<xref rid=\"fwad015-FN72\" ref-type=\"fn\"><sup>72</sup></xref> This means that, applying a safety margin, the true threshold for abortion as a means of resolving the individual’s emergency situation is 20–22 weeks in the Netherlands.<xref rid=\"fwad015-FN73\" ref-type=\"fn\"><sup>73</sup></xref></p>", "<p>The impact of Article 82a of the WvS is to impose a flexible time-limit upon abortion, enabling viability (and thus the threshold for lawful abortion) to move alongside developments in perinatology. There have been significant developments in perinatology since the Wafz came into force in 1984, advances that have enabled premature children to survive at progressively earlier gestations.<xref rid=\"fwad015-FN74\" ref-type=\"fn\"><sup>74</sup></xref> When the Wafz was enacted, extremely premature neonates born below 26 weeks’ gestation were not treated and so did not survive in the Netherlands.<xref rid=\"fwad015-FN75\" ref-type=\"fn\"><sup>75</sup></xref> However, the current professional guidance issued by the Dutch Societies of Paediatricians (NVK) and for Obstetrics and Gynaecology (NVOG) states that treatment for extremely premature neonates should be offered to those born at 24 weeks’ gestation, after consultation with the parents.<xref rid=\"fwad015-FN76\" ref-type=\"fn\"><sup>76</sup></xref> Thus, the current boundaries for lawful abortion and active treatment for premature neonates intersect at 24 weeks. The NVK and NVOG guideline is currently under review, giving rise to concern that if changes are made to determinations about the viability and the associated appropriateness of treatment in the neonatal intensive care setting, those changes will impact upon the gestational threshold for abortion and reduce the time limit for abortion. Addressing this concern, both the Second Review of the Wafz and the 2022 Late Termination of Pregnancy Evaluation report recommended that the link between the threshold for abortion and medical advances in the survival of extremely premature births should be severed and that the 24-week time limit currently applicable to abortion on non-medical grounds should be inserted into the Wafz.<xref rid=\"fwad015-FN77\" ref-type=\"fn\"><sup>77</sup></xref> The new Dutch government has yet to take action on these recommendations.</p>", "<title>3. Safeguarding pregnant person’s health both in relation to the performance of the termination itself and through good aftercare</title>", "<p>The Wafz and Bafz go further than the AA 1967, providing a detailed framework for the provision of abortion, emphasizing the need to safeguard pregnant persons’ health going beyond the requirement in the Abortion Act 1967 that abortion is performed only by a registered medical practitioner in licensed premises. The requirements of due care are intended to ensure that the pregnant person is able to make a careful decision regarding the termination of their pregnancy.<xref rid=\"fwad015-FN78\" ref-type=\"fn\"><sup>78</sup></xref> Underscoring the narrative of pregnant persons as requiring guidance and being unable to make a responsible decision to terminate a pregnancy without assistance, requirements include that the attending doctor must inform the pregnant person about alternatives to abortion and that access be provided to psychology and social care professionals to assist them, should they so wish.<xref rid=\"fwad015-FN79\" ref-type=\"fn\"><sup>79</sup></xref> Through this detailed framework,<xref rid=\"fwad015-FN80\" ref-type=\"fn\"><sup>80</sup></xref> the distinctive nature of abortion compared to other medical procedures is highlighted, it is subjected to additional rules outside the general legal framework applicable to medical treatment, thereby stigmatizing both the pregnant person and the doctor.<xref rid=\"fwad015-FN81\" ref-type=\"fn\"><sup>81</sup></xref></p>", "<title>4. Abortions falling outside the scope of the termination of pregnancy act</title>", "<p>The Wafz is applicable only to abortions performed prior to viability and conceptualizes abortion as a solution for a pregnant person’s emergency situation caused by unwanted pregnancy. Thus, the Act is designed to regulate abortion of the type that would be covered by section 1(1)(a) AA 1967 in England and Wales. For that reason, the Wafz does not provide justifications for abortion in the case of a threat to the pregnant person’s life or health (maternal indication),<xref rid=\"fwad015-FN82\" ref-type=\"fn\"><sup>82</sup></xref> or abortion based upon fetal anomalies (embryopathic indication),<xref rid=\"fwad015-FN83\" ref-type=\"fn\"><sup>83</sup></xref> rendering post-viability ‘therapeutic’ abortion a crime.<xref rid=\"fwad015-FN84\" ref-type=\"fn\"><sup>84</sup></xref></p>", "<p>Abortions performed on maternal or embryopathic grounds prior to viability will result in the termination of what will often be very much wanted pregnancies; however, they will be permitted as cases of resolving the pregnant person’s emergency situation and benefit from the indemnity set out in Article 296(5) of the WvS. Once the fetus attains viability, pregnancy cannot be lawfully terminated under the Wafz. However, that is not to say that abortion is not available in such cases; rather, recourse is had to the justification of necessity<xref rid=\"fwad015-FN85\" ref-type=\"fn\"><sup>85</sup></xref> and what Sjef Gevers has termed a restrained prosecution policy.<xref rid=\"fwad015-FN86\" ref-type=\"fn\"><sup>86</sup></xref> A key distinction between pre- and post-viability abortion is that while abortion prior to 24 weeks is regarded as a matter for clinical expertise, the performance of ‘late’ abortions is subjected to scrutiny, highlighting the enhanced status of the fetus in law from the point at which viability will generally occur.</p>", "<title>a. Fetal anomaly</title>", "<p>In many cases, fetal anomalies are not identified prior to the 20-week anomaly scan, leaving little time for the pregnancy to be terminated prior to viability. The impact of Article 82a of the WvS is to render all abortions after viability a crime against life, concurrently with exposing the doctor to liability for terminating a pregnancy under Article 296 of the WvS. Nevertheless, a framework has been established to regulate abortion on the basis of fetal anomaly through the 2016 Ministerial Regulations of the Assessment Committee for Late Terminations of Pregnancy and Termination of Life in Neonates.<xref rid=\"fwad015-FN87\" ref-type=\"fn\"><sup>87</sup></xref> Two categories of late termination of pregnancy for fetal anomaly are set out.<xref rid=\"fwad015-FN88\" ref-type=\"fn\"><sup>88</sup></xref> Category 1 consists of cases where the fetus would be expected to die immediately after birth; for example, anencephaly, double pulmonary hypoplasia, trisomy 13 (Patau’s syndrome), and 18 (Edward’s syndrome). The second category of late terminations of pregnancy concerns cases where one or more conditions are present in the fetus which lead to serious and irreparable functional disorders; for example, spina bifida. Thus, abortion on embryopathic grounds is not limited to cases of fatal fetal anomaly, but the ground is considerably narrower than that set out in section 1(1)(d) of the AA and will not include late onset conditions, such as Huntington’s, or conditions perceived as less severe, such as Down’s syndrome. The impact of this is significant as in cases not falling within either category the termination can only lawfully take place prior to 24 weeks on the general emergency ground, leaving little time after diagnosis to decide about termination. This leads to a bottleneck in abortion provision, forcing some people to access later abortion by travelling to another country or resorting to purchasing abortion pills on the internet.<xref rid=\"fwad015-FN89\" ref-type=\"fn\"><sup>89</sup></xref></p>", "<p>In both categories, the termination must be reported to the municipal pathologist by the attending doctor as a case of unnatural death. Following a post-mortem, the municipal pathologist will notify the public prosecutor who has to give a declaration of no objection to burial, or cremation before either can take place. Moreover, the attending doctor is required to submit a report detailing compliance with the due care criteria to the Assessment Committee for Late Termination of Pregnancy and Termination of Life in Newborns. The committee (made up of four doctors, a lawyer and an ethicist) is responsible for assessing all reported cases of late termination of pregnancy (<italic toggle=\"yes\">both</italic> category 1 and 2) <italic toggle=\"yes\">and</italic> cases of termination of life in neonates, underscoring the increased status endowed upon the fetus after viability would generally be expected to occur.</p>", "<p>In category 1 (fatal anomaly) cases, there is no reasonable expectation that the fetus will survive outside the uterus and therefore it is not considered viable. Article 82a of the WvS finds no application, but Article 296(5) of the WvS and the provisions of the Wafz do apply. Upon reviewing the case, if the Committee finds that the attending doctor acted in accordance with the Wafz and professional guidance, they will be deemed to have complied with the due care criteria,<xref rid=\"fwad015-FN90\" ref-type=\"fn\"><sup>90</sup></xref> and will be exempt from criminal liability. The file will be closed. If, however, the Committee finds that the doctor has not complied with the due care criteria, it will inform the Health and Youth Care Inspectorate (IGJ) which may initiate disciplinary proceedings, or can report the case to the Board of Procurators General (BPG) if it believes that an offence has been committed.</p>", "<p>Category 2 (conditions leading to serious and irreparable functional disorder) cases are more complex because the fetus is considered viable on the basis of gestational age, creating the potential for concurrent liability under Articles 289 (murder) with 82a, and 296 (abortion) of the WvS.<xref rid=\"fwad015-FN91\" ref-type=\"fn\"><sup>91</sup></xref> Stricter scrutiny is therefore applied to termination for a non-fatal anomaly both in terms of the identification of the due care criteria to be applied and the institution of a double review after the termination. While the regulations define due care by reference to professional practice and guidelines in category 1 cases, specific due care criteria are applicable to category 2 cases.<xref rid=\"fwad015-FN92\" ref-type=\"fn\"><sup>92</sup></xref> These cumulative criteria require that the attending doctor:</p>", "<p>is convinced that the anomalies are such that medical intervention after birth would be futile according to prevailing medical opinion and there is no reasonable doubt about the diagnosis and the prognosis based on it;</p>", "<p>is convinced that the fetus is currently suffering, or will foreseeably suffer, without prospect of improvement;</p>", "<p>has fully informed the parents of the diagnosis and the prognosis, reaching the consensus that there is no reasonable alternative to termination;</p>", "<p>the pregnant [person] has explicitly requested termination of the pregnancy due to [their] physical or psychological suffering caused by the situation;</p>", "<p>the doctor has consulted at least one other, independent doctor, who has given [their]written opinion on the aforementioned due care requirements, or, if an independent doctor could not reasonably be consulted, has consulted the medical team, which has given its written opinion on the above;</p>", "<p>the pregnancy was terminated with due medical care.<xref rid=\"fwad015-FN93\" ref-type=\"fn\"><sup>93</sup></xref></p>", "<p>The criteria are broadly drafted and the LTP Evaluation 2022 noted that doctors find it particularly difficult to interpret the requirement of hopeless and unbearable suffering,<xref rid=\"fwad015-FN94\" ref-type=\"fn\"><sup>94</sup></xref> and to be certain that the ‘no reasonable doubt’ threshold is satisfied in the absence of DNA diagnosis, where the severity assessment can be made solely on the basis of imaging.<xref rid=\"fwad015-FN95\" ref-type=\"fn\"><sup>95</sup></xref> Only 33% of respondents to the evaluation reported that they found the category 2 due care requirements sufficiently clearly formulated.<xref rid=\"fwad015-FN96\" ref-type=\"fn\"><sup>96</sup></xref> Moreover, only 57% of respondents said that it is mostly clear which category cases fall into.<xref rid=\"fwad015-FN97\" ref-type=\"fn\"><sup>97</sup></xref> However, the distinction is crucial because, unlike category 1 cases, the Committee <italic toggle=\"yes\">must</italic> forward its finding in all category 2 cases to the Board of Procurators General,<xref rid=\"fwad015-FN98\" ref-type=\"fn\"><sup>98</sup></xref> even if it concludes that the doctor complied with the due care criteria. While Committee findings carry significant weight in the decision of whether to prosecute doctors, prosecuting authorities are not bound by the findings of the Committee in deciding whether to prosecute the attending doctor.<xref rid=\"fwad015-FN99\" ref-type=\"fn\"><sup>99</sup></xref> Category 2 cases thus will feel risky for doctors.</p>", "<p>The scheme for reviewing and reporting instances of late termination of pregnancy based on an embryopathic indication resembles the scheme adopted by the Termination of Life on Request and Assisted Suicide (Review Procedures) Act 2001, but with an important distinction in category 2 cases. The automatic referral in these cases has a chilling effect upon doctors’ willingness to perform late abortions,<xref rid=\"fwad015-FN100\" ref-type=\"fn\"><sup>100</sup></xref> and its inclusion is particularly surprising given that the automatic referral to the prosecuting authorities in assisted dying cases<xref rid=\"fwad015-FN101\" ref-type=\"fn\"><sup>101</sup></xref> was abolished by the Termination of Life on Request and Assisted Suicide (Review Procedures) Act 2001 <italic toggle=\"yes\">precisely because of</italic> its impact upon doctors’ willingness to report euthanasia.<xref rid=\"fwad015-FN102\" ref-type=\"fn\"><sup>102</sup></xref> Indeed, only a small number of cases of late termination of pregnancy are reported in the Netherlands each year,<xref rid=\"fwad015-FN103\" ref-type=\"fn\"><sup>103</sup></xref> and it could be suggested that cases of embryopathic abortion are underreported due to doctors’ unwillingness to invite prosecution for providing medical treatment. Nevertheless, the 2022 LTP Evaluation found no evidence of underreporting. It did, however, note that the potential for prosecution and the degree of uncertainty about the potential for criminal liability often render doctors very reluctant to perform late abortions. It recognized that doctors prefer, instead, to refer pregnant persons to doctors in other jurisdictions, or to perform embryopathically indicated abortions prior to the 24th week as an instance of resolving their emergency situation, thus not triggering a reporting requirement and subsequent scrutiny.<xref rid=\"fwad015-FN104\" ref-type=\"fn\"><sup>104</sup></xref> Referrals are generally made to clinics in neighbouring Belgium, where no time limit applies to abortions performed on the basis of an embryopathic indication. Moreover, the criteria for what will constitute a ‘particularly severe and incurable disease’ justifying embryopathic abortion are not defined in the Belgian Act regulating abortion,<xref rid=\"fwad015-FN105\" ref-type=\"fn\"><sup>105</sup></xref> providing significantly broader access to embryopathically indicated abortions, including, for example, cases of Down’s syndrome that would not meet the criteria for category 2 in the Netherlands.</p>", "<p>A significant problem is uncertainty for treating health professionals, uncertainty that results from the fact that the question of whether the legal requirements have been met is only addressed <italic toggle=\"yes\">after</italic> the occurrence of the termination of pregnancy. There is no mechanism for doctors to apply for certification that their categorization, or actions in terminating a pregnancy are lawful in advance of the termination. Given the enhanced due care criteria applied to category 2 cases (where the fetus is viable),<xref rid=\"fwad015-FN106\" ref-type=\"fn\"><sup>106</sup></xref> the determination of whether the case should be categorized as a category 1, or 2 case is crucial. For example, in relation to category 2 cases, the attending doctor is required to obtain a second opinion on the applicability of the due care criteria.<xref rid=\"fwad015-FN107\" ref-type=\"fn\"><sup>107</sup></xref> If the assessment committee finds that a doctor wrongly categorized a case as category 1, there is no opportunity to comply with the due care requirement of a second opinion retrospectively. Inevitably, the doctor will fail to comply with a key due care criterium and be referred to the prosecuting authorities.</p>", "<p>In the context of abortion, there is nothing similar to the SCEN network, a network of doctors trained in providing independent assessments in relation to termination of life. SCEN has proved very important in the euthanasia context, with the Regional Euthanasia Review Committees consistently recommending the use of a SCEN consultant as a means of ensuring the high quality of the required second opinion.<xref rid=\"fwad015-FN108\" ref-type=\"fn\"><sup>108</sup></xref> Professionalization of the consultation process has much to recommend it—SCEN has ensured the availability of highly trained, experienced consultants throughout the country, experts who are able to offer advice, having a thorough knowledge of the statutory requirements relating to euthanasia, and who can also offer support to the attending doctor. Such high-quality consultation is important, and if introduced into the abortion process would function not only as a means of confirming that the requirements for termination of pregnancy are met, but also operate as a form of a priori review, allowing doctors to feel more secure in their decisions.<xref rid=\"fwad015-FN109\" ref-type=\"fn\"><sup>109</sup></xref></p>", "<p>The retrospective assessment of compliance with the due care criteria creates significant uncertainty for doctors.<xref rid=\"fwad015-FN110\" ref-type=\"fn\"><sup>110</sup></xref> Both the 2013 and 2022 evaluations of the late termination of pregnancy regulations recognized that doctors are hesitant to perform late clinically indicated abortions in the Netherlands due to the fear that they could be prosecuted and convicted of a serious criminal offence. The evaluations found that the dual control mechanism applied to category 2 abortions is unduly burdensome and recommended that only cases where the doctor has failed to comply with the due care criteria should be referred to the prosecutorial authorities.<xref rid=\"fwad015-FN111\" ref-type=\"fn\"><sup>111</sup></xref> Nevertheless, to date, there has never been a prosecution for a late termination of pregnancy under the Ministerial Regulations.<xref rid=\"fwad015-FN112\" ref-type=\"fn\"><sup>112</sup></xref> Seeking to avoid the uncertainty and stigma engendered by a referral to the prosecution authorities, doctors try to make decisions about abortion before the end of the 23rd week of pregnancy, allowing them to take advantage of the exemption from criminal liability set out in Article 296 (5) of the WvS, without having to submit to review, or ‘invite’ prosecution. This highlights the potential impact of revisions to the guideline on perinatal care, because a reduction in the viability threshold could reduce the time available to use the exemption designed to allow assisting a pregnant person in an emergency situation, in an already tight timeframe after the 20-week anomaly scan. For that reason, both the Second Review of the Wafz and 2022 LTP Evaluation recommended that the current 24-week threshold (implicit in the penal code, but explicit in the ministerial regulations relating to late termination of pregnancy) should be retained and <italic toggle=\"yes\">viewed separately</italic> from the treatment threshold applied to neonates.<xref rid=\"fwad015-FN113\" ref-type=\"fn\"><sup>113</sup></xref></p>", "<p>In cases where it was not possible to terminate the pregnancy within the 24-week limit, the Second Review of the Wafz and 2022 LTP Evaluation noted that doctors sometimes referred patients abroad for terminations, rather than offering abortion in the Netherlands.<xref rid=\"fwad015-FN114\" ref-type=\"fn\"><sup>114</sup></xref> This underlines how limited the protection afforded to fetal life by the restrictive and oppressive approach adopted in the Netherlands actually is. It also demonstrates the magnitude of the viability threshold’s potential impact upon pregnant people, disadvantaging those who are unable to travel to obtain an abortion in another jurisdiction, whether due to work and caring commitments, age, or lack of funding, and undermining both the continuity of care and the provision of post-abortion care. The 24-week cut-off point for crisis-based abortions also impacts upon the psychological wellbeing of those affected—pregnant persons may feel compelled to request an abortion before complete clarity is available in relation to the likely severity of the condition and before they have had the time to come to terms with the diagnosis.<xref rid=\"fwad015-FN115\" ref-type=\"fn\"><sup>115</sup></xref> Alternatively, they may be left with no alternative to travelling to another jurisdiction in order to access abortion and suffering the associated stigma of undergoing what might in the Netherlands be categorized as an ‘unlawful’ abortion.<xref rid=\"fwad015-FN116\" ref-type=\"fn\"><sup>116</sup></xref></p>", "<title>b. Maternal indication</title>", "<p>The ministerial regulation of late terminations of pregnancy<xref rid=\"fwad015-FN117\" ref-type=\"fn\"><sup>117</sup></xref> deals solely with abortions based upon an embryopathic indication, post-viability abortions on the basis of a maternal indication fall out with the Wafz, exposing the doctor to criminal liability under both Articles 289 (murder) with 82a, and 296 (abortion) of the WvS concurrently. However, abortion due to a maternal indication <italic toggle=\"yes\">can</italic> be justified by necessity.<xref rid=\"fwad015-FN118\" ref-type=\"fn\"><sup>118</sup></xref> According to the Dutch Association for Obstetrics and Gynaecology (NVOG), maternal indications warranting termination of pregnancy to reduce severe maternal morbidity and prevent mortality include hypertensive disorders, severe impairment of cardiac function, rejection of a transplant organ and sepsis.<xref rid=\"fwad015-FN119\" ref-type=\"fn\"><sup>119</sup></xref> Generally, in the case of a maternal indication for abortion, labour will be induced. In such cases, the intention is not to kill the fetus and if the child is stillborn no offence will be committed.<xref rid=\"fwad015-FN120\" ref-type=\"fn\"><sup>120</sup></xref> If the fetus dies as a result of the termination, the unnatural death must be reported to the municipal pathologist, but no referral to an assessment committee, or the prosecuting authorities is required.<xref rid=\"fwad015-FN121\" ref-type=\"fn\"><sup>121</sup></xref></p>", "<p>In comparison with embryopathically indicated abortion, abortion based on averting serious harm to the pregnant person’s life or health is subject to relatively few rules and is primarily dealt with by professional guidance.<xref rid=\"fwad015-FN122\" ref-type=\"fn\"><sup>122</sup></xref> Clinical expertise is recognized, but in the context of a maternal indication the exercise of that expertise is not subjected to oversight by an independent review commission, or the prosecution authorities. The two indications are distinct: in the case of a maternal indication, there is a claim to self-defence, the pregnant person’s life and/or health is prioritized over that of the fetus.<xref rid=\"fwad015-FN123\" ref-type=\"fn\"><sup>123</sup></xref> However, it is clear that this indication is narrowly construed, being limited to physical rather than mental health.<xref rid=\"fwad015-FN124\" ref-type=\"fn\"><sup>124</sup></xref> Furthermore, it cannot be used to justify late abortion in circumstances where the pregnant person finds themself in an emergency situation unrelated to an imminent threat to life or health, for example, where they seek a late abortion due to domestic violence. In such cases, the often-vulnerable people will be left with no alternative but to travel to obtain an abortion in another country or to procure abortifacients without medical support.</p>", "<title>III. COMPARATIVE ANALYSIS</title>", "<p>Reflecting upon the regulatory frameworks for abortion in England and Wales and the Netherlands, two key themes appear: (i) the use and impact of the criminal law to regulate abortion; and (ii) the framing of abortion as a medical decision aimed at alleviating a crisis, rather than as an individual’s reproductive choice. Central to both themes is the significance attributed to viability by the law. We argue that viability, a concept of uncertain parameters, is ill-suited to, and overemphasized in, the abortion context,<xref rid=\"fwad015-FN125\" ref-type=\"fn\"><sup>125</sup></xref> and that abortion has no place in the criminal law. Pregnant people should be empowered to exercise their autonomy and reproductive freedom, rather than be subject to a third-party decision that abortion is permissible in the circumstances, <italic toggle=\"yes\">whatever the stage of pregnancy</italic>.</p>", "<title>A. Criminalization</title>", "<p>In both jurisdictions, abortion is constructed as a crime,<xref rid=\"fwad015-FN126\" ref-type=\"fn\"><sup>126</sup></xref> albeit with an exception when performed by a doctor in accordance with the AA 1967 (England and Wales) or the Wafz 1981 (the Netherlands). The use of the criminal law to regulate abortion is symbolic, as Andrew Simester and Andreas von Hirsch argue, ‘criminal law has a communicative function which the civil law does not. It speaks with a distinctively moral voice.’<xref rid=\"fwad015-FN127\" ref-type=\"fn\"><sup>127</sup></xref> In the context of abortion, this distinctively moral voice over-regulates and exceptionalizes abortion compared to other forms of healthcare.</p>", "<p>Abortion (both medical and surgical) is an incredibly common procedure in the UK;<xref rid=\"fwad015-FN128\" ref-type=\"fn\"><sup>128</sup></xref> in 2021, there were 214,256 abortions in England and Wales (around 16.8 per 1000 women).<xref rid=\"fwad015-FN129\" ref-type=\"fn\"><sup>129</sup></xref> Despite the fact that it is so common, and much more common than other procedures, no other medical procedure is subject to the same level of regulation where detailed requirements are set out concerning where the procedure may be undertaken, by whom and when.<xref rid=\"fwad015-FN130\" ref-type=\"fn\"><sup>130</sup></xref> These requirements are not dictated by medical risk, instead, they are designed to underline the idea that abortion is <italic toggle=\"yes\">not</italic> a standard medical procedure.<xref rid=\"fwad015-FN131\" ref-type=\"fn\"><sup>131</sup></xref> The fact that abortion is treated differently from other medical procedures ensures that the stigma attached to it endures.<xref rid=\"fwad015-FN132\" ref-type=\"fn\"><sup>132</sup></xref> Indeed, the very fact that abortion remains a crime has a chilling effect,<xref rid=\"fwad015-FN133\" ref-type=\"fn\"><sup>133</sup></xref> with serious consequences for access. Moreover, as the WHO notes, criminalization can significantly impact upon ‘the provision of quality care’ by suppressing healthcare professionals’ ‘actions due to the fear of reprisals or penalties.’<xref rid=\"fwad015-FN134\" ref-type=\"fn\"><sup>134</sup></xref> This is echoed by the 2022 LTP Evaluation’s finding that doctors were reluctant to perform late abortions even when permitted by the regulations, preferring to refer pregnant persons to clinics abroad due to concern about the potential for incurring criminal liability. This concern extends to a misplaced fear of prosecution for referring their patient to a clinic in another jurisdiction where late abortion is lawful.<xref rid=\"fwad015-FN135\" ref-type=\"fn\"><sup>135</sup></xref> Such concerns were found not only to limit access to later abortion on embryopathic grounds in the Netherlands, but also to negatively impact upon proper transfer to another doctor and aftercare where pregnant people sought abortion in another jurisdiction.<xref rid=\"fwad015-FN136\" ref-type=\"fn\"><sup>136</sup></xref></p>", "<p>This chilling effect is particularly pronounced in the Netherlands,<xref rid=\"fwad015-FN137\" ref-type=\"fn\"><sup>137</sup></xref> where post-viability abortions fall outside the scope of the Wafz. Article 82a of the WvS extends the scope of the crimes against life delineated in the Penal Code to apply to the viable fetus, making viability the boundary between lawful medical termination of pregnancy and a crime against life. Pre-viability abortion (even in the case of maternal or embryopathic indication) is framed as resolving the pregnant person’s emergency situation and will not require notification to an Assessment Committee, or the prosecution authorities. After viability, their emergency situation will be disregarded in all but the most extreme circumstances, indicating the crucial nature of viability in this context. Post-viability abortion may be permissible in the case of a maternal or a narrowly defined embryopathic indication, but if the fetus is viable such abortions will constitute criminal acts and require justification.</p>", "<p>The impact of criminalization was criticized by the Central Expert Committee on Late Termination of Pregnancy Regulations, leading to the recommendation that the Dutch Penal Code should be amended to include an exemption for termination after viability on the basis of an embryopathic (encompassing both categories) and a maternal indication.<xref rid=\"fwad015-FN138\" ref-type=\"fn\"><sup>138</sup></xref> Currently, where the doctor complies with the due care criteria, abortion in the case of a threat to the pregnant person’s life or health will be justified by reference to necessity. A criminal investigation will only be initiated if there are grounds to believe that the due care criteria have not been satisfied. Similarly, abortions performed on the basis of fatal fetal anomaly, where crucially the fetus is judged non-viable, will not be referred to the prosecuting authorities if the Assessment Committee is satisfied that the usual due care criteria were fulfilled. However, in the case of non-fatal fetal anomaly, the regulations demand an automatic referral to the prosecution authorities, regardless of the conclusion reached by the committee. Seen in this light, merely conducting an abortion on the basis of fetal anomaly might be perceived as <italic toggle=\"yes\">inviting</italic> review and ultimately prosecution. Unsurprisingly, this has a chilling effect, rendering many doctors reluctant to perform abortions post-viability, to subject themselves to a criminal investigation. The categorization of post-viability abortion as a criminal act is not just empty symbolism. The potential for prosecution <italic toggle=\"yes\">is</italic> real, particularly in the case of category 2 (non-fatal) embryopathic abortion;<xref rid=\"fwad015-FN139\" ref-type=\"fn\"><sup>139</sup></xref> the stigma is real.<xref rid=\"fwad015-FN140\" ref-type=\"fn\"><sup>140</sup></xref></p>", "<p>In England and Wales, viability takes a similarly central role as we outlined earlier because abortion is available on socio-medical grounds before 24 weeks, but after this point it constitutes a crime unless performed to save the pregnant person’s life or avert grave permanent injury to their health, or an embryopathic indication. It is important to note that the embryopathic indication is comparatively broad in England and Wales, especially when compared to the Netherlands; it requires a substantial risk that the fetus will be ‘handicapped’, rather than ‘no reasonable doubt’ about the prognosis and diagnosis.<xref rid=\"fwad015-FN141\" ref-type=\"fn\"><sup>141</sup></xref> Despite requiring only that the doctors form the opinion in good faith that there is a substantial risk the child will be ‘seriously handicapped’, cases such as <italic toggle=\"yes\">Jepson</italic> and <italic toggle=\"yes\">Crowter</italic> have underlined the ill-defined nature of the indication. In 2022, the Court of Appeal reasoned that doctors are used to making decisions assessing risk and degree of disability and that ‘Parliament's use of broad concepts such as “substantial risk” and “serious handicap” properly reflects that context’.<xref rid=\"fwad015-FN142\" ref-type=\"fn\"><sup>142</sup></xref> However, the British Medical Association has argued that doctors are anxious ‘about the risk of criminal prosecution if their clinical judgment is challenged in relation to a [post-viability] abortion’, leading to concern that pregnant persons are ‘sometimes encouraged to make decisions before the 24-week time limit’.<xref rid=\"fwad015-FN143\" ref-type=\"fn\"><sup>143</sup></xref></p>", "<p>The viability threshold is particularly burdensome in the non-lethal fetal anomaly context in both jurisdictions. It is not until 20–22 weeks’ gestation that the fetal organs are sufficiently developed to enable anomalies to be identified by ultrasound. If terminations are to be performed before 24 weeks, little time is available to the pregnant person to seek advice and counselling if desired, to understand the nature of the fetal anomaly, and make a decision about termination. Moreover, in some cases clarity about the diagnosis and prognosis may not be achieved before the 24th week, leading to pressure to make a decision without the full facts before the artificial deadline that results from professionals’ concerns about the potential for criminal liability in the case of late termination of pregnancy.<xref rid=\"fwad015-FN144\" ref-type=\"fn\"><sup>144</sup></xref> The chilling effect of the criminal law is evident in both jurisdictions; pregnant people are pressured into making quick decisions in order to ensure they have a pre- rather than post-viability abortion. Where it is too late for this, some people find themselves having to travel abroad to access abortion or may source medication online to end their pregnancies without medical assistance; others will find themselves forced to continue the pregnancy to term.<xref rid=\"fwad015-FN145\" ref-type=\"fn\"><sup>145</sup></xref></p>", "<p>While viability is determinative of the relative ease of access to abortion (or indeed, if it is permissible at all), this threshold only applies to cases of medical termination of pregnancy. Where the abortion is induced <italic toggle=\"yes\">outside</italic> the scope of the Act, it is criminalized from implantation onwards. Significantly, and unlike the Dutch law, the pregnant person themselves may commit the offence of procuring their own miscarriage in England and Wales (section 58 OAPA 1861), or later in pregnancy the offence of child destruction (section 1 of the ILPA 1929), an important point given the wide-scale accessibility of abortion pills on the internet.<xref rid=\"fwad015-FN146\" ref-type=\"fn\"><sup>146</sup></xref> Recently, there has been a significant increase in individuals being charged with procuring a miscarriage for sourcing and administering abortifacients without medical support.<xref rid=\"fwad015-FN147\" ref-type=\"fn\"><sup>147</sup></xref> In such cases, viability is regarded as an aggravating factor and the pregnant person is framed as an aggressor. This characterization is evident in the sentencing of Sarah Catt, who bought misoprostol online after failing to obtain an abortion at two clinics due to the late stage of her pregnancy. Upon sentencing her to eight years imprisonment, Cooke J stressed:</p>", "<p>Representing the ‘strong arm of the law’, cogent reasons are required to justify the use of criminal law to regulate any area of law and its use is particularly disproportionate in the case of a procedure framed, in both jurisdictions considered here, as medical treatment.<xref rid=\"fwad015-FN149\" ref-type=\"fn\"><sup>149</sup></xref> The protection afforded to the fetus by the criminal law is largely symbolic; while subject to monitoring, abortion remains widely available up to viability in both jurisdictions. However, the symbolism is important, as Rebecca Cook has argued, ‘By framing abortion as a crime societies ascribe deviance to those seeking and providing it.’<xref rid=\"fwad015-FN150\" ref-type=\"fn\"><sup>150</sup></xref></p>", "<p>Similarly, the protection afforded to pregnant persons’ life and health through the criminalization of abortion is limited. This is exemplified in those circumstances where impacted pregnant persons are left with no option but to source a termination outside the jurisdiction. Where abortions are sought in other jurisdictions, pregnant persons often have more limited opportunities for follow-up care and may find it distressing to complete the termination abroad and then potentially bring home the remains of their fetus, or commence the termination abroad, travelling home while it is in progress. Alternatively, abortion-seekers must avail themselves of unlawful opportunities to purchase abortion pills online. The continued regulation of abortion as a crime acts as a barrier to access, engendering uncertainty and fear on the part of doctors at the boundary of viability and stigmatizing those seeking to exercise their reproductive liberty.<xref rid=\"fwad015-FN151\" ref-type=\"fn\"><sup>151</sup></xref> In its 2022 abortion care guidelines, the WHO noted the problem of stigma arising from criminalization and recommended the full decriminalization of abortion by:</p>", "<p>On the international stage, there have been increasing calls to decriminalize abortion due to the harm that arises from its regulation as a crime.<xref rid=\"fwad015-FN153\" ref-type=\"fn\"><sup>153</sup></xref> Thus, the United Nations Special Rapporteurs have repeatedly called for states to decriminalize abortion.<xref rid=\"fwad015-FN154\" ref-type=\"fn\"><sup>154</sup></xref> Both the Netherlands and the UK have ratified the UN Convention on the Elimination of All Forms of Discrimination Against Women (CDEAW), that specifies that women should have the right to control their reproduction: ‘the same rights to decide freely and responsibly on the number and spacing of their children and to have access to the information, education and means to enable them to exercise these rights.’<xref rid=\"fwad015-FN155\" ref-type=\"fn\"><sup>155</sup></xref> In condemning the United Kingdom for a legal framework that only allowed abortion in Northern Ireland where necessary to save the pregnant person’s life, the Committee on CDEAW found that ‘criminalization of abortion amounts to discrimination against women’.<xref rid=\"fwad015-FN156\" ref-type=\"fn\"><sup>156</sup></xref> The legal framework in question was sections 58–59 of the OAPA 1861,<xref rid=\"fwad015-FN157\" ref-type=\"fn\"><sup>157</sup></xref> which has now been repealed in Northern Ireland but is still the basis of the law on abortion in England and Wales. We suggest that the time has come for both jurisdictions, and others across the globe, to follow the lead of jurisdictions in Latin America (Argentina, Colombia, Mexico),<xref rid=\"fwad015-FN158\" ref-type=\"fn\"><sup>158</sup></xref> to remove abortion from the ambit of the criminal law<xref rid=\"fwad015-FN159\" ref-type=\"fn\"><sup>159</sup></xref> and to subject it to the normal rules applicable to medical treatment. As Herring and others have explained: ‘abortion services are already (and would remain) subject to a dense web of other regulation, including general provisions of criminal and civil law, licensing and inspection requirements, and professional oversight.’<xref rid=\"fwad015-FN160\" ref-type=\"fn\"><sup>160</sup></xref> Thus, decriminalization abortion would still be appropriately regulated, rather than over-regulated.</p>", "<title>B. The medicalization of abortion and disregard for autonomy</title>", "<p>Both jurisdictions characterize abortion as a medical solution to a ‘crisis’ pregnancy up to viability, foregrounding medical authority rather than human rights and devolving abortion decisions to the medical profession. In framing abortion entirely as a medical matter, rather than a broader matter of controlling one’s own reproductive freedom (whether conceptualized as the right to bodily integrity, or liberty to decide whether and how to reproduce), access to abortion remains fragile. In adopting a medical model of regulation, both jurisdictions fail to recognize a role for pregnant people’s autonomy beyond their ability to request an abortion and the necessity that they consent to the procedure. This stands in direct contention with WHO’s recommendations that abortion be available on request, and that legal frameworks should not ‘restrict abortion by grounds,’<xref rid=\"fwad015-FN161\" ref-type=\"fn\"><sup>161</sup></xref> or gestational time limits.<xref rid=\"fwad015-FN162\" ref-type=\"fn\"><sup>162</sup></xref></p>", "<p>Abortion is <italic toggle=\"yes\">exceptionalized—</italic>subjected to additional rules outside the general legal framework applicable to medical treatment—in both legal frameworks.<xref rid=\"fwad015-FN163\" ref-type=\"fn\"><sup>163</sup></xref> There are no good clinical reasons to separate out abortion as distinct from other areas of healthcare; the procedure is very safe and there are no legitimate justifications for treating abortion medications and procedures as distinct from other healthcare interventions with similarly low levels of risk/invasiveness. While some may argue that there are justifications for treating abortion ’differently,’ such conceptions of the treatment are about moral perceptions of the appropriateness of the treatment.<xref rid=\"fwad015-FN164\" ref-type=\"fn\"><sup>164</sup></xref> The exceptionalism in treating abortion differently is stigmatizing to both the pregnant person (who is framed as requiring assistance to make a careful choice and whose choice is subject to validation by a third party (the doctor applying a set of legal rules)) and the doctor who terminates the pregnancy.<xref rid=\"fwad015-FN165\" ref-type=\"fn\"><sup>165</sup></xref></p>", "<p>Abortion is widely available prior to viability and funded by the state in both jurisdictions, however the procedural requirements in both Dutch and English law emphasize that it is not simply a reproductive choice, but a medical solution, one that uniquely requires state supervision.<xref rid=\"fwad015-FN166\" ref-type=\"fn\"><sup>166</sup></xref> These procedural requirements, doing both the work of ‘moralising’ the choice to have an abortion and the work of helping people have abortions, have significant impacts on the quality of care in a multitude of ways,<xref rid=\"fwad015-FN167\" ref-type=\"fn\"><sup>167</sup></xref> including, for example, delaying access for bureaucratic reasons. That pre-viability abortions are widely available in both jurisdictions is the result of the liberal approach taken by doctors to abortion, minimizing the impact of the substantive and procedural requirements on individuals needing abortion.<xref rid=\"fwad015-FN168\" ref-type=\"fn\"><sup>168</sup></xref> However, despite the availability of abortion, reproductive freedom is fragile because it is dependent upon medical benevolence rather than the right to control one’s own body and reproductive future.</p>", "<p>The wording of the Dutch Act emphasizes that it is not the individual’s desire to terminate their pregnancy but their emergency situation that renders abortion permissible. Similarly, Sally Sheldon’s work analysing the passage of the AA 1967 identified that only ‘3 images of femininity … [were] presented in the debates: the [pregnant person] as minor, as victim and as mother.’<xref rid=\"fwad015-FN169\" ref-type=\"fn\"><sup>169</sup></xref> In each case, it was argued that the pregnant person was unable, or unfit, to elect an abortion alone. The procedural requirements imposed in the Acts in both jurisdictions emphasize the pregnant person’s lack of agency. The requirement that two doctors agree that an abortion is permissible in England and Wales,<xref rid=\"fwad015-FN170\" ref-type=\"fn\"><sup>170</sup></xref> or that a doctor determines that there is no alternative means of resolving the individual’s emergency situation than to terminate the pregnancy in the Netherlands, serve only to delay access to abortion and to underline that pregnant people are judged incapable of making the decision to have an abortion for themselves while professional judgement is preserved and prioritized.<xref rid=\"fwad015-FN171\" ref-type=\"fn\"><sup>171</sup></xref></p>", "<p>The very limited role ascribed to autonomy is disregarded once the fetus achieves viability, even though people can experience pregnancy during the third trimester as a crisis situation in exactly the same way as prior to viability. It is the <italic toggle=\"yes\">pregnancy</italic> and not the gestational age of the fetus that constitutes the emergency. The British Pregnancy Advisory Service conducted research into the reasons for ‘late’ abortions and found that rarely was this due to delayed decision-making.<xref rid=\"fwad015-FN172\" ref-type=\"fn\"><sup>172</sup></xref> Generally, respondents had only recently become aware that they were pregnant (because they were using contraception, breastfeeding, or had irregular periods), and some were vulnerable because of domestic violence, or were teenagers.<xref rid=\"fwad015-FN173\" ref-type=\"fn\"><sup>173</sup></xref> We argue that the viability threshold that prevents such people from accessing safe and legal abortion is inappropriate and stigmatizing. It is also based upon a false premise as there is no evidence that removing the viability threshold would lead to an increase in later term abortions in either jurisdiction,<xref rid=\"fwad015-FN174\" ref-type=\"fn\"><sup>174</sup></xref> but it would, we suggest, lead to better and safer care for those seeking abortion by obviating the need to travel abroad or to obtain abortion pills online and risking prosecution.</p>", "<title>C. Viability</title>", "<p>The saying ‘timing is everything’ proves particularly true in the case of abortion regulation where time defines the boundary between criminal abortion and permissible medical practice. Both jurisdictions start from the position that the fetus is not a legal person,<xref rid=\"fwad015-FN175\" ref-type=\"fn\"><sup>175</sup></xref> but have taken an incrementalist approach to regulating abortion. In the Netherlands, this has been taken to an extreme as Article 82a of the WvS extends the scope of the crimes against life to apply to a fetus. It thus conflates the fetus with a newborn<xref rid=\"fwad015-FN176\" ref-type=\"fn\"><sup>176</sup></xref> and eschews the qualifying characteristic applied to homicide offences in England and Wales—that the person killed must have been born alive. By comparison, although the ILPA creates the offence of child destruction in England and Wales, it does not treat the fetus as synonymous with a child. Indeed, the offence of child destruction is a specific offence created precisely to protect ‘the child capable of being born alive,’ rather than extending the ambit of the offences of murder or infanticide. Moreover, even though the maximum penalty for child destruction is life imprisonment, unlike the sentence for murder, it is not a mandatory life sentence; thus, clearly distinguishing between the ‘killing’ of a fetus and a person extant.</p>", "<p>In both jurisdictions, viability represents the cut-off point beyond which a pregnancy cannot be terminated unless it poses a threat to the pregnant person’s life or health or is embryopathically indicated. It might be argued that viability is a ‘compromise position’ because it allows abortion on broader grounds before viability and then only on strict therapeutic grounds afterwards. However, such a conceptualization fails to recognize the incongruity of applying an unrelated medical concept (one that is used to estimate the likelihood of survival if the fetus were to be born at a given point in time) to determining whether an individual can terminate an unwanted pregnancy. Furthermore, placing significant emphasis on the different ‘justifications’ for abortion earlier and later in a pregnancy does a disservice to reproductive autonomy: specifically, in failing to recognize that there is a need for abortion later in pregnancy for ‘a broad range of reasons.’<xref rid=\"fwad015-FN177\" ref-type=\"fn\"><sup>177</sup></xref> It disregards the lived experiences of persons experiencing difficult pregnancies or pregnancy in difficult circumstances. The WHO explicitly recommends against laws/other regulations prohibiting abortions based on viability (or gestational age limits)<xref rid=\"fwad015-FN178\" ref-type=\"fn\"><sup>178</sup></xref> and yet both England and Wales and the Netherlands continue to do so.</p>", "<title>i. The construct of viability: definition and parameters</title>", "<title>a. Legal certainty</title>", "<p>The need for certainty is particularly important in criminal law where the liberty of the individual is at stake. However, reliance upon viability in the regulation of abortion breaches this requirement both by its inherent vagueness and the uncertainty it creates in the application of the law. We argue that references to viability, whether as a general concept as in Article 82a of the WvS and the ILPA (albeit with a rebuttable presumption of viability set at 28 weeks), or as a particular point in time (24 weeks) in the AA, fail to recognize the inherently uncertain boundaries of viability. Article 82a of the WvS describes viability as being present when the ‘fetus can reasonably be expected to have the ability to survive outside the mother’s body.’ Similarly, section 1 of the ILPA refers to ‘a child capable of being born alive.’ Both of these phrases require clarification—<italic toggle=\"yes\">how long must an entity survive after birth</italic>? The Dutch Supreme Court has stated that it is not necessary to expect the neonate to survive for a lengthy period of time to fulfil the criteria of Article 82a of the WvS,<xref rid=\"fwad015-FN179\" ref-type=\"fn\"><sup>179</sup></xref> while the English Court of Appeal noted that an integral characteristic of a ‘child capable of being born alive’ is the ability to breathe (with or without the support of a ventilator).<xref rid=\"fwad015-FN180\" ref-type=\"fn\"><sup>180</sup></xref> It would appear that both Acts require little more than the <italic toggle=\"yes\">capacity</italic> for live birth, with no requirement that the child once born alive (taking at least one breath) have the capacity for longer-term survival. However, the meaning attributed to both provisions is subjective and has the potential to change with technology.<xref rid=\"fwad015-FN181\" ref-type=\"fn\"><sup>181</sup></xref></p>", "<p>Neonatal viability is a medical assessment and depends upon many variables, including the size, weight sex and gestational age of the fetus, the geographic location of the pregnant person, and the medical facilities available in that location.<xref rid=\"fwad015-FN182\" ref-type=\"fn\"><sup>182</sup></xref> Clinicians assess whether a particular fetus is likely to survive outside the uterus. Thus, viability is fetus specific, rather than a general measurement capable of application to all pregnancies. It is also an assessment that changes over time, with developments in perinatology enhancing the ability to support survival at ever earlier gestations.<xref rid=\"fwad015-FN183\" ref-type=\"fn\"><sup>183</sup></xref> Viability, therefore, represents not a determinate line, but a flexible boundary, rendering it ill-suited to the function of a legal bright line that legislatures seem to imagine.</p>", "<title>b. The disconnect between viability as a threshold for neonatal treatment and a threshold for lawful abortion</title>", "<p>The current boundaries for socio-medical abortion and active treatment for extremely premature neonates roughly converge, but abortion and perinatal care are very different forms of medical treatment. In abortion, the fetus is not intended to survive, whereas in the case of (extremely) premature neonates, all medical care is focused upon trying to ensure its survival. In the case of an unwanted pregnancy, the expectation will generally be that if the pregnancy continues, the child will be born healthy at full term. In the case of an extremely premature neonate, the child is born with all the health problems prematurity entails and a decision will have to be taken about whether active care should be provided.<xref rid=\"fwad015-FN184\" ref-type=\"fn\"><sup>184</sup></xref> The danger is that as the threshold for active treatment reduces in line with technological developments, it may be argued that the threshold for ‘social’ abortions should be reduced in line with viability. We argue that the two thresholds are distinct and that the status of the fetus should not be conflated with that of a neonate.</p>", "<p>From a clinical perspective, the concept of viability is uncertain. Developments in perinatology have enhanced the ability to support survival at even earlier gestations, but it is important to recognize that even those born alive will not necessarily remain alive for long; many will be too physiologically immature to survive longer-term, and many may experience (common) fatal complications in neonatal intensive care. Moreover, considering viability as a concept denoting whether a child is likely to be able to survive birth is an oversimplification. Viability is not a binary issue, as Leo Han and others have argued, ‘A meaningful discussion of neonatal viability includes not just survival, but honest and candid dialogue with the pregnant person and [their] family about what kind of life to expect.’<xref rid=\"fwad015-FN185\" ref-type=\"fn\"><sup>185</sup></xref> Both jurisdictions accept that abortion can be justified in cases of non-fatal fetal anomaly and so recognize that the capacity for survival alone will not suffice as a justification for prohibiting abortion. However, there seems to be a mismatch in the protection afforded to the fetus, in comparison to the newborn, particularly in the Netherlands. The second Dutch category is much more narrowly drawn than its English comparator, as it requires a condition that will lead to a serious and irreparable functional disorder. The fact that cases exist where abortion cannot lawfully be provided, but where doctors might determine that an extremely premature neonate should not be treated, underlines the fact that termination and active treatment of neonates are distinct. The fetus in utero should not be given greater protection than its neonatal counterpart.</p>", "<p>The embedding of fetal viability in the law on abortion is ethically problematic. Viability is a medical concept developed to determine when active treatment of a premature neonate is appropriate, not to determine whether a pregnancy can be terminated. The two situations are entirely distinct,<xref rid=\"fwad015-FN186\" ref-type=\"fn\"><sup>186</sup></xref> a fact reflected in the legal status accorded to the entity in question. While the fetus at 24 weeks’ gestation <italic toggle=\"yes\">may</italic> survive birth, the fact that it is physically located inside a person with their own rights and interests is highly significant. Unlike the neonate, the fetus at 24 weeks’ gestation has not made morally significant biological adaptations to the environment,<xref rid=\"fwad015-FN187\" ref-type=\"fn\"><sup>187</sup></xref> it has no independent existence and is functionally integrated into the pregnant person.<xref rid=\"fwad015-FN188\" ref-type=\"fn\"><sup>188</sup></xref> Nevertheless, a viability threshold does not seek to balance those interests; instead, it emphasizes the potential for life of the fetus, elevating the biological status of the fetus to trump the pregnant person’s autonomy, bodily integrity and dignity interests in all but the most extreme circumstances. However, the mere imposition of a viability threshold does little to protect fetal life in practice, rendering its value primarily symbolic. It creates access barriers and bottlenecks as pregnant people and their doctors try to terminate a pregnancy prior to the threshold or refer pregnant people to other countries where late abortions are available. Desperate people, such as Sarah Catt, unable to access abortion via the medical process, purchase abortion pills online and risk criminal sanction.<xref rid=\"fwad015-FN189\" ref-type=\"fn\"><sup>189</sup></xref> The use of the viability threshold makes it more difficult to access late abortion, disproportionally impacting upon the vulnerable, the young and those lacking the financial means or the knowledge of how to access abortion after viability. In short, the viability threshold does little to protect fetal life, but endangers pregnant people’s health.</p>" ]	[ "<title>Acknowledgements</title>", "<p>All authors contributed to the introduction. S.H. wrote Section II: Legal Frameworks: the Netherlands; E.C.R. wrote Section II: Legal Frameworks: England and Wales. S.H. and E.C.R. wrote Section III, the comparative analysis, and Section IV, the conclusion together. Ld.P. and E.J.vW. were involved in the initial conceptualization of the article and commented on drafts. A companion piece by the same authors that focuses upon the ethics of viability in the context of regulating abortion is in progress, led by Ld.P. and E.J.vW.</p>", "<p>\n<italic toggle=\"yes\">Conflict of interest statement</italic>. None declared.</p>" ]	[]	[]	[]	[]	[]	[ "<disp-quote content-type=\"extract\"><p>Any person who gives a [person] treatment, when he knows or has reasonable cause to suspect that this treatment may terminate the pregnancy, shall be liable to a term of imprisonment not exceeding four years and six months or a category four fine.</p></disp-quote>", "<disp-quote content-type=\"extract\"><p>if the [person] considers that [their] emergency situation cannot be terminated in any other way, the doctor shall satisfy himself that the [person] made and maintained [their] request voluntarily, after careful consideration and in awareness of [their] responsibility for unborn life and of the consequences for [their]self and others.<xref rid=\"fwad015-FN62\" ref-type=\"fn\"><sup>62</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p>The gravamen of this offence is that, at whatever stage life can be said to begin, the child in the womb here was so near to birth that in my judgement all right thinking people would consider this offence more serious than manslaughter or any offence on the calendar other than murder.<xref rid=\"fwad015-FN148\" ref-type=\"fn\"><sup>148</sup></xref></p></disp-quote>", "<disp-quote><p>removing abortion from all penal/criminal laws, not applying other criminal offences (e.g., murder, manslaughter) to abortion and ensuring there are no criminal penalties for having, assisting with, providing information about, or providing abortion, for all relevant actors.<xref rid=\"fwad015-FN152\" ref-type=\"fn\"><sup>152</sup></xref></p></disp-quote>" ]	[]	[]	[ "<fn-group><title>Footnotes</title><fn id=\"fwad015-FN1\"><label>1</label><p>On the importance of time in medical law see J Harrington, ‘Time as Dimension of Medical Law’ (2012) 20 Medical Law Review 491, and more specifically in the context of abortion and human rights, see J Erdman, ‘Theorizing Time in Abortion Law and Human Rights’ (2017) 19 Health Human Rights 29.</p></fn><fn id=\"fwad015-FN2\"><label>2</label><p>J Glover, <italic toggle=\"yes\">Causing Death and Saving Lives</italic> (Penguin 1990) 124.</p></fn><fn id=\"fwad015-FN3\"><label>3</label><p>A Zaitchik, ‘Viability and the Morality of Abortion’ (1981) 10 Philosophy & Public Affairs 18; M Hawking, ‘The Viable Violinist’ (2016) 30 Bioethics 312; D Jensen, ‘Birth, Meaningful Viability and Abortion’ (2015) 41 JME 460.</p></fn><fn id=\"fwad015-FN4\"><label>4</label><p>Some exceptions: EC Romanis, ‘Is “Viability” Viable? Abortion, Conceptual Confusion and the Law in England and Wales and the United States’ (2020) 7 Journal of Law Biosciences <doi.org/10.1093/jlb/lsaa059>; L De Proost and others, ‘The Edge of Perinatal Viability: Understanding the Dutch Position’ (2021) 9 Frontiers in Pediatrics 634290; Erdman (n 1).</p></fn><fn id=\"fwad015-FN5\"><label>5</label><p>See Romanis (n 4) 3–4.</p></fn><fn id=\"fwad015-FN6\"><label>6</label><p>De Proost (n 4) 3.</p></fn><fn id=\"fwad015-FN7\"><label>7</label><p>P Singer, <italic toggle=\"yes\">Practical Ethics</italic>, 3rd edn (CUP 2011) 126.</p></fn><fn id=\"fwad015-FN8\"><label>8</label><p>IG Cohen and S Sayeed, ‘Fetal Pain, Abortion, Viability and the Constitution’ (2011) 39 Journal of Law, Medicine & Ethics 235, 237.</p></fn><fn id=\"fwad015-FN9\"><label>9</label><p>World Health Organization, ‘Abortion Care Guideline’ <<ext-link xlink:href=\"https://www.who.int/publications/i/item/9789240039483\" ext-link-type=\"uri\">https://www.who.int/publications/i/item/9789240039483</ext-link>> 28, accessed 16 March 2023.</p></fn><fn id=\"fwad015-FN10\"><label>10</label><p>\n<italic toggle=\"yes\">Tweede evaluatie Wet afbreking zwangerschap</italic>, 2020 (Second Review of the Termination of Pregnancy Act), hereinafter Second Review of the Wafz, 11, 62ff; D Wilkinson, ‘Lifesaving Treatment for Babies Born at 22 Weeks doesn’t Mean Abortion Law should Change’, <italic toggle=\"yes\">The Conversation</italic> (2019) < <ext-link xlink:href=\"https://theconversation.com/lifesaving-treatment-for-babies-born-at-22-weeks-doesnt-mean-abortion-law-should-change-125845\" ext-link-type=\"uri\">https://theconversation.com/lifesaving-treatment-for-babies-born-at-22-weeks-doesnt-mean-abortion-law-should-change-125845</ext-link>> accessed 16 March 2023.</p></fn><fn id=\"fwad015-FN11\"><label>11</label><p>De Proost (n 4).</p></fn><fn id=\"fwad015-FN12\"><label>12</label><p>Second Review of the Wafz (n 10) 11, 62ff.</p></fn><fn id=\"fwad015-FN13\"><label>13</label><p>S de Zordo and others ‘Gestational Age Limits for Abortion and Cross-border Reproductive Care in Europe: A Mixed-methods Study’ (2020) 128(5) BJOG 838.</p></fn><fn id=\"fwad015-FN14\"><label>14</label><p>WHO (n 9) 28. Specifically referring to the context in England and Wales see S Sheldon, ‘The Decriminalisation of Abortion: An Argument for Modernisation’ (2016) 36 Oxford Journal of Legal Studies 345, 334–65; BPAS, ‘<italic toggle=\"yes\">But I was using contraception ….’ Why Women Present for Abortions After 20 Weeks</italic> (2017) <<ext-link xlink:href=\"https://www.bpas.org/media/2027/late-abortion-report-v02.pdf\" ext-link-type=\"uri\">https://www.bpas.org/media/2027/late-abortion-report-v02.pdf</ext-link>> accessed 16 March 2023, and in the Netherlands see Second Review of the Wafz (n 10).</p></fn><fn id=\"fwad015-FN15\"><label>15</label><p>WHO (n 9).</p></fn><fn id=\"fwad015-FN16\"><label>16</label><p>Eg, Special Rapporteur on the right of everyone to the enjoyment of the highest attainable standard of physical and mental health, Interim Report to the General Assembly (2011) (UN Doc A/66/254); Special Rapporteur on torture and other cruel, inhuman or degrading treatment or punishment, Report to the Human Rights Council (2016) (UN Doc A/HRC/31/57).</p></fn><fn id=\"fwad015-FN17\"><label>17</label><p>Note that a doctor is also guilty even if the person is not pregnant. The pregnant person can also commit this offence by procuring their own miscarriage if they were pregnant. See, for example, <italic toggle=\"yes\">R v Sarah Louise Catt</italic> (2012), unreported; <italic toggle=\"yes\">R v Natalie Towers</italic> (2015), unreported.</p></fn><fn id=\"fwad015-FN18\"><label>18</label><p>From implantation <italic toggle=\"yes\">(R (Smeaton) v Secretary of State for Health</italic> [2002] EWHC 610 (Admin)) to term.</p></fn><fn id=\"fwad015-FN19\"><label>19</label><p>ILPA 1929, s 1(2).</p></fn><fn id=\"fwad015-FN20\"><label>20</label><p>A Grubb, ‘Abortion Law in England: The Medicalization of a Crime’ (1990) 18 Law Medicine & Healthcare 146, 149; Romanis (n 4) 5.</p></fn><fn id=\"fwad015-FN21\"><label>21</label><p>AA 1967, s 1 (1) (a)–(d).</p></fn><fn id=\"fwad015-FN22\"><label>22</label><p>ibid, s 1 (2).</p></fn><fn id=\"fwad015-FN23\"><label>23</label><p>E Cave and M Brazier, <italic toggle=\"yes\">Medicine, Patients and the Law</italic> (Manchester UP 2016) 404.</p></fn><fn id=\"fwad015-FN24\"><label>24</label><p>ibid; E Jackson, <italic toggle=\"yes\">Regulating Reproduction: Law, Technology and Autonomy</italic> (Hart 2001) 80.</p></fn><fn id=\"fwad015-FN25\"><label>25</label><p>BMA, <italic toggle=\"yes\">The Law and Ethics of Abortion: BMA views</italic>, 2020 [2.1.5]; Royal College of Obstetricians and Gynaecologists, <italic toggle=\"yes\">Submission to the House of Commons Science and Technology Committee Abortion Inquiry</italic> (2006) [2.1.1]; E Raymond and D Grimes, ‘The Comparative Safety of Legal Induced Abortion and Childbirth in the United States’ (2012) 119 Obstetrics & Gynecology 215.</p></fn><fn id=\"fwad015-FN26\"><label>26</label><p>P Lohr and others, ‘How would Decriminalisation Affect Women’s Health?’ in S Sheldon and K Wellings (eds), <italic toggle=\"yes\">Decriminalising Abortion in the UK</italic> (Policy Press 2020).</p></fn><fn id=\"fwad015-FN27\"><label>27</label><p>JA Parsons and EC Romanis, <italic toggle=\"yes\">Early Medical Abortion, Equality of Access, and the Telemedical Imperative</italic> (OUP 2021) 17.</p></fn><fn id=\"fwad015-FN28\"><label>28</label><p>ibid.</p></fn><fn id=\"fwad015-FN29\"><label>29</label><p>Romanis (n 4) 5.</p></fn><fn id=\"fwad015-FN30\"><label>30</label><p>A Grubb, ‘The New Law of Abortion: Clarification or Ambiguity?’ (1991) Criminal Law Review 659, 661.</p></fn><fn id=\"fwad015-FN31\"><label>31</label><p>Romanis (n 4) 11.</p></fn><fn id=\"fwad015-FN32\"><label>32</label><p>ibid 5.</p></fn><fn id=\"fwad015-FN33\"><label>33</label><p>Grubb (n 20) 149; J Keown, ‘The Scope of the Offence of Child Destruction’ (1988) 104 <italic toggle=\"yes\">LQR</italic> 120, 123ff. Homicide has always, in English law, been restricted to those born alive, E Coke <italic toggle=\"yes\">Institutes</italic> III, 1648, 50, and affirmed by the House of Lords in <italic toggle=\"yes\">Attorney-General’s Reference (No 3 of 1994)</italic> [1998] AC 245.</p></fn><fn id=\"fwad015-FN34\"><label>34</label><p>ILPA 1929, s 1(1).</p></fn><fn id=\"fwad015-FN35\"><label>35</label><p>Romanis (n 4) 7. See also J K Mason, <italic toggle=\"yes\">The Troubled Pregnancy: Legal Rights and Wrongs in Reproduction</italic> (CUP 2007) 21; EC Romanis, ‘Challenging the ‘Born Alive’ Threshold: Fetal Surgery, Artificial Wombs, and the English Approach to Legal Personhood’ (2020) 28 Medical Law Review 93–123.</p></fn><fn id=\"fwad015-FN36\"><label>36</label><p>Grubb (n 30) 663.</p></fn><fn id=\"fwad015-FN37\"><label>37</label><p>See, for example, <italic toggle=\"yes\">R v Davison</italic> (2021) unreported; <italic toggle=\"yes\">R v Wilson</italic> [2017] 1 Cr App R (S). But note <italic toggle=\"yes\">R v Mohammed</italic> (2007) unreported, where an individual was convicted of child destruction following a termination at 34 weeks gestation. It was not established who had terminated the pregnancy.</p></fn><fn id=\"fwad015-FN38\"><label>38</label><p>\n<italic toggle=\"yes\">C v S</italic> [1988] 1 QB 135; <italic toggle=\"yes\">Rance and Another v Mid-Downs Health Authority and Another</italic> [1991] 1 QB 587.</p></fn><fn id=\"fwad015-FN39\"><label>39</label><p>\n<italic toggle=\"yes\">R v Bako</italic> (2015), unreported.</p></fn><fn id=\"fwad015-FN40\"><label>40</label><p>See, for example, <italic toggle=\"yes\">R v Davison</italic> (2021) unreported: 29 weeks; <italic toggle=\"yes\">R v Wilson</italic> [2017] 1 Cr App R (S): 32 weeks; <italic toggle=\"yes\">R</italic> v <italic toggle=\"yes\">Mohammed</italic> (2007) unreported: 34 weeks.</p></fn><fn id=\"fwad015-FN41\"><label>41</label><p>Grubb (n 20) 150; Romanis (n 35) 116.</p></fn><fn id=\"fwad015-FN42\"><label>42</label><p>AA 1967, s 1(1)(b).</p></fn><fn id=\"fwad015-FN43\"><label>43</label><p>The examples given in the HL debates: HL Vol 522 Col 1039.</p></fn><fn id=\"fwad015-FN44\"><label>44</label><p>s 1(1)(d) AA 1967.</p></fn><fn id=\"fwad015-FN45\"><label>45</label><p>RCOG, <italic toggle=\"yes\">Termination of pregnancy for fetal abnormality in England, Scotland and Wales</italic>, 2010, 9; BMA (n 25) [2.1.4].</p></fn><fn id=\"fwad015-FN46\"><label>46</label><p>See for example S McGuinness, ‘Law, Reproduction, and Disability: Fatally “Handicapped”?’ (2013) 21 Medical Law Review 213; R Scott, ‘Interpreting the Disability Ground of the Abortion Act’ (2005) 64 Cambridge Law Journal 388, 396.</p></fn><fn id=\"fwad015-FN47\"><label>47</label><p>\n<italic toggle=\"yes\">Crowter v Secretary of State for Health and Social Care</italic> [2021] EWHC 2536. The claimants sought a declaration of incompatibility in respect of s 1(1)(d) AA 1967, arguing that it is incompatible with arts 2, 3, 8 and 14 of the European Convention on Human Rights because it differentiates between pregnancies where there is a substantial risk that, if born, a child would be ‘seriously handicapped’ and pregnancies where it would not, permitting only the former category to be terminated after viability absent a medical indication. Although the claimants focused upon Down’s syndrome, they argued that this distinction would be impermissible in any case where a risk of ‘serious handicap’ was used. The court dismissed the claim, finding that the focus of s 1(1)(d) is the rights of the pregnant person and their medical treatment, rather than the fetus even after viability [102]. For an excellent analysis of this decision see Z Tongue, ‘<italic toggle=\"yes\">Crowter v Secretary of State for Health and Social Care</italic> [2021] EWHC 2536: Discrimination, Disability, and Access to Abortion’ (2021) 30 Medical Law Rev 177. Moreover, as the Supreme Court recognized in <italic toggle=\"yes\">Re Northern Ireland Human Rights Commission’s Application for Judicial Review</italic> [2018] UKSC 27, ‘the current legislation already recognises important limitations on the interests and protection of the unborn fetus. It permits abortion of a healthy fetus in circumstances where the mother’s life would be at risk or where she would suffer serious long-term damage to her physical or psychological health. There is therefore no question of any absolute protection of even a healthy fetus,’ [119] <italic toggle=\"yes\">per</italic> Lord Mance.</p></fn><fn id=\"fwad015-FN48\"><label>48</label><p>\n<italic toggle=\"yes\">Jepson v Chief Constable of West Mercia Police</italic> [2003] EWHC 3318 (Admin). Jepson sought judicial review of the decision not to prosecute doctors who had terminated a pregnancy involving a viable fetus with a cleft palate. Following a police investigation, the West Mercia Chief Crown Prosecutor confirmed that on the evidence the doctors had formed the necessary opinion in good faith and that there should be no charges against them.</p></fn><fn id=\"fwad015-FN49\"><label>49</label><p>RCOG (n 45) 8.</p></fn><fn id=\"fwad015-FN50\"><label>50</label><p>ibid.</p></fn><fn id=\"fwad015-FN51\"><label>51</label><p>ibid 9.</p></fn><fn id=\"fwad015-FN52\"><label>52</label><p>BMA (n 25) [2.1.1]; This is discussed further below, Section IV.</p></fn><fn id=\"fwad015-FN53\"><label>53</label><p>\n<italic toggle=\"yes\">Wetboek van Strafrecht.</italic>\n</p></fn><fn id=\"fwad015-FN54\"><label>54</label><p>\n<italic toggle=\"yes\">Wet afbreking zwangerschap.</italic>\n</p></fn><fn id=\"fwad015-FN55\"><label>55</label><p>\n<italic toggle=\"yes\">Besluit afbreking zwangerschap.</italic>\n</p></fn><fn id=\"fwad015-FN56\"><label>56</label><p>Kamerstukken II 1978/79, 15475, 3 <italic toggle=\"yes\">Regelen met betrekking tot het afbreken van zwangerschap (Wet afbreking zwangerschap)</italic> (Explanatory Memorandum, Regulations regarding the Termination of Pregnancy (Wafz)), 9–10.</p></fn><fn id=\"fwad015-FN57\"><label>57</label><p>Explanatory Memorandum (n 56) 9–10, 15–17. The Explanatory Memorandum to the Act explains that: ‘Induced abortion is a measure that can only be justified by the needs of [pregnant persons]. However, we do not consider it possible to define these emergencies in the law. The circumstances that can justify the termination of a pregnancy in individual cases cannot be translated into general terms, let alone recorded in a legal formula’, 15–16.</p></fn><fn id=\"fwad015-FN58\"><label>58</label><p>The premise of the Act is that abortion will result from an unwanted pregnancy; that only unwanted pregnancies are terminated. However, where a pregnancy is terminated due to a risk to the pregnant person’s health or life, or because of fetal anomalies, the pregnancy was usually desired, or at least the pregnant person had decided to continue the pregnancy.</p></fn><fn id=\"fwad015-FN59\"><label>59</label><p>art 296 (1) WvS.</p></fn><fn id=\"fwad015-FN60\"><label>60</label><p>ibid</p></fn><fn id=\"fwad015-FN61\"><label>61</label><p>art 296 (5) WvS.</p></fn><fn id=\"fwad015-FN62\"><label>62</label><p>art 5(2)(b) Wafz.</p></fn><fn id=\"fwad015-FN63\"><label>63</label><p>art 5(2)(c) Wafz.</p></fn><fn id=\"fwad015-FN64\"><label>64</label><p>art 5(2)(a) Wafz.</p></fn><fn id=\"fwad015-FN65\"><label>65</label><p>art 3 Wafz; the Act designated a reflection period of five days except where necessary to save life, but this was subject to sustained criticism, see for example <italic toggle=\"yes\">Evaluatie Wet afbreking zwangerschap</italic> (Review of the Termination of Pregnancy Act) 2005, 158; Second Review of the Termination of Pregnancy Act 2020 (n 10) 83–86; J de Bree, ‘<italic toggle=\"yes\">Bezint eer ge begint: de beraadtermijn voor abortus in gezondheidsrechtelijk perspectief</italic>’ (2021) 45(4) <italic toggle=\"yes\">Tijdschrift voor Gezondheidsrecht</italic> 374. In 2022, an amendment was passed, replacing the fixed reflection period with a flexible period, allowing doctors and pregnant persons to determine the appropriate length of time in the circumstances, VAO Pregnancy and Birth, AO 10/12.</p></fn><fn id=\"fwad015-FN66\"><label>66</label><p>Explanatory Memorandum (n 56) at [23].</p></fn><fn id=\"fwad015-FN67\"><label>67</label><p>arts 289, 82a WvS.</p></fn><fn id=\"fwad015-FN68\"><label>68</label><p>art 296 WvS.</p></fn><fn id=\"fwad015-FN69\"><label>69</label><p>If the pregnant person induces the abortion themselves, they are liable to prosecution for child murder, or infanticide, arts 290, 291, 82a WvS. The pregnant person is excluded from the ambit of art 296, cf s 58 OAPA 1861 where the pregnant person is one of the addressees of the prohibition.</p></fn><fn id=\"fwad015-FN70\"><label>70</label><p>Explanatory Memorandum (n 56) 32–33. Similarly, art 2 Burial and Cremation Act 1991 (<italic toggle=\"yes\">Wet op de lijkbezorging</italic>) defines stillbirth as a fetus born at a gestational age of at least 24 weeks, or at an earlier gestation if it survives more than 24 hours after birth, recognising that viability may occur below 24 weeks.</p></fn><fn id=\"fwad015-FN71\"><label>71</label><p>NJ 1991, 217: HR, May 29, 1990, No 87203.</p></fn><fn id=\"fwad015-FN72\"><label>72</label><p>ibid 5.1.</p></fn><fn id=\"fwad015-FN73\"><label>73</label><p>Second Review of the Wafz (n 10) 60.</p></fn><fn id=\"fwad015-FN74\"><label>74</label><p>F Söderström and others, ‘Outcomes of a Uniformly Active Approach to Infants Born at 22-24 Weeks of Gestation’ (2021) 106 Archives of Disease in Childhood. Fetal and Neonatal Edition 413.</p></fn><fn id=\"fwad015-FN75\"><label>75</label><p>De Proost (n 4).</p></fn><fn id=\"fwad015-FN76\"><label>76</label><p>MW de Laat and others, ‘Richtlijn “Perinataal beleid bij extreme vroeggeboorte”’ (Guideline ‘Perinatal care for extremely premature neonates’) (2010) Ned Tijdschr Geneeskd 1.</p></fn><fn id=\"fwad015-FN77\"><label>77</label><p>Second Review of the Wafz (n 10) 67; <italic toggle=\"yes\">Evaluatie Regeling beoordelingscommissie late zwangerschapsafbreking en levensbeëindiging bij pasgeborenen</italic> (Evaluation of the Assessment Committee Regulations for Late Termination of Pregnancy and Termination of Life in Newborns), 2022 (hereinafter LTP Evaluation 2022) recommendation 1, 129.</p></fn><fn id=\"fwad015-FN78\"><label>78</label><p>art 5 Wafz.</p></fn><fn id=\"fwad015-FN79\"><label>79</label><p>ibid.</p></fn><fn id=\"fwad015-FN80\"><label>80</label><p>The Act also sets out what will constitute good aftercare, requiring for example that after the abortion the pregnant person should be provided with contraceptive advice as well as a follow-up examination and any medical treatment she requires, art 5 Wafz.</p></fn><fn id=\"fwad015-FN81\"><label>81</label><p>S Halliday, ‘Protecting Human Dignity: Reframing the Abortion Debate to Respect the Dignity of Choice and Life’ (2016) 13(4) Contemporary Issues in Law 287; Parsons and Romanis (n 27).</p></fn><fn id=\"fwad015-FN82\"><label>82</label><p>Cf s 1(1)(c) and (b) Abortion Act 1967, respectively.</p></fn><fn id=\"fwad015-FN83\"><label>83</label><p>Cf s 1(1)(d) Abortion Act 1967.</p></fn><fn id=\"fwad015-FN84\"><label>84</label><p>Post-viability abortions will constitute a crime both under Article 296 WvS (abortion) and other crimes against life (arts 289, 290, 291 WvS – homicide, child murder and infanticide).</p></fn><fn id=\"fwad015-FN85\"><label>85</label><p>art 40 WvS.</p></fn><fn id=\"fwad015-FN86\"><label>86</label><p>S Gevers, ‘Third Trimester Abortion for Fetal Abnormality’ (1999) 13 Bioethics 306, 312.</p></fn><fn id=\"fwad015-FN87\"><label>87</label><p>Minister of Security and Justice and the Minister of Health, Welfare and Sport <italic toggle=\"yes\">Regeling beoordelingscommissie late zwangerschapsafbreking en levensbeëindiging bij pasgeborenen</italic>, 11 December 2015, reference 885614-145412-PG.</p></fn><fn id=\"fwad015-FN88\"><label>88</label><p>ibid art 1.</p></fn><fn id=\"fwad015-FN89\"><label>89</label><p>Second Review of the Wafz (n 10) 46, 60; ZonMW <italic toggle=\"yes\">Evaluatie van de Regeling centrale deskundigencommissie late zwangerschapsafbreking en levensbeëindiging bij pasgeborenen</italic> (Evaluation of the Central Expert Committee on Late Termination of Pregnancy Regulations in a category 2 case and termination of life in neonates), 2013, 12, 68–69, 74; <italic toggle=\"yes\">Evaluatie Regeling beoordelingscommissie late zwangerschapsafbreking en levensbeëindiging bij pasgeborenen</italic> (Evaluation of the Assessment Committee Regulations for Late Termination of Pregnancy and Termination of Life In Newborns), 2022, see especially chapter 3.</p></fn><fn id=\"fwad015-FN90\"><label>90</label><p>art 5 Regulations (n 87).</p></fn><fn id=\"fwad015-FN91\"><label>91</label><p>The justification of necessity (art 40 WvS) will apply if the doctor has complied with the specific category 2 due care criteria.</p></fn><fn id=\"fwad015-FN92\"><label>92</label><p>art 6 Regulations (n 87).</p></fn><fn id=\"fwad015-FN93\"><label>93</label><p>ibid.</p></fn><fn id=\"fwad015-FN94\"><label>94</label><p>LTP Evaluation 2022 (n 77) 3.51.</p></fn><fn id=\"fwad015-FN95\"><label>95</label><p>ibid 4.42.</p></fn><fn id=\"fwad015-FN96\"><label>96</label><p>ibid 4.42, table 4.1.</p></fn><fn id=\"fwad015-FN97\"><label>97</label><p>ibid 3.4.1, table 3.7.</p></fn><fn id=\"fwad015-FN98\"><label>98</label><p>In contrast, the review committees that assess compliance with the due care criteria for euthanasia are only required to refer cases of non-compliance, art 9(2) Termination of Life on Request and Assisted Suicide (Review Procedures) Act 2001.</p></fn><fn id=\"fwad015-FN99\"><label>99</label><p>If the Committee finds that the doctor has acted in accordance with the due care criteria, there will, in principle, be no reason for the prosecuting authorities to investigate or prosecute the doctor, <italic toggle=\"yes\">Aanwijzing vervolgingsbeslissing inzake late zwangerschapsafbreking en levensbeëindiging bij pasgeborenen</italic> (2017A003) (Prosecution decision regarding late termination of pregnancy and termination of life in newborns), 2017, 4.2. Significantly, just as in cases regarding euthanasia, the BPG have made it clear that even where the procedural elements of the due care criteria have not been complied with, the justification of necessity can still apply. Therefore, the principal consideration will be whether a substantive requirement has been met, for example, the requirement that the doctor was convinced that the fetus was suffering hopelessly, Prosecution Decision.</p></fn><fn id=\"fwad015-FN100\"><label>100</label><p>LTP Evaluation 2013 (n 89) 65–66; LTP Evaluation 2022 (n 77), see especially 9–14, 80, 115.</p></fn><fn id=\"fwad015-FN101\"><label>101</label><p>The 1998 reporting procedure for euthanasia cases required that all cases of euthanasia and assisted suicide be referred to the prosecution authorities. See further S Halliday, ‘Regulating Active Voluntary Euthanasia: What can England and Wales Learn from Belgium and the Netherlands’ in A Garwood-Gowers and others (eds), <italic toggle=\"yes\">Contemporary Issues in Healthcare Law and Ethics</italic> (Elsevier 2005) 281ff; S Halliday, ‘Comparative Reflections upon the Assisted Dying Bill 2013: A Plea for a more European Approach’ (2013) 13 Medical Law International 135.</p></fn><fn id=\"fwad015-FN102\"><label>102</label><p>See further Halliday 2005 (n 101) and 2013 (n 101).</p></fn><fn id=\"fwad015-FN103\"><label>103</label><p>LTP Evaluations 2013 and 2022 (n 89 and n 77). In 2018, 11 reports of late termination of pregnancy categories 1 and 2 were received by the Committee, LZA/LP beoordelingscommissie late zwangerschapsafbreking en levensbeëindiging bij pasgeborenen <italic toggle=\"yes\">Jaarverslag 2021</italic> (Assessment Committee for Late Termination of Pregnancy and Termination of Life in Newborns Annual Report 2021), 2022, [2.2]. In contrast, in 2019, 2020 and 2021 only three, four and seven reports respectively were received, statistics more consistent with the number of reports in 2016 and 2017, LZA/LP <italic toggle=\"yes\">beoordelingscommissie late zwangerschapsafbreking en levensbeëindiging bij pasgeborenen Jaarverslag 2021</italic> (Assessment Committee for Late Termination of Pregnancy and Termination of Life in Newborns Annual Report 2021), 2022, [2.1].</p></fn><fn id=\"fwad015-FN104\"><label>104</label><p>LTP Evaluation 2022 (n 77) 9–14, 5.54, 5.5.</p></fn><fn id=\"fwad015-FN105\"><label>105</label><p>art 2, 5°Belgian Act on the Voluntary Termination of Pregnancy. For a detailed analysis of the Belgian law, see F de Meyer, ‘Late Termination of Pregnancy in Belgium: Exploring its Legality and Scope’ (2020) 27 European Journal of Health Law 9.</p></fn><fn id=\"fwad015-FN106\"><label>106</label><p>art 6 Regulations (n 87).</p></fn><fn id=\"fwad015-FN107\"><label>107</label><p>Noticeably, there is no requirement that the second opinion confirms the view of the attending doctor. However, if a doctor were to perform a late termination of pregnancy following a non-confirmatory second opinion, that would undoubtedly operate as a red flag to the Assessment Committee and the 2022 LTP Evaluation found that in such circumstances doctors were unlikely to offer a termination (n 77) 71.</p></fn><fn id=\"fwad015-FN108\"><label>108</label><p>The preference for a second opinion provided by a SCEN physician is set out in the Regional Review Committee’s <italic toggle=\"yes\">Euthanasia Code 2022: Review Procedures in Practice</italic>, 2022, 27. See further Halliday 2005 (n 101) and 2013 (n 101).</p></fn><fn id=\"fwad015-FN109\"><label>109</label><p>See further Halliday 2013 (n 101).</p></fn><fn id=\"fwad015-FN110\"><label>110</label><p>A further source of insecurity can be attributed to the different way in which late termination of pregnancy for fetal anomaly is regulated, in comparison to euthanasia cases. The latter is regulated by statute, with an exemption from liability in the Penal Code similar to art 296(5) WvS, the former through only Ministerial Regulations without an exemption from liability built into the Penal Code. The LTP Evaluations recommended that the Penal Code should be amended to include an exemption for termination after viability on the basis of an embryopathic (encompassing both categories) and a maternal indication: LTP Evaluation 2013 (n 89) 13, 106; LTP Evaluation 2022 (n 77) recommendation 22.</p></fn><fn id=\"fwad015-FN111\"><label>111</label><p>LTP Evaluation 2013 (n 89) 65–66, 106, 108; LTP Evaluation 2022 (n 77) 7.4.2, recommendation 20.</p></fn><fn id=\"fwad015-FN112\"><label>112</label><p>Written answer to parliamentary questions about going abroad for abortion by Minister De Jonge, Minister for Health, Wellbeing and Sport, 27/09/2021: <<ext-link xlink:href=\"https://www.rijksoverheid.nl/binaries/rijksoverheid/documenten/kamerstukken/2021/09/27/beantwoording-kamervragen-over-het-artikel-zij-moest-naar-belgie-voor-de-abortus-van-haar-ernstig-gehandicapte-kind-omdat-artsen-verzwegen-dat-het-ook-in-nederland-kon/beantwoording-kamervragen-over-het-artikel-zij-moest-naar-belgie-voor-de-abortus-van-haar-ernstig-gehandicapte-kind-omdat-artsen-verzwegen-dat-het-ook-in-nederland-kon.pdf\" ext-link-type=\"uri\">https://www.rijksoverheid.nl/binaries/rijksoverheid/documenten/kamerstukken/2021/09/27/beantwoording-kamervragen-over-het-artikel-zij-moest-naar-belgie-voor-de-abortus-van-haar-ernstig-gehandicapte-kind-omdat-artsen-verzwegen-dat-het-ook-in-nederland-kon/beantwoording-kamervragen-over-het-artikel-zij-moest-naar-belgie-voor-de-abortus-van-haar-ernstig-gehandicapte-kind-omdat-artsen-verzwegen-dat-het-ook-in-nederland-kon.pdf</ext-link>> accessed 16 March 2023.</p></fn><fn id=\"fwad015-FN113\"><label>113</label><p>Second Review of the Wafz (n 10) [3.5]; LTP Evaluation 2022 (n 77) 3.5.1, recommendation 1.</p></fn><fn id=\"fwad015-FN114\"><label>114</label><p>Second Review of the Wafz (n 10) 46, 60; LTP Evaluation 2013 (n 89) 12, 74, LTP Evaluation 2022 (n 77) 9ff, 66ff.</p></fn><fn id=\"fwad015-FN115\"><label>115</label><p>The 2022 LTP Evaluation acknowledged that the viability threshold results in pressure to make a decision before the 24th week. Putative parents interviewed reported that by opting for termination before that time they had a choice, albeit not necessarily a fully informed choice; a choice that might not be available to them after the viability threshold was met due to the narrow interpretation of the due care criteria, LTP Evaluation 2022 (n 77) 3.4.1.</p></fn><fn id=\"fwad015-FN116\"><label>116</label><p>For details of the reported impact upon pregnant persons see LTP Evaluation 2022 (n 77) 45–47, 67.</p></fn><fn id=\"fwad015-FN117\"><label>117</label><p>(n 87).</p></fn><fn id=\"fwad015-FN118\"><label>118</label><p>art 40 WvS.</p></fn><fn id=\"fwad015-FN119\"><label>119</label><p>Dutch Association for Obstetrics and Gynaecology (NVOG), <italic toggle=\"yes\">Modelprotocol: Medisch handelen bij beëindigen van de zwangerschap op maternale indicatie</italic> (Model protocol: Medical treatment in the case of termination of pregnancy on maternal indication), 2017, [2.2].</p></fn><fn id=\"fwad015-FN120\"><label>120</label><p>Duijst <italic toggle=\"yes\">Tekst &Commentaar Gezondheidsrecht, commentaar op aanhef Wafz</italic>, art 296 WvS.</p></fn><fn id=\"fwad015-FN121\"><label>121</label><p>The prosecution policy concludes that the doctor’s actions will be justified by necessity and that criminal investigation will not be indicated, Prosecution Decision (n 99) 5. However, the NVOG protocol requires all cases of late termination on a maternal indication to be reported to the Netherlands Obstetric Surveillance System to enable late pregnancy termination on maternal indication to be registered and analysed, NVOG model protocol (n 119) [3.2].</p></fn><fn id=\"fwad015-FN122\"><label>122</label><p>See (n 119).</p></fn><fn id=\"fwad015-FN123\"><label>123</label><p>Where such a threat exists, there is no question of waiting for the fetus to die before intervening, as has been reported in recent Polish cases: <<ext-link xlink:href=\"https://www.theguardian.com/global-development/2022/jan/27/protests-flare-across-poland-after-death-of-young-mother-denied-an-abortion\" ext-link-type=\"uri\">https://www.theguardian.com/global-development/2022/jan/27/protests-flare-across-poland-after-death-of-young-mother-denied-an-abortion</ext-link>> accessed 17 March 2023.</p></fn><fn id=\"fwad015-FN124\"><label>124</label><p>NVOG model protocol (n 119) [2.2].</p></fn><fn id=\"fwad015-FN125\"><label>125</label><p>S Sheldon, ‘The Decriminalisation of Abortion: An Argument for Modernisation’ (2016) 36 Oxford Journal of Legal Studies 334; Erdman (n 1); S Halliday ‘Maintaining the Criminal Prohibition of Abortion as a Means of Protecting Women: Alternative Facts and Realities in reproductive Law and Policy’, in A Sinn and others (eds), <italic toggle=\"yes\">Populismus und alternative Fakten</italic> (Mohr Siebeck 2020) 105; Romanis (n 4).</p></fn><fn id=\"fwad015-FN126\"><label>126</label><p>On the rhetoric and use of the criminal law to regulate abortion see Halliday (n 125).</p></fn><fn id=\"fwad015-FN127\"><label>127</label><p>AP Simester and A von Hirsch, <italic toggle=\"yes\">Crimes, Harms, and Wrongs: On the Principles of Criminalisation</italic> (Hart 2011) 5. On the decriminalisation of abortion see Sheldon (n 14); S Sheldon and K Wellings (eds.), <italic toggle=\"yes\">Decriminalising Abortion in the UK: What Would It Mean?</italic> (BUP 2019).</p></fn><fn id=\"fwad015-FN128\"><label>128</label><p>Sheldon (n 14) 344.</p></fn><fn id=\"fwad015-FN129\"><label>129</label><p>Department for Health and Social Care, ‘Abortion Statistics, England and Wales: 2021’ <<ext-link xlink:href=\"https://www.gov.uk/government/statistics/abortion-statistics-for-england-and-wales-2021/abortion-statistics-england-and-wales-2021\" ext-link-type=\"uri\">https://www.gov.uk/government/statistics/abortion-statistics-for-england-and-wales-2021/abortion-statistics-england-and-wales-2021</ext-link>> accessed 24 March 2023. NB: we use the language of women here as this is what is used by the report.</p></fn><fn id=\"fwad015-FN130\"><label>130</label><p>Halliday (n 81); Halliday (n 125); EC Romanis and others, ‘The Excessive Regulation of early Abortion Medication in the United Kingdom: The Case for Reform’ (2022) 1 Medical Law Review 4; Parsons and Romanis (n 27).</p></fn><fn id=\"fwad015-FN131\"><label>131</label><p>M Heath and E Mulligan, ‘Abortion in the Shadow of the Criminal Law? The Case of South Australia’ (2016) 37 Adelaide Law Review 41, 65.</p></fn><fn id=\"fwad015-FN132\"><label>132</label><p>See also RJ Cook, ‘Stigmatized Meanings of Criminal Abortion Law’ in RJ Cook and others (eds), <italic toggle=\"yes\">Abortion law in Transnational Perspective: Cases and Controversies</italic> (University of Pennsylvania Press 2014) 353; S Sheldon and others, ‘The Abortion Act 1967: A Biography’ (2019) 39 Legal Studies 18.</p></fn><fn id=\"fwad015-FN133\"><label>133</label><p>See, for example, BMA (n 25) [2.1.1], reporting doctors concerns about the risk of prosecution in relation to the exercise of their clinical judgement in the context of embryopathic abortion. See also S Saraiya, ‘Conceiving Criminality: An Evaluation of Abortion Decriminalization Reform in New York and Great Britain’ (2018) 57 Columbia Journal of Transnational Law 174. In <italic toggle=\"yes\">A, B and C v Ireland</italic> [2010] ECHR 2032, the European Court of Human Rights recognised that ‘the criminal provisions of the 1861 Act would constitute a significant chilling factor for both women and doctors in the medical consultation process, regardless of whether or not prosecutions have in fact been pursued under that Act’, [254]. This case concerned three people who had travelled to England from Ireland in order to terminate their pregnancy and considered the application of the OAPA 1861 in Ireland, prior to the repeal of Article 40.3.3 Irish Constitution, at a time when abortion could only lawfully be performed in Ireland for the purpose of saving the pregnant person’s life, <italic toggle=\"yes\">AG v X</italic> [1992] IESC 1. However, we suggest that the Court’s recognition of the impact of the criminal law was not limited to the Irish context, but applies more generally to the criminalisation of abortion in any jurisdiction. The chilling effect of the fact that abortion after 24 weeks constitutes a (potentially justifiable) crime notwithstanding a maternal or embryopathic indication in the Netherlands, is a recurrent theme throughout the LTP Evaluation 2022 (n 77).</p></fn><fn id=\"fwad015-FN134\"><label>134</label><p>WHO (n 9) 22.</p></fn><fn id=\"fwad015-FN135\"><label>135</label><p>LTP Evaluation 2022 (n 77) 9–10, 66ff.</p></fn><fn id=\"fwad015-FN136\"><label>136</label><p>ibid.</p></fn><fn id=\"fwad015-FN137\"><label>137</label><p>See also LTP Evaluation 2022 (n 77) 124.</p></fn><fn id=\"fwad015-FN138\"><label>138</label><p>LTP Evaluation 2022 (n 77) 13, 106.</p></fn><fn id=\"fwad015-FN139\"><label>139</label><p>art 2 Ministerial Regulations (n 87) imposes a mandatory referral to the Prosecution Authorities of all category 2 (non-fatal embryopathic) cases, even in cases where the Committee finds that the doctor has acted in accordance with the due care criteria.</p></fn><fn id=\"fwad015-FN140\"><label>140</label><p>See generally LTP Evaluation 2022 (n 77), particularly chapter 4.</p></fn><fn id=\"fwad015-FN141\"><label>141</label><p>Cf art 6 Ministerial regulations (n 87).</p></fn><fn id=\"fwad015-FN142\"><label>142</label><p>\n<italic toggle=\"yes\">R (Crowter) v Secretary of State for Health and Social Care</italic> [2022] EWCA Civ 1559 [98] per Underhill LJ.</p></fn><fn id=\"fwad015-FN143\"><label>143</label><p>BMA (n 25) [2.1.1].</p></fn><fn id=\"fwad015-FN144\"><label>144</label><p>Second Review of the Wafz (n 10) 3.5.4; LTP Evaluation 2022 (n 77) 3.4.1. The Evaluation found that 43% of respondents reported that there is often ‘insufficient time to complete diagnostics between the 20-week ultrasound and the 24<sup>th</sup> week of pregnancy’ and 21% reported that the 24th week threshold often causes pregnant people to ‘experience time pressure when making an informed choice about whether or not to continue the pregnancy if a serious abnormality is found,’ table 3.1. In the context of England and Wales similar concerns about time pressure have been expressed by the BMA, BMA (n 25) [2.1.1].</p></fn><fn id=\"fwad015-FN145\"><label>145</label><p>Tongue (n 47) 183; LTP Evaluation 2022 (n 77) 3.5.4.</p></fn><fn id=\"fwad015-FN146\"><label>146</label><p>See Halliday (n 125).</p></fn><fn id=\"fwad015-FN147\"><label>147</label><p>Eg, ‘Oxford mum denies trying to ‘procure miscarriage’ in 2021’ <<ext-link xlink:href=\"https://www.oxfordmail.co.uk/news/20281951.oxford-mum-denies-trying-procure-miscarriage-2021/\" ext-link-type=\"uri\">https://www.oxfordmail.co.uk/news/20281951.oxford-mum-denies-trying-procure-miscarriage-2021/</ext-link>> accessed 17 March 2023.</p></fn><fn id=\"fwad015-FN148\"><label>148</label><p>\n<italic toggle=\"yes\">R v Sarah Louise Catt</italic> (2012), unreported, 17 September 2012; Halliday (n 125) 119–20. Not all cases of suspected abortion will be prosecuted. In 2022, the Observer reported that people who have had a miscarriage, or stillbirth, are being subjected to police investigations, accused of having illegal abortions, <<ext-link xlink:href=\"https://www.theguardian.com/world/2022/jul/02/women-accused-of-abortions-in-england-and-wales-after-miscarriages-and-stillbirths\" ext-link-type=\"uri\">https://www.theguardian.com/world/2022/jul/02/women-accused-of-abortions-in-england-and-wales-after-miscarriages-and-stillbirths</ext-link>> accessed 17 March 2023.</p></fn><fn id=\"fwad015-FN149\"><label>149</label><p>See Halliday (n 125).</p></fn><fn id=\"fwad015-FN150\"><label>150</label><p>Cook (n 132), 348.</p></fn><fn id=\"fwad015-FN151\"><label>151</label><p>WHO (n 9) 22; W Nowicka, ‘Sexual and Reproductive Rights and the Human Rights Agenda: Controversial and Contested’ (2011) 19 Reproductive Health Matters 119; F de Londras and others, ‘The Impact of Criminalisation on Abortion-related Outcomes: A Synthesis of Legal and Health Evidence’ (2022) 7 BMJ Global Health e010409, doi:10.1136/bmjgh-2022-010409.</p></fn><fn id=\"fwad015-FN152\"><label>152</label><p>WHO (n 9) 24.</p></fn><fn id=\"fwad015-FN153\"><label>153</label><p>de Londras (n 151) 2.</p></fn><fn id=\"fwad015-FN154\"><label>154</label><p>Special Rapporteur on the right of everyone to the enjoyment of the highest attainable standard of physical and mental health, Interim Report to the General Assembly (2011) (UN Doc A/66/254); Special Rapporteur on torture and other cruel, inhuman or degrading treatment or punishment, Report to the Human Rights Council (2016) (UN Doc A/HRC/31/57).</p></fn><fn id=\"fwad015-FN155\"><label>155</label><p>art 16 (1) (e).</p></fn><fn id=\"fwad015-FN156\"><label>156</label><p>CEDAW (2018) Report of the inquiry concerning the United Kingdom of Great Britain and Northern Ireland under art 8 of the Optional Protocol to the Convention on the Elimination of All Forms of Discrimination against Women. CEDAW/C/OP.8/GBR/1.</p></fn><fn id=\"fwad015-FN157\"><label>157</label><p>The Abortion Act 1967 does not extend to Northern Ireland, instead abortion was regulated in Northern Ireland by the OAPA 1861. ss 58 and 59 OAPA were repealed in Northern Ireland by s 9 Northern Ireland (Executive Formation etc) Act 2019.</p></fn><fn id=\"fwad015-FN158\"><label>158</label><p>L Taylor, ‘How South America became a Global Role Model for Abortion Rights’ (2022) BMJ <<ext-link xlink:href=\"https://doi.org/10.1136/bmj.o1908\" ext-link-type=\"uri\">https://doi.org/10.1136/bmj.o1908</ext-link>>.</p></fn><fn id=\"fwad015-FN159\"><label>159</label><p>EC Romanis, ‘The End of (Reproductive) Liberty as we know it: A Note on Dobbs V. Jackson Women’s Health 597 USC __ (2022),’ (2023) Medical Law International <<ext-link xlink:href=\"https://doi.org/10.1177/096853322311545\" ext-link-type=\"uri\">https://doi.org/10.1177/096853322311545</ext-link>>.</p></fn><fn id=\"fwad015-FN160\"><label>160</label><p>J Herring and others, ‘Would Decriminalisation Mean Deregulation?’ in S Sheldon and K Wellings (eds), <italic toggle=\"yes\">Decriminalising Abortion in the UK</italic> (Policy Press 2020) 58.</p></fn><fn id=\"fwad015-FN161\"><label>161</label><p>WHO (n 9) 26.</p></fn><fn id=\"fwad015-FN162\"><label>162</label><p>ibid 28.</p></fn><fn id=\"fwad015-FN163\"><label>163</label><p>C Borgmann, ‘Abortion exceptionalism and Undue Burden Preemption’ (2014) 71 Washington and Lee Law Review 1047; specifically in the English and Welsh context: Parsons and Romanis (n 27), and in the context of England and Germany: Halliday (n 81) and (n 125).</p></fn><fn id=\"fwad015-FN164\"><label>164</label><p>Sheldon (n 14) 346; Romanis and others (n 130) 18.</p></fn><fn id=\"fwad015-FN165\"><label>165</label><p>AM Sorhaindo and AF Lavelanet ‘Why does Abortion Stigma Matter? A Scoping Review and Hybrid Analysis of Qualitative Evidence Illustrating the Role of Stigma in the Quality of Abortion Care’ (2022) 311 Social Science & Medicine <<ext-link xlink:href=\"https://doi.org/10.1016/j.socscimed.2022.115271\" ext-link-type=\"uri\">https://doi.org/10.1016/j.socscimed.2022.115271</ext-link>>, 2.</p></fn><fn id=\"fwad015-FN166\"><label>166</label><p>Halliday (n 81); Halliday (n 125); Romanis and others (n 130), 9–18.</p></fn><fn id=\"fwad015-FN167\"><label>167</label><p>Sorhaindo (n 165), 2; WHO (n 9) 22, 61.</p></fn><fn id=\"fwad015-FN168\"><label>168</label><p>Telemedical abortion has reduced access barriers significantly in the UK (Parsons and Romanis (n 27)), but is not available in the Netherlands.</p></fn><fn id=\"fwad015-FN169\"><label>169</label><p>S Sheldon, <italic toggle=\"yes\">Beyond Control: Medical Power and Abortion Law</italic> (Pluto Press 1997) 35.</p></fn><fn id=\"fwad015-FN170\"><label>170</label><p>If the abortion is immediately necessary a second signature is not required, s 1(4) AA 1967.</p></fn><fn id=\"fwad015-FN171\"><label>171</label><p>Halliday (n 125) 113.</p></fn><fn id=\"fwad015-FN172\"><label>172</label><p>The study concerned pregnancies over 20 weeks GA, including some individuals seeking abortion both before and after viability.</p></fn><fn id=\"fwad015-FN173\"><label>173</label><p>BPAS, <italic toggle=\"yes\">Why Women Present for Abortions After 20 Weeks</italic> (2017) 8.</p></fn><fn id=\"fwad015-FN174\"><label>174</label><p>Romanis (n 4) 26.</p></fn><fn id=\"fwad015-FN175\"><label>175</label><p>\n<italic toggle=\"yes\">Re MB</italic> [1997] EWCA Civ 309, [60]; J. de Boer and others, <italic toggle=\"yes\">Mr. C. Assers Handleiding tot de beoefening van het Nederlands Burgerlijk Recht. 1. Personen- en familierecht. Deel I. De persoon, afstamming en adoptie, gezag en omgang, levensonderhoud, bescherming van meerderjarigen</italic>, Wolters Kluwer, 19th edn 2020, s 1 [34–35].</p></fn><fn id=\"fwad015-FN176\"><label>176</label><p>The significant differences between a fetus and a newborn are thoroughly explored for their moral and legal significance elsewhere, see: K Greasley, <italic toggle=\"yes\">Arguments about Abortion: Personhood, Morality and Law</italic> (OUP 2017); Romanis (n 4).</p></fn><fn id=\"fwad015-FN177\"><label>177</label><p>Tongue (n 47) 185.</p></fn><fn id=\"fwad015-FN178\"><label>178</label><p>WHO (n 9) 28.</p></fn><fn id=\"fwad015-FN179\"><label>179</label><p>See (n 71).</p></fn><fn id=\"fwad015-FN180\"><label>180</label><p>\n<italic toggle=\"yes\">C v S</italic> [1988] 1 QB 135, 151.</p></fn><fn id=\"fwad015-FN181\"><label>181</label><p>De Proost (n 4) 116.</p></fn><fn id=\"fwad015-FN182\"><label>182</label><p>Romanis (n 4) 3; LM Di Stefano and others, ‘Viability and Thresholds for Treatment of Extremely Preterm Infants: Survey of UK Neonatal Professionals’ (2021) 106 Archives of Disease in Childhood. Fetal and Neonatal Edition F596; R Wertheimer, ‘Understanding the Abortion Argument’ (1971) 1 Philosophy & Public Affairs 67, 82; L Han and others, ‘Blurred Lines: Disentangling the Concept of Fetal Viability from Abortion Law’ (2018) 28 Women’s Health Issues 287.</p></fn><fn id=\"fwad015-FN183\"><label>183</label><p>Di Stefano (n 182); HC Glass and others, ‘Outcomes for Extremely Premature Infants’ (2015) 120 Anesth Analg 1337; S Santhakumaran and others, ‘Survival of very Preterm Infants Admitted to Neonatal Care in England 2008-2014: Time Trends and Regional Variation’ (2018) 103 Archives of Disease in Childhood. Fetal and Neonatal Edition F208.</p></fn><fn id=\"fwad015-FN184\"><label>184</label><p>Second Review of the Wafz (n 10) 56 and 64.</p></fn><fn id=\"fwad015-FN185\"><label>185</label><p>Han (n 182) 287.</p></fn><fn id=\"fwad015-FN186\"><label>186</label><p>Romanis (n 4) 115.</p></fn><fn id=\"fwad015-FN187\"><label>187</label><p>K. Greasley (n 176) 190–91.</p></fn><fn id=\"fwad015-FN188\"><label>188</label><p>S Halliday, <italic toggle=\"yes\">Autonomy and Pregnancy: A Comparative Analysis of Compelled Obstetric Intervention</italic> (Routledge 2016) 175–84.</p></fn><fn id=\"fwad015-FN189\"><label>189</label><p>\n<italic toggle=\"yes\">R v Sarah Louise Catt</italic> (n 148).</p></fn><fn id=\"fwad015-FN190\"><label>190</label><p>L Eades, ‘Social Realities, Biological Realities: The 24-week Foetus in Contemporary T English Abortion Activism’ (2019) 74 Women's Studies International Forum 20, 21.</p></fn><fn id=\"fwad015-FN191\"><label>191</label><p>See also de Londras (n 151) 4, 6.</p></fn></fn-group>" ]	[]	[]	[]	{ "acronym": [], "definition": [] }	0	CC BY	no	2024-01-13 23:36:46	Med Law Rev. 2023 May 30; 31(4):538-563	oa_package/8c/23/PMC10681352.tar.gz
PMC10681357	37253392	[ "<title>I. INTRODUCTION</title>", "<p>While errors in medical diagnosis are common and have been the subject of much attention in the field of medical negligence,<xref rid=\"fwad009-FN1\" ref-type=\"fn\"><sup>1</sup></xref> the different dimensions of diagnosis have only recently begun to be properly unbundled in law and medicine.<sup><xref rid=\"fwad009-FN2\" ref-type=\"fn\"><sup>2</sup></xref></sup> As our prior work demonstrates, there are three distinct types of diagnostic acts that should be distinguished: the formation of the diagnosis, the communication of the diagnosis to the patient, and the recording of the diagnosis.<xref rid=\"fwad009-FN3\" ref-type=\"fn\"><sup>3</sup></xref> Unbundled in this way, it becomes clear that each dimension raises important and complex legal questions that are worthy of distinct analysis. These questions challenge the assumption that all three dimensions of diagnosis should be governed by the <italic toggle=\"yes\">Bolam/Bolitho</italic> standard (under which medical practice cannot be found negligent if it is accepted by a body of medical practitioners, unless the court finds the practice cannot withstand logical scrutiny).<xref rid=\"fwad009-FN4\" ref-type=\"fn\"><sup>4</sup></xref> Given the importance of medical diagnosis, the enduring critiques of the <italic toggle=\"yes\">Bolam/Bolitho</italic> standard, and the frequency of patient complaints about diagnosis, these questions constitute some of most important frontiers of medical negligence law.</p>", "<p>This article is part of a broader project exploring medical diagnosis from clinical, legal, ethical, and anthropological perspectives. Amongst our previous papers is an article in this journal assessing the legal standards of care that apply to the formation, communication, and recording of diagnoses.<xref rid=\"fwad009-FN5\" ref-type=\"fn\"><sup>5</sup></xref> When deciding whether a doctor has negligently breached the duty of care owed to a patient during medical diagnosis, what standard defines reasonable conduct for doctors? In that paper, we showed that case law is not settled. Typically, courts in England and Wales have applied the <italic toggle=\"yes\">Bolam/Bolitho</italic> standard on the grounds that diagnostic decisions are grounded in clinical judgement. However, lower courts in <italic toggle=\"yes\">Muller v King’s College Hospital NHS Foundation Trust</italic><xref rid=\"fwad009-FN6\" ref-type=\"fn\"><sup>6</sup></xref> and <italic toggle=\"yes\">Brady v Southend University Hospital NHS Foundation Trust</italic><xref rid=\"fwad009-FN7\" ref-type=\"fn\"><sup>7</sup></xref> have invited senior courts to depart from <italic toggle=\"yes\">Bolam/Bolitho</italic> in situations they call ‘pure diagnostic’ cases. Furthermore, the Supreme Court decisions in <italic toggle=\"yes\">Montgomery v Lanarkshire</italic><xref rid=\"fwad009-FN8\" ref-type=\"fn\"><sup>8</sup></xref> and <italic toggle=\"yes\">Darnley v Croydon Health Services NHS Trust</italic><xref rid=\"fwad009-FN9\" ref-type=\"fn\"><sup>9</sup></xref> cast doubt on the applicability of <italic toggle=\"yes\">Bolam/Bolitho</italic> for, respectively, communication and recording of diagnoses. In analysing these issues, our prior work adopted a standard doctrinal methodology,<xref rid=\"fwad009-FN10\" ref-type=\"fn\"><sup>10</sup></xref> but we identified the need for additional empirical research,<xref rid=\"fwad009-FN11\" ref-type=\"fn\"><sup>11</sup></xref> which this article provides. Thus, we recommend that this article be read in conjunction with our 2022 publication in this journal, which provides more detail and analysis of the background case law.<xref rid=\"fwad009-FN12\" ref-type=\"fn\"><sup>12</sup></xref></p>", "<p>One of the central insights of our prior work is that different standards might apply to the different acts in the diagnostic context. If so, this would parallel the ways that different standards apply to different acts in the treatment context, where <italic toggle=\"yes\">Bolam/Bolitho</italic> applies to the performance of the treatment itself, while <italic toggle=\"yes\">Montgomery</italic> applies to the communication of the treatment risks. Clarifying the standards that apply in the diagnostic context is essential, as these standards must be incorporated in medical education, clinical guidelines, and patient care. This clarification is also relevant to legal proceedings and could lead to different results in some circumstances.<xref rid=\"fwad009-FN13\" ref-type=\"fn\"><sup>13</sup></xref></p>", "<p>In our prior work, however, we were not able to reach a clear answer for two of our questions: (i) whether <italic toggle=\"yes\">Montgomery</italic> should apply to information about alternative diagnoses and (ii) whether <italic toggle=\"yes\">Bolam/Bolitho</italic> should not apply in cases of ‘pure diagnosis’. The limited reported case law on these issues, along with the fact that the vast majority of medical negligence complaints are resolved without going to court, created blind spots here. To answer these questions, we interviewed barristers and solicitors who could provide insight into how these types of diagnosis cases are being resolved—insights based on empirical data that could not be obtained from other sources. We asked for their views on the standards that apply to the formation and communication of diagnosis, and on the direction in which the law should develop.</p>", "<p>In this article, we present and analyse the results of these interviews, which shed light not only on the two questions posed but also on three cross-cutting themes. First, <italic toggle=\"yes\">Bolam/Bolitho</italic> is criticised on two grounds that are often conflated: its paternalism and its deference to the medical profession. Second, adopting different standards for different aspects of treatment and diagnosis may be justified in principle, but there might be circumstances in which this is difficult or does not make sense in practice. Third, new conceptions of patients, doctors, and courts are being articulated in terms of rights or responsibilities over risks. In mapping these issues at the frontiers of medical negligence, this article identifies pressure points for potentially significant legal developments in the near future.</p>" ]	[ "<title>II. METHODOLOGY</title>", "<p>An initial list of potential participants was created by reviewing medical negligence judgments, which list the parties’ barristers and instructing firms of solicitors. Further potential participants were added through snowballing. Between 11 December 2020 and 25 February 21, one of us (ILG) invited 134 medical negligence lawyers to participate in the study via email. This email contained a link to the study’s THISCOVERY webpage which contained a participant information sheet, consent form and booking platform where the participant could opt for a telephone call or an online interview.</p>", "<p>A semi-structured interview guide was generated from case law analysis in previous studies and two workshops held in Cambridge: the first (in July 2019) had 20 participants drawn from across law, medicine, philosophy, sociology, and anthropology; the second (in January 2020) focused on practicing and academic doctors and lawyers. At the second workshop, participants were asked to read the prepared reviews of case law and literature, in order to identify areas that needed further exploration. Through this process, we decided to focus the interviews on two questions that our research had identified as being highly contested in case law and literature: whether <italic toggle=\"yes\">Montgomery</italic> should apply to the communication of information about alternative diagnoses and whether <italic toggle=\"yes\">Bolam/Bolitho</italic> should not apply in cases of ‘pure diagnosis’.<xref rid=\"fwad009-FN14\" ref-type=\"fn\"><sup>14</sup></xref> We refer to these as the ‘core questions’.</p>", "<p>In total, 31 interviews with barristers and solicitors were undertaken by ILG over a period of three months in 2021. ##TAB##0##Table 1## provides more details about the participants, who were a mix of claimant-focused, defendant-focused and mixed practice lawyers whose experience ranged from six to 40+ years.</p>", "<p>These interviews were recorded and transcribed verbatim by a professional transcription service. The transcripts were anonymised by giving each participant a numerical designation and indicating whether they were a solicitor or a barrister.</p>", "<p>The interviews were analysed in NVivo Pro12 by ILG, ZF and AM using the Framework approach.<xref rid=\"fwad009-FN15\" ref-type=\"fn\"><sup>15</sup></xref> Framework is an approach to qualitative analysis designed for applied (often policy-related) research, intended to enable systematic, transparent analysis of empirical datasets, often by teams, towards identified practical objectives.<xref rid=\"fwad009-FN16\" ref-type=\"fn\"><sup>16</sup></xref> After reading the first transcripts, initially identified themes were used to generate a coding framework, which was discussed with an external collaborator (GM); transcripts were coded by three researchers with legal or medical expertise (ZF, AM and ILG) and consolidated and iterated in team discussions. Themes generated during the analysis process were discussed and validated by wider members of the research team (JS and KL). Data collection and analysis were concurrent, with early findings directing further enquiries in interviews. Illustrative quotes of the emerging themes identified are to be found in ##TAB##1##Table 2##.</p>", "<p>This study (IRAS ID: 265331) was approved by the East of England—Essex Research Ethics Committee.</p>" ]	[ "<title>III. RESULTS AND ANALYSIS</title>", "<title>A. Should <italic toggle=\"yes\">Montgomery</italic> apply to information about alternative diagnoses?</title>", "<title>1. Context</title>", "<p>Following the Supreme Court decision in <italic toggle=\"yes\">Montgomery</italic>, doctors must ensure that their patients are aware of any ‘material risks’ involved in any recommended treatments, and materiality is defined by a two prong test: ‘The test of materiality is whether, in the circumstances of the particular case, <italic toggle=\"yes\">a reasonable person in the patient's position</italic> would be likely to attach significance to the risk, or the doctor is or should reasonably be aware that <italic toggle=\"yes\">the particular patient</italic> would be likely to attach significance to it.’<xref rid=\"fwad009-FN17\" ref-type=\"fn\"><sup>17</sup></xref> In adopting this patient-led standard, and rejecting a ‘profession-led’ standard,<xref rid=\"fwad009-FN18\" ref-type=\"fn\"><sup>18</sup></xref> the Supreme Court explained that the latter would sanction differences in practice that were not attributable to different interpretations of medical science, but merely ‘divergent attitudes among doctors as to the degree of respect owed to their patients’.<xref rid=\"fwad009-FN19\" ref-type=\"fn\"><sup>19</sup></xref></p>", "<p>In the literature, <italic toggle=\"yes\">Montgomery</italic> is widely described as a significant move towards a healthcare model based on a partnership between patient and doctor, elevating patient autonomy and shifting away from the traditionally paternalistic medical professional-led approach.<xref rid=\"fwad009-FN20\" ref-type=\"fn\"><sup>20</sup></xref> Rather than simply disclose what a logical body of doctors would consider it necessary to disclose, the treating doctor must consider the patient’s perspective, objectively and subjectively. However, the full scope and contours of this patient-based duty remain unsettled.<xref rid=\"fwad009-FN21\" ref-type=\"fn\"><sup>21</sup></xref></p>", "<p>There are two related dimensions of uncertainty that are relevant to our enquiry. First, <italic toggle=\"yes\">Montgomery</italic> states that doctors must inform their patients of ‘reasonable alternative or variant treatments’, but does not explain whether this reasonableness is defined by a patient-led or a profession-led standard. Second, because <italic toggle=\"yes\">Montgomery</italic> was a case about risks of proposed treatments, the Court did not explain whether doctors must also inform their patients of other types of related risks or information. For these reasons, one key unresolved question is whether a doctor might be required to disclose reasonable alternative diagnoses, and if so, whether a doctor-led or patient-led standard would apply.</p>", "<p>An extension of <italic toggle=\"yes\">Montgomery</italic> to some diagnostic matters is not hard to imagine, given that information about alternative diagnoses and related risks can have the same value for patients as information about treatment risks. For example, it can be valuable in making autonomous decisions about one’s healthcare, and it can also be helpful in avoiding harm (for example, where fatal or serious diagnoses are on the list of differential diagnosis, or where a patient needs to respond to changing or worsening symptoms).<xref rid=\"fwad009-FN22\" ref-type=\"fn\"><sup>22</sup></xref> However, it is conceivable that extending <italic toggle=\"yes\">Montgomery</italic> in this way could create additional time pressures on doctors, encourage defensive medicine, or increase litigation.<xref rid=\"fwad009-FN23\" ref-type=\"fn\"><sup>23</sup></xref></p>", "<p>Questions about the extension of <italic toggle=\"yes\">Montgomery</italic> to the communication of diagnostic information have not yet been addressed by the courts of England and Wales,<xref rid=\"fwad009-FN24\" ref-type=\"fn\"><sup>24</sup></xref> though equivalent questions have been addressed in other jurisdictions, including Scotland,<xref rid=\"fwad009-FN25\" ref-type=\"fn\"><sup>25</sup></xref> Singapore,<xref rid=\"fwad009-FN26\" ref-type=\"fn\"><sup>26</sup></xref> and the USA.<xref rid=\"fwad009-FN27\" ref-type=\"fn\"><sup>27</sup></xref> One of the main aims of our interviews, therefore, was to explore whether lawyers in England and Wales thought that <italic toggle=\"yes\">Montgomery</italic> could require the disclosure of diagnostic information, and whether they were, in fact, bringing these types of claims.</p>", "<title>2. Interview results</title>", "<p>Most interviewees suggested that <italic toggle=\"yes\">Montgomery</italic> should extend to the disclosure of alternative diagnoses on the ground that the principle of patient autonomy demands that patients be fully informed of diagnostic options.<xref rid=\"fwad009-FN28\" ref-type=\"fn\"><sup>28</sup></xref> They thought that <italic toggle=\"yes\">Montgomery</italic> required doctors to involve patients in their own care, including in diagnosis. As one solicitor put it,</p>", "<p>Extending <italic toggle=\"yes\">Montgomery</italic> to differential diagnosis was seen as an application of the move away from paternalistic healthcare to a partnership between doctor and patient; one interviewee summarised this view by saying that</p>", "<p>This approach enables patients to assess risks and benefits in conjunction with their doctors and make decisions based on risk-benefit analyses that align with their personal values and priorities. A number of interviewees pointed out that, just as there are risks and benefits with treatments, there are similar risks and benefits associated with differential diagnosis, since</p>", "<p>Interviewees suggested that the management of these risks was a responsibility to be shared between patients and medical professionals, rather than left to one or the other. They therefore thought that the disclosure of differential diagnoses fell squarely within the parameters of <italic toggle=\"yes\">Montgomery</italic>.</p>", "<p>Interviewees also provided a number of examples of cases from their own practices which illustrated that failure to disclose diagnostic uncertainty can materially affect a patient’s agency in making medical decisions. In one case, a patient with high-blood pressure, obesity, and a history of smoking presented to A&E with neurological symptoms. It was unclear whether they were suffering from migraine or whether they had experienced a Transient Ischaemic Attack (TIA), sometimes described as a ‘mini-stroke’. The patient was ultimately diagnosed with migraine but was told that they needed to change their lifestyle in order to avoid suffering a stroke. They later suffered a stroke and argued that, had they been informed that they <italic toggle=\"yes\">might</italic> have had a TIA—and that this was the reason for the lifestyle advice—they would have taken the advice more seriously lost weight and not suffered a stroke at all.</p>", "<p>The interviewee thought that this type of case fitted better within the parameters of <italic toggle=\"yes\">Montgomery</italic>, rather than <italic toggle=\"yes\">Bolam/Bolitho—</italic>that the patient’s complaint related not to treatment received or an incorrect diagnosis, but rather to the failure to fully disclose uncertainty over her diagnosis which had deprived them of informed decision-making agency as to their lifestyle.<xref rid=\"fwad009-FN32\" ref-type=\"fn\"><sup>32</sup></xref> Harm might have been avoided had the patient been informed of the seriousness of her differential diagnoses. The interviewee thought that both the avoidance of harm and support for patient autonomy were key reasons for imposing a <italic toggle=\"yes\">Montgomery</italic> duty in relation to the disclosure of diagnosis.<xref rid=\"fwad009-FN33\" ref-type=\"fn\"><sup>33</sup></xref></p>", "<p>In another example, an ultrasound of a pregnant woman revealed that the foetus had clubfoot. In most cases, clubfoot can be easily corrected but it can also be an indicator of a congenital syndrome known as arthrogryposis, which can lead to profound physical disability. In this case, the doctors chose not to inform the woman that arthrogryposis was on the list of differential diagnoses because the risk was small and they felt that ‘no mother would possibly want to have a termination for clubfoot’.<xref rid=\"fwad009-FN34\" ref-type=\"fn\"><sup>34</sup></xref> However, the woman claimed that she personally would have asked to terminate the pregnancy if she had been informed of the risk of a serious disability like arthrogryposis, however small. The failure to fully inform her of alternative diagnoses had deprived her of the opportunity to make decisions about her pregnancy in accordance with her personal priorities.</p>", "<p>Despite agreeing that, in principle, <italic toggle=\"yes\">Montgomery</italic> should apply to the disclosure of diagnostic uncertainty, some interviewees raised concerns about differentiating the standards that define negligent diagnostic communication and negligent treatment (which is governed by the profession-led standard of <italic toggle=\"yes\">Bolam/Bolitho</italic>). They raised two types of concerns. First, it could be difficult to draw a line between diagnosis and treatment. In their view, both formed part of a continuous medical encounter, where disclosure of diagnostic uncertainty has an inevitable effect on the treatment pursued by a patient. As one interviewee said,</p>", "<p>Second, some interviewees questioned the <italic toggle=\"yes\">purpose</italic> of trying to draw this line. They thought that in most cases, diagnostic uncertainty was important precisely <italic toggle=\"yes\">because</italic> of its effect on a patient’s future treatment. Failure to disclose diagnostic uncertainty could result in the patient pursuing an unsatisfactory treatment pathway. As one interviewee said,</p>", "<p>For this reason, they thought that a doctor who failed to disclose diagnostic uncertainty could be challenged under an ordinary application of <italic toggle=\"yes\">Montgomery</italic> for failing to disclose reasonable alternative or variant treatments, or under <italic toggle=\"yes\">Bolam/Bolitho</italic> for failing to recommend appropriate treatment. Furthermore, given the need for a claimant to prove damage, a claimant in such a case would almost inevitably point to harm arising from a <italic toggle=\"yes\">treatment</italic> decision. Some interviewees thought that it was easier to characterise this sort of fact pattern as a negligent treatment case, bypassing the need to differentiate the relevant standard.</p>", "<title>B. Should <italic toggle=\"yes\">Bolam/Bolitho</italic> not apply in ‘pure diagnosis’ cases?</title>", "<title>1. Context</title>", "<p>There has long been a debate about the extent to which courts should defer to the medical profession in judging cases of medical negligence, and while it is generally agreed that a profession-led standard should be used, it is important to recognise that not all profession-led standards are equally deferential.<xref rid=\"fwad009-FN37\" ref-type=\"fn\"><sup>37</sup></xref> For example, some common law jurisdictions adopt a standard that requires doctors to exercise reasonable skill and care as defined by their profession as a whole—and as determined by a judge or jury after hearing expert evidence. In England and Wales, by contrast, a doctor need only follow a practice that is accepted by some members of the profession under <italic toggle=\"yes\">Bolam</italic>, and when there is a disagreement between experts about what a reasonable doctor would do, the judge is not authorised to decide which is right.<xref rid=\"fwad009-FN38\" ref-type=\"fn\"><sup>38</sup></xref> Rather, under <italic toggle=\"yes\">Bolitho</italic>, the judge is only authorised to reject a body of medical opinion ‘if, in a rare case, it can be demonstrated that the professional opinion is not capable of withstanding logical analysis’.<xref rid=\"fwad009-FN39\" ref-type=\"fn\"><sup>39</sup></xref> Thus, although <italic toggle=\"yes\">Bolitho</italic> limits <italic toggle=\"yes\">Bolam’s</italic> deference to the medical profession, the <italic toggle=\"yes\">Bolam/Bolitho</italic> approach adopted in England and Wales is still significantly more deferential than that in other common law jurisdictions.</p>", "<p>This deference has given rise to the question of whether there are cases of misdiagnosis in which <italic toggle=\"yes\">Bolam/Bolitho</italic> should not apply. For example, it has been argued that a different standard should apply in ‘pure diagnosis’ cases that involve only a ‘diagnosis of the condition … with no decision made or advice given about treatment or further diagnostic procedures’,<xref rid=\"fwad009-FN40\" ref-type=\"fn\"><sup>40</sup></xref> and where there cannot be two ‘right’ or ‘respectable’ answers.<xref rid=\"fwad009-FN41\" ref-type=\"fn\"><sup>41</sup></xref> Medical experts at the centre of such cases might include histopathologists, radiologists, sonographers, cytoscreeners, and genetic laboratories.</p>", "<p>While arguments to treat such cases differently were rejected by the Court of Appeal in <italic toggle=\"yes\">Penney v East Kent Health Authority</italic>,<xref rid=\"fwad009-FN42\" ref-type=\"fn\"><sup>42</sup></xref> Kerr J implicitly invited higher courts to revisit this question in <italic toggle=\"yes\">Muller v King’s College Hospital NHS Foundation Trust.</italic><xref rid=\"fwad009-FN43\" ref-type=\"fn\"><sup>43</sup></xref> In that case, Kerr J stated <italic toggle=\"yes\">obiter</italic> that the expert’s diagnosis in the case was based on a histopathological slide analysis that was straightforwardly right or wrong (in this case, wrong) and thus did not involve the exercise of medical judgement that justified deference under the <italic toggle=\"yes\">Bolam/Bolitho</italic> approach.<xref rid=\"fwad009-FN44\" ref-type=\"fn\"><sup>44</sup></xref> However, he explained that he was nevertheless required to follow the <italic toggle=\"yes\">Bolam/Bolitho</italic> approach, and he found negligence under what he described as a ‘liberal invocation’ of the <italic toggle=\"yes\">Bolitho</italic> exception.<xref rid=\"fwad009-FN45\" ref-type=\"fn\"><sup>45</sup></xref></p>", "<p>Kerr J’s critique of <italic toggle=\"yes\">Bolam/Bolitho</italic> was also advanced by Deputy Judge Lewis QC in <italic toggle=\"yes\">Brady v Southend University Hospital NHS Trust</italic>.<xref rid=\"fwad009-FN46\" ref-type=\"fn\"><sup>46</sup></xref> In this case, he drew a distinction between ‘treatment cases’, where there are ‘choices and options available and risks and benefits that need to be considered’, and ‘pure diagnosis’ cases, where there is ‘there is no weighing of risks against benefits, and no decision to treat or not to treat’.<xref rid=\"fwad009-FN47\" ref-type=\"fn\"><sup>47</sup></xref> Lewis J stated that in the latter, there is ‘limited scope for any genuine difference of medical opinion’ and that ‘a diagnosis based upon a scan is usually either right or wrong’.<xref rid=\"fwad009-FN48\" ref-type=\"fn\"><sup>48</sup></xref> For this reason, he suggested that <italic toggle=\"yes\">Bolam/Bolitho</italic> should not apply to such cases. However, like Kerr J, he concluded that he was bound by <italic toggle=\"yes\">Penney</italic>,<xref rid=\"fwad009-FN49\" ref-type=\"fn\"><sup>49</sup></xref> and that, in any event, the facts of <italic toggle=\"yes\">Brady</italic> did not fall in the pure diagnosis category.<xref rid=\"fwad009-FN50\" ref-type=\"fn\"><sup>50</sup></xref></p>", "<p>As <italic toggle=\"yes\">obiter dicta</italic> from respected judges can lead to appeals and, potentially, legal developments, we decided to ask the interviewees for their views on the decision in <italic toggle=\"yes\">Muller</italic>.</p>", "<title>2. Interview results</title>", "<p>There was a strong division of opinion between those interviewees who supported <italic toggle=\"yes\">Muller’s</italic> diagnosis/treatment distinction and those who did not.</p>", "<p>Those in favour of Kerr J’s reasoning supported it on the basis that they thought the deferential approach to the opinion of a body of medical experts in <italic toggle=\"yes\">Bolam/Bolitho</italic> was inappropriate when it came to questions of fact. One interviewee suggested that this was ‘<italic toggle=\"yes\">a complete illogicality</italic>’ because the <italic toggle=\"yes\">Bolam/Bolitho</italic> test was designed to apply where there is a range of options (for example in relation to treatment) for which doctors must weigh risks and benefits and could reasonably come to different conclusions.<xref rid=\"fwad009-FN51\" ref-type=\"fn\"><sup>51</sup></xref> The rationale for the <italic toggle=\"yes\">Bolam/Bolitho</italic> test did not apply to pure diagnosis questions, where the doctor was either right or wrong. Some interviewees suggested that courts could reduce <italic toggle=\"yes\">Bolam</italic>-style deference with the <italic toggle=\"yes\">Bolitho</italic> exception in pure diagnosis cases, by asking whether it was logical to reach that diagnosis, but they concluded that this was unsatisfactory. As one interviewee stated, ‘<italic toggle=\"yes\">we need to be a bit more sophisticated</italic>’ by properly identifying cases in which <italic toggle=\"yes\">Bolam/Bolitho</italic> is—and is not—appropriate.<xref rid=\"fwad009-FN52\" ref-type=\"fn\"><sup>52</sup></xref></p>", "<p>Part of the interviewees’ support for Kerr J’s reasoning in <italic toggle=\"yes\">Muller</italic> seemed to be driven by a broader dissatisfaction with the deferential approach taken in <italic toggle=\"yes\">Bolam/Bolitho.</italic> They thought that doctors should not have so much authority over the legal standards that apply to them. Particularly in ‘pure diagnosis’ cases, medical experts should not have the last word on the applicable standard where the medical issues appear to turn on questions of fact, such as whether a diagnosis was correct or not. Rather, these cases were better resolved by applying the test of reasonable skill and care that applies elsewhere in the law of negligence, under which the judge—taking into account expert evidence—decides whether an expert has acted reasonably. They suggested that <italic toggle=\"yes\">Bolitho</italic> did not always solve the problem of unjustified deference and that the <italic toggle=\"yes\">Bolam/Bolitho</italic> approach had been applied too broadly.<xref rid=\"fwad009-FN53\" ref-type=\"fn\"><sup>53</sup></xref> As one interviewee stated,</p>", "<p>On the other hand, a large proportion of interviewees opposed Kerr J’s reasoning in <italic toggle=\"yes\">Muller</italic> on the basis that a clear line cannot be easily drawn between ‘pure diagnosis’ and ‘pure treatment’ cases. They argued that the vast majority of the former cases are actually exercises in interpreting data which can lead to different views. Although most interviewees acknowledged that there were some cases in which there was eventually a clear right answer, they thought that, in most cases, there was room for ‘genuine argument’ over how to interpret the data at the time of the diagnosis.<xref rid=\"fwad009-FN55\" ref-type=\"fn\"><sup>55</sup></xref> One barrister believed that this kind of interpretation called for clinical expertise:</p>", "<p>This view was echoed by a number of interviewees who pointed out that the process of interpretation requires doctors to make judgement calls, informed by their clinical knowledge and experience, as to the most likely diagnosis and the appropriate next steps. One interviewee in particular noted that it was very difficult to separate out this interpretive exercise from other elements of the medical encounter that involve skill and expertise, since making a diagnosis is part of a continuous process of interaction between doctor and patient.<xref rid=\"fwad009-FN57\" ref-type=\"fn\"><sup>57</sup></xref> Interviewees who opposed Kerr J’s reasoning concluded that the degree of clinical expertise involved in making what Kerr J termed ‘pure diagnosis’ made it appropriate for assessment by a responsible body of medical opinion under <italic toggle=\"yes\">Bolam/Bolitho</italic>.</p>", "<title>C. Cross cutting themes at the frontiers of clinical negligence</title>", "<p>Our interviews not only shed light on the two questions that we posed, but also revealed a set of three common themes that underly these frontiers of clinical negligence.</p>", "<title>1. Criticism of Bolam/Bolitho</title>", "<p>Dissatisfaction with the <italic toggle=\"yes\">Bolam/Bolitho</italic> standard was a common thread in the interviews. Many interviewees were critical of its widespread application across very different types of cases in the past,<xref rid=\"fwad009-FN58\" ref-type=\"fn\"><sup>58</sup></xref> and they were sceptical about whether it should apply to both the communication and formation of diagnoses. They often favoured different standards of care for different aspects of clinical practice.</p>", "<p>It is important to recognise, however, that their reasons for rejecting <italic toggle=\"yes\">Bolam/Bolitho</italic> differed across the two questions. When asked what standard should apply to the communication of diagnoses, they criticised <italic toggle=\"yes\">Bolam/Bolitho</italic> on the grounds that it allows a paternalistic approach to the practice of medicine. This concern was grounded in respect for patient autonomy. By contrast, when asked about what standard should apply in pure diagnosis cases, they criticised <italic toggle=\"yes\">Bolam/Bolitho</italic> on the grounds that it is overly deferential to the medical profession. This critique was grounded in rule of law concerns about the proper role of the judiciary.</p>", "<p>The two different critiques also focus on different domains of decision-making. The first focuses on <italic toggle=\"yes\">Bolam/Bolitho’</italic>s impact on the relationship between doctors and patients, advocating a greater role for patients in <italic toggle=\"yes\">medical</italic> decision-making. The second focuses on <italic toggle=\"yes\">Bolam/Bolitho’</italic>s effect on the relationship between the medical profession and the court, advocating a reduced role for doctors in <italic toggle=\"yes\">legal</italic> decision-making.</p>", "<p>Interviewees did not always differentiate between these two sets of reasons for rejecting <italic toggle=\"yes\">Bolam/Bolitho</italic>, but it is important to avoid conflating them when the law develops at these two frontiers. While rejections of paternalism and rejections of deference can support the same changes in the law, as in <italic toggle=\"yes\">Montgomery</italic>, this will not always be the case.</p>", "<title>2. Differentiating treatment and diagnosis</title>", "<p>Both of our questions assumed that a clear line can be drawn between treatment and diagnosis, but this is a relatively new exercise in the law of clinical negligence, which has typically lumped them together.<xref rid=\"fwad009-FN59\" ref-type=\"fn\"><sup>59</sup></xref> For example, the <italic toggle=\"yes\">Bolitho</italic> exception applies to ‘cases of diagnosis and treatment’,<xref rid=\"fwad009-FN60\" ref-type=\"fn\"><sup>60</sup></xref> and <italic toggle=\"yes\">Hunter v Hanley</italic> (the Scottish equivalent of <italic toggle=\"yes\">Bolam</italic>) states that ‘in the realm of <italic toggle=\"yes\">diagnosis and treatment</italic> there is ample scope for genuine difference of opinion’.<xref rid=\"fwad009-FN61\" ref-type=\"fn\"><sup>61</sup></xref> It is therefore not surprising that the desirability and feasibility of differentiating treatment and diagnosis was a second cross-cutting theme.</p>", "<p>Two points are worth flagging here.</p>", "<p>First, many interviewees no longer assumed, as the law long has, that diagnosis and treatment should be governed by a single standard. Rather, they carefully considered whether and how treatment and diagnosis should be disentangled, and the standards that should apply to each. For example, some interviewees stated that there cannot be a genuine difference of opinion in pure diagnosis cases, contrary to the <italic toggle=\"yes\">Hunter v Hanley</italic> quotation above. The importance of recognising different standards was aptly summarised by a barrister who said that in every case, they asked themselves:</p>", "<p>This demonstrates a substantial departure from previous approaches that elided the difference between diagnosis and treatment under a single standard.</p>", "<p>Second, some thought that differentiating standards was justified in principle, but that there were circumstances in which it was difficult or did not make sense in practice. For example, some interviewees thought that in relation to both the core questions, treatment and diagnosis could be intimately connected, making it difficult to apply different standards to each. They also questioned the practical value of drawing the distinction, given that many common fact patterns could be characterised as either negligent treatment or negligent diagnosis; for example, a failure to communicate diagnostic uncertainty that leads to incorrect and harmful treatment. They suggested that in these circumstances, disaggregating the standard along a treatment–diagnosis boundary added unnecessary complexity and did not help to delineate the scope of the <italic toggle=\"yes\">Montgomery</italic> and <italic toggle=\"yes\">Bolam/Bolitho</italic> standards.</p>", "<p>Thus, it seems that a tension and challenge for medical law may lie ahead. The trend among practitioners, as well as in reported cases, is to move away from the application of a single standard to all types of cases. But, as interviewees’ discussion of the treatment/diagnosis distinction reveals, it can sometimes be difficult to disaggregate and differentiate standards on grounds that are coherent and significant in practice.</p>", "<title>3. Rights and responsibilities over risk</title>", "<p>A third cross-cutting theme in our interviews was the articulation of new rights and responsibilities in terms of the risks inherent in pursuing medical treatment. This can be seen in both the medical and legal domains.</p>", "<p>In the medical domain, this was identifiable in answers to the question of whether <italic toggle=\"yes\">Montgomery</italic> should apply to the communication of diagnostic uncertainty. Here, many interviewees commented on how the role of responding to risk should be distributed among the different actors in the diagnostic process. Most suggested that at least some rights or responsibilities should lie with the patient, necessitating the disclosure of at least some diagnostic uncertainty.</p>", "<p>In the legal domain, this theme can be seen in answers to the question of whether <italic toggle=\"yes\">Bolam/Bolitho</italic> should apply to pure diagnosis cases. Here, some interviewees argued that the applicability of <italic toggle=\"yes\">Bolam/Bolitho</italic> should be defined and limited on the basis of whether a doctor is making a decision based on the weighing of risks. They suggested that if a doctor is weighing risks, such that there is not an objectively correct decision, the reasonableness of the decision should be determined by <italic toggle=\"yes\">Bolam/Bolitho</italic> (at least while this remains the general standard for those exercising professional skill)<italic toggle=\"yes\">.</italic> However, in pure diagnosis cases, where they saw no weighing of risks, but rather a decision that was either correct or incorrect, they concluded that reasonableness should be determined by a judge based on expert testimony.</p>", "<p>Thus, across both domains, interviewees were thinking in terms of risk management when defining the relative rights and responsibilities of patients, doctors, and judges.</p>" ]	[]	[ "<title>IV. CONCLUSION</title>", "<p>Our interviews focused on two questions at the frontiers of medical negligence law that emerged from our prior work: (i) whether <italic toggle=\"yes\">Montgomery</italic> should apply to the communication of alternative diagnoses, and (ii) whether <italic toggle=\"yes\">Bolam/Bolitho</italic> should not apply in ‘pure diagnosis’ cases. Most interviewees concluded that <italic toggle=\"yes\">Montgomery</italic> should apply to communicating alternative diagnoses, as they thought that patient autonomy requires patients to be informed and involved in the diagnostic process, especially where diagnostic uncertainty affects a patient’s decisions about treatment. Opinions on cases of pure diagnosis, however, were more divided. Some interviewees thought that <italic toggle=\"yes\">Bolam/Bolitho</italic> should not apply on the grounds that these cases do not involve the weighing of risks in choosing between different options that can all be correct. Others thought that most diagnoses (including those that are termed ‘pure diagnosis’) involve interpretation and the possibility for reasonable disagreement, thus warranting the type of deference provided by <italic toggle=\"yes\">Bolam/Bolitho.</italic></p>", "<p>While the interviews did not settle our core questions to the extent that we had hoped, they confirmed that these issues are at the frontiers of medical negligence where we may see legal developments in the near future, with advocates bringing these debates before the courts. We have previously argued that the different dimensions of medical diagnosis raise interesting and complex legal issues,<xref rid=\"fwad009-FN63\" ref-type=\"fn\"><sup>63</sup></xref> and our interviews revealed that lawyers in the field are increasingly thinking about these issues and applying their views in practice (including when it comes to settling cases). Our interviews also provided a wealth of experience and empirical examples against which to assess the views we had explored in our body of work to date. Prevailing assumptions in the field, such as the widespread application of <italic toggle=\"yes\">Bolam/Bolitho</italic> and the dominance of the medical practitioner in managing the diagnostic process, are being challenged. Other themes, such as the careful disaggregation of different parts of the medical encounter, are also coming to the fore. These indicate a future direction of travel for the law of medical negligence, through which we hope the legal and practical complexities highlighted by our core questions will be further unravelled and clarified.</p>" ]	[ "<p>Annie Mackley, Kathleen Liddell and Jeffrey M Skopek contributed equally to this work.</p>", "<title>Abstract</title>", "<p>While errors in medical diagnosis are common and often litigated, the different dimensions of diagnosis—formation, communication, recording—have received much less legal attention. When the process of diagnosis is differentiated in this way, new and contentious legal questions emerge that challenge the appropriateness of the <italic toggle=\"yes\">Bolam/Bolitho</italic> standard. To explore these challenges, we interviewed 31 solicitors and barristers and asked them: (i) whether <italic toggle=\"yes\">Montgomery</italic> should apply to information about alternative diagnoses; and (ii) whether the <italic toggle=\"yes\">Bolam/Bolitho</italic> standard should be rejected in ‘pure diagnosis’ cases. Our qualitative analysis of the interviews sheds light not only on the two questions posed, but also on three cross-cutting themes. First, <italic toggle=\"yes\">Bolam/Bolitho</italic> is criticised on two grounds that are often conflated: its paternalism for patients and its deference to medical professionals. Second, adopting different standards for different aspects of treatment and diagnosis may be justified in principle, but it can sometimes be difficult or not make sense in practice. Third, new conceptions of patients, doctors, and courts are being articulated in terms of rights or responsibilities over risks. In mapping these issues at the frontiers of medical negligence, this empirical study identifies potential pressure points for future legal developments.</p>" ]	[]	[ "<title>Acknowledgements</title>", "<p>We are grateful to the participants who kindly agreed to be interviewed, and we thank the Thiscovery team (<ext-link xlink:href=\"https://www.thiscovery.org/about\" ext-link-type=\"uri\">https://www.thiscovery.org/about</ext-link>) for their support in building this project. This research was supported by Wellcome Trust grant 20813/Z/17/Z, ‘Diagnosing Diagnosis: A Multidisciplinary Perspective. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission ZF is based at The Healthcare Improvement Studies Institute (THIS Institute), University of Cambridge, and ILG was funded by a fellowship there. THIS Institute is supported by the Health Foundation, an independent charity committed to bringing about better health and healthcare for people in the UK.</p>" ]	[]	[ "<table-wrap position=\"float\" id=\"fwad009-T1\"><label>Table 1.</label><caption><p>Participants’ background and experience</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/><col valign=\"top\" align=\"char\" char=\".\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"1\" colspan=\"1\">Year of experience, years</th><th rowspan=\"1\" colspan=\"1\">Barristers</th><th rowspan=\"1\" colspan=\"1\">Solicitors</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">0–9</td><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td rowspan=\"1\" colspan=\"1\">10–19</td><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td rowspan=\"1\" colspan=\"1\">20–29</td><td rowspan=\"1\" colspan=\"1\">8</td><td rowspan=\"1\" colspan=\"1\">5</td></tr><tr><td rowspan=\"1\" colspan=\"1\">30–39</td><td rowspan=\"1\" colspan=\"1\">4</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">40+</td><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Total</td><td rowspan=\"1\" colspan=\"1\">21</td><td rowspan=\"1\" colspan=\"1\">10</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"fwad009-T2\"><label>Table 2.</label><caption><p>Emerging themes and illustrative quotations</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col valign=\"top\" align=\"left\" span=\"1\"/><col valign=\"top\" align=\"left\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"1\" colspan=\"1\">Theme</th><th align=\"center\" rowspan=\"1\" colspan=\"1\">Illustrative quotations</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Dissatisfaction with <italic toggle=\"yes\">Bolam/Bolitho</italic> in communicating diagnostic uncertainty</td><td rowspan=\"1\" colspan=\"1\">‘It should be confined to the dustbin of history. It’s not acceptable in the modern world.’ (BAR 58786)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I think <italic toggle=\"yes\">Montgomery</italic> is nibbling away at <italic toggle=\"yes\">Bolam</italic> quietly.’ (BAR 59716)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I think <italic toggle=\"yes\">Montgomery</italic> has opened the door in the sense that we now know very clearly that the <italic toggle=\"yes\">Bolam</italic> test doesn’t apply to one area, which is the provision of information and advice to patients. And the fact that the court has been very clear in saying it doesn’t apply there, I think does sort of open the possibility that it may not apply elsewhere.’ (SOL 59953)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">The body of doctors test in <italic toggle=\"yes\">Bolam</italic> has got a kind of momentum that, in my view, it doesn’t really deserve.’ (BAR 59823)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<hr/>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">The emphasis on autonomy in communicating diagnoses</td><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I think it is because when you are talking through with your patient what you are planning to do next, which they do now. I mean, they didn't, you know, 30/40 years ago. You just got told, this is what we’re going to do. They wouldn’t even tell you what the diagnosis… the differential diagnosis was. Or even what the working diagnosis was. And I think those days have gone. And that is partly due to <italic toggle=\"yes\">Montgomery</italic> but it think it’s a, sort of, rather wider change in medical practice.’ (BAR 59663)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘The <italic toggle=\"yes\">Montgomery</italic> mindset is wider than just that. The <italic toggle=\"yes\">Montgomery</italic> mindset is, what can I do to empower my patient and make my patient my equal so that everything that I do is in dialogue with my patient? And I give them the information that they need to be an equal partner in how we go about addressing whatever is that brought them through the door?’ (BAR 59949)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I think the point of <italic toggle=\"yes\">Montgomery</italic> and some of the cases after is that the … it’s moving away from the paternalism approach to medicine. And I think the extension to that must be that the patient ought to be informed of not only if there is a diagnosis what the diagnosis is; but of the … well, to an extent the differential diagnosis. I don’t think it would be reasonable to expect a doctor to list off every possible differential diagnosis the patient might have.’ (SOL 59657)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘If paternalism is dead and <italic toggle=\"yes\">Montgomery</italic> kind of killed paternalism then it seems to me that patients should be fully informed, should be part of the process and informed of not just the reasonable treatment options but the reasonable differential diagnosis.’ (SOL 60968)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">‘<italic toggle=\"yes\">Montgomery</italic> obviously a shift towards focusing on autonomy and the right of the patient to sort of be involved in and make decisions about their own care, and I think it’s fair to say that’s gone wider than just consent issues and those sorts of cases’, ‘<italic toggle=\"yes\">Montgomery</italic> is not all-encompassing in that sense, but it does indicate a broader shift towards a focus on the rights and I was going to say interests of the patient but I suppose what I mean more is the rights of the patient to be involved in their own care and their own diagnosis, which is a significant shift away from <italic toggle=\"yes\">Bolam</italic>.’ (BAR 60618)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Dissatisfaction with <italic toggle=\"yes\">Bolam/Bolitho</italic> in pure diagnosis</td><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘The reason I think it’s spot on is that, there's a lovely irony about this, which is that the <italic toggle=\"yes\">Bolam</italic> test, the <italic toggle=\"yes\">Bolam</italic> body of doctors test, includes the reference to the word, logical. Because it's the <italic toggle=\"yes\">Bolitho</italic> element of that test is that it has to withstand the logical analysis of risk and benefits. And the reason that I'm in agreement with the Judge in <italic toggle=\"yes\">Muller</italic> is that, there is a complete illogicality, ironically, trying to apply that test to say the interpretation of a slide, as I think it was in <italic toggle=\"yes\">Muller</italic>. Because either the abnormality is there, or it isn't.’ (BAR 61460)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘My own personal view is that, applying the <italic toggle=\"yes\">Bolam</italic> body of doctors test to scenarios where it just clearly is illogical to apply it, we should call that out and just say, look, this is not right.’ (BAR 59823)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘There haven’t been that many decided cases on what you might call pure diagnosis, and the obvious legal test would be reasonable care: has the doctor exercised reasonable care and skill in making the diagnosis? It seems that where the law has got to is a complete muddle and we have to apply the <italic toggle=\"yes\">Bolam</italic> test, which makes no sense, to diagnosis whatsoever. But the way the court gets round the illogicality of the <italic toggle=\"yes\">Bolam</italic> test is to apply the <italic toggle=\"yes\">Bolitho</italic> and say, well, we’ll be suspicious, exercise a high degree of suspicion about the defence. A reasonable body of doctors would have made this mistake? You have to ask the question: would it be logical to reach that diagnosis?’ (SOL 59953)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I mean I do notice that when people write, a lot of lawyers writing about cases make comments about <italic toggle=\"yes\">Bolam</italic> is the test to breach a QC. And I always look at that and raise my eyebrow and think, well, you know, it is in some cases but it’s not in all cases. And we need to be a bit more sophisticated.’ (SOL 59953)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘It strikes me that <italic toggle=\"yes\">Bolam</italic> should still apply though. I mean, you could get it wrong but it depends on why you’ve got it wrong and what was going on, and if an expert would say, well, yes, you got it wrong but actually it was very difficult to get it right and a responsible body would have made the same mistake, then yes, I don’t see why <italic toggle=\"yes\">Bolam</italic> wouldn’t apply in that case.’ (BAR 60618)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘You know, it doesn’t really make sense to me to say <italic toggle=\"yes\">Bolam</italic> doesn’t apply because it’s a binary choice. In a way, a lot of medical decisions are binary choices, right? You know, you either treat or you don’t treat or you diagnose or don’t diagnose that thing. So yes, I do struggle to understand the reasoning there.’ (BAR 60618)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">‘I can see the difference but you’ve still ultimately got professionals having to exercise professional judgment around the diagnosis and around the interpretation of the histopathology. And so, whilst you can retrospectively say that, you know, objectively yes it was, or it wasn’t this, when you’re judging the standard that’s been given by the histopathologist, reviewing that slide, then surely you’ve got to apply the same standards as you would for a treatment case. Because they need to do what a responsible body of professional histopathologists would do.’ (SOL 60340)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘Personally, I don’t think it (deference) should have some role to play. I think, unfortunately, it does have some role to play because the courts have said it does, but I don’t really think it adds to anything. So the issue is, what is there on the slide to be seen?’ (SOL 59953)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I also think that there could be scope for the judge to decide the particular findings of fact. It looked like this, as a matter of fact, not it was an area of uncertainty. It could have been one thing or it could have been the other. But it was actually condition A, not condition B, when you look at it. It was malignant cell. I would take the <italic toggle=\"yes\">Bolam</italic> at face value. Just because another expert says it was okay, frankly I don’t think it’s going to pass muster.’ (SOL 60969)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">‘There are certainly cases where you think, why did they miss it? You know, barn door. But there are also cases where there’s genuine argument, you count up the number of abnormal nuclei in the field you’re looking at or the shape of the cells, or whatever it may be.’ (BAR 60224)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<hr/>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Treatment/diagnosis distinction in pure diagnosis cases</td><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘Whenever I look at a case, I’m very careful to work out, is this a <italic toggle=\"yes\">Bolam</italic> body of doctors case, is this a pure diagnosis case of reasonable skill and care, is it a histology case, is it an interpretation case, is it a <italic toggle=\"yes\">Montgomery</italic> case?’ (BAR 59823)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘It’s interesting if you’re saying that radiology can either be right or wrong, there’s either a lesion there or not. I think there is still interpretation in that.’ (SOL 60506)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘So my view is that actually pure diagnosis is sort of when … I think it’s difficult because I don’t think everything is always that cut and dried.’ (SOL 61613)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘Yeah, so he’s kind of right in saying that there is something different with diagnosis versus treatment, because usually treatment is being done on the basis of a diagnostic determination that already exists. And the treatment is a series of options for which you can consent or not consent to. There is a difference in them, but there is more of a blurring than maybe that might indicate.’ (BAR 59769)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I don’t think there is ever a clear demarcation between the two, because actually the whole process is one of interaction between clinician and patient both ways, an information exchange. And so actually, I’m not sure that the kind of purity of the division is something that could be sustained.’ (BAR 59716)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">‘I can’t really see any advantages at the moment, I mean, certainly not in my work, to having a different test applying to diagnosis as to treatment. They do go very hand in hand. They go hand in hand in a doctor’s mind as well, so if ultimately this is a test of the doctor’s decision-making and his ability to provide reasonable advice to his patient then I can’t really see why you’d divide the two.’ (SOL 59178)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<hr/>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Treatment/diagnosis distinction in communicating diagnostic uncertainty</td><td rowspan=\"1\" colspan=\"1\">‘It seems to me that by definition when you’re thinking of treatment options you have also got to be thinking of differential diagnosis, so I don’t know whether your brain can untangle it in the way that the lawyers are trying to get them to do it.’ (BAR 59820)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘It’s almost always going to be the case if there is a dispute about diagnosis failing to consider, but it’s going to be about failing to consider a serious differential and, therefore, failing to treat it.’ (BAR 59928)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘It seems, to me, and I’ve probably said this already, that <italic toggle=\"yes\">Montgomery</italic> only really strays into this where there are decisions to be made.’ (BAR 59928)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I think it’s when treatment starts to be involved with that that Montgomery sort of comes more to the front of my mind.’ (BAR 60618)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I think the test will have to be, and this is where I think <italic toggle=\"yes\">Montgomery</italic> is aligned, it’ll have to be where a diagnosis is unclear and treatments—diagnostic treatments, not cures but exploratory treatments—are required.’ (SOL 59657)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘I do think we’re still in <italic toggle=\"yes\">Bolam</italic> territory and I don't think that <italic toggle=\"yes\">Montgomery</italic> particularly plays out, unless you’re looking at consent to diagnostic processes or a treatment pathway.’ (SOL 60340)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘If there is uncertainty, that predicates that there is a risk in pursuing a particular line of treatment based on that diagnosis and that must come within the parameters of <italic toggle=\"yes\">Montgomery</italic>, in my view.’ (BAR 58982)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">'On one level you can start breaking that down into treatment versus diagnosis or <italic toggle=\"yes\">Bolam</italic> v <italic toggle=\"yes\">Montgomery</italic>, but on another level it’s actually just well, what does the patient need to know to be informed about the next steps? And I think if you take a much more holistic, pragmatic approach you don’t get bogged down in these tiny distinctions.’ (BAR 59820)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<hr/>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Risk management in communicating diagnoses</td><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘And there are risks involved in having that, but there’s a one per cent risk, if we don’t do this, that we will miss the thing that’s inside of you, that is ultimately going to be very, very serious. I think, in that situation, of course, the clinician must tell the patient what the something serious is, because there are … there’s a decision to be made there, there are risks and benefits on either side and that is precisely within <italic toggle=\"yes\">Montgomery</italic>.’ (BAR 59928)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘Most cases, the patient has a right to know and is entitled to know the ups and the downs and the risks of … the concerns that a doctor has.’ (BAR 59749)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<hr/>‘It’s very hard to see why patient autonomy shouldn’t apply to the question of which possible diagnoses should be investigated? You know, my body, my choice. It’s very odd. If I’m entitled to say what should be done to my body, why am I not entitled to say what should be looked into? Doctor, I don’t want you to instigate the possibility of prostate cancer, because, whatever it may be, my dad had a horrible treatment which I don’t want to undergo, or it brings up memories that I don’t want to deal with. Why shouldn’t I have that option?’ (BAR 60224)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">‘<italic toggle=\"yes\">Montgomery</italic> isn’t actually … just about informed consent, it’s probably more accurately about risk and disclosure of the risk, so to the extent that decisions had to be made about risk or I suppose decisions have to be made more broadly about how a person discharges their right to personal autonomy, then questions of a diagnosis could be relevant to that context.’ (BAR 60225)</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[ "<disp-quote content-type=\"extract\"><p><italic toggle=\"yes\">‘Patients should be fully informed, … part of the process, and informed of not just the reasonable treatment options but the reasonable differential diagnosis</italic>’.<xref rid=\"fwad009-FN29\" ref-type=\"fn\"><sup>29</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p><italic toggle=\"yes\">‘[Doctors should ask:] what can I do to empower my patient and make my patient my equal so that everything I do is in dialogue with my patient?’</italic><xref rid=\"fwad009-FN30\" ref-type=\"fn\"><sup>30</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p><italic toggle=\"yes\">if there is uncertainty, that predicates that there is a risk in pursuing a particular line of treatment based on that diagnosis</italic>.<xref rid=\"fwad009-FN31\" ref-type=\"fn\"><sup>31</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p><italic toggle=\"yes\">I don’t know whether your brain can untangle it in the way that the lawyers are trying to get them to do it</italic>.<xref rid=\"fwad009-FN35\" ref-type=\"fn\"><sup>35</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p><italic toggle=\"yes\">It seems to me that, by definition, when you are thinking of treatment options you have also got to be thinking of differential diagnosis</italic>.<xref rid=\"fwad009-FN36\" ref-type=\"fn\"><sup>36</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p><italic toggle=\"yes\">the body of doctors’ test in Bolam has kind of got a momentum that, in my view, it doesn’t really deserve</italic>.<xref rid=\"fwad009-FN54\" ref-type=\"fn\"><sup>54</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p><italic toggle=\"yes\">Even in something like the interpretation of a scan, there is room for more than one view, and it’s not necessarily negligent to prefer one view over the other</italic>.<xref rid=\"fwad009-FN56\" ref-type=\"fn\"><sup>56</sup></xref></p></disp-quote>", "<disp-quote content-type=\"extract\"><p><italic toggle=\"yes\">Is this a Bolam body of doctors case? Is this a pure diagnosis of reasonable skill and care? Is it a histology case? Is it an interpretation case? It is a Montgomery case?</italic><xref rid=\"fwad009-FN62\" ref-type=\"fn\"><sup>62</sup></xref></p></disp-quote>" ]	[]	[]	[ "<fn-group><title>Footnotes</title><fn id=\"fwad009-FN1\"><label>1</label><p>M Jones, <italic toggle=\"yes\">Medical Negligence</italic> (5th edn, Sweet & Maxwell 2018) [4-10]–[4-50]; J Laing and others (eds), <italic toggle=\"yes\">Principles of Medical Law</italic> (4th edn, OUP 2017) s 4.74.</p></fn><fn id=\"fwad009-FN2\"><label>2</label><p>K Liddell and others, ‘Differentiating Negligent Standards of Care in Diagnosis’ (2022) 30 Medical Law Review 33, <<ext-link xlink:href=\"https://doi.org/10.1093/medlaw/fwab046\" ext-link-type=\"uri\">https://doi.org/10.1093/medlaw/fwab046</ext-link>>; M Khazen and others, ‘Anatomy of Diagnosis in a Clinical Encounter: How Clinicians Discuss Uncertainty with Patients’ (2022) 23 BMC Prim Care 153, doi: 10.1186/s12875-022-01767-y; National Academies of Sciences, Engineering, and Medicine, <italic toggle=\"yes\">Improving Diagnosis in Health Care</italic>, Chapter 2: The Diagnostic Process (The National Academies Press 2015), <<ext-link xlink:href=\"https://doi.org/10.17226/21794\" ext-link-type=\"uri\">https://doi.org/10.17226/21794</ext-link>>.</p></fn><fn id=\"fwad009-FN3\"><label>3</label><p>Liddell and others (n 2).</p></fn><fn id=\"fwad009-FN4\"><label>4</label><p>\n<italic toggle=\"yes\">Bolam v Friern Hospital Management Committee</italic> [1957] 1 WLR 582; <italic toggle=\"yes\">Bolitho v City & Hackney Health Authority</italic> [1998] AC 232.</p></fn><fn id=\"fwad009-FN5\"><label>5</label><p>ibid.</p></fn><fn id=\"fwad009-FN6\"><label>6</label><p>[2017] EWHC 128 (QB).</p></fn><fn id=\"fwad009-FN7\"><label>7</label><p>\n<underline>[</underline>2020] EWHC 158 (QB).</p></fn><fn id=\"fwad009-FN8\"><label>8</label><p>[2015] UKSC 11.</p></fn><fn id=\"fwad009-FN9\"><label>9</label><p>[2018] UKSC 50.</p></fn><fn id=\"fwad009-FN10\"><label>10</label><p>We also conducted a systematic literature review to assess the impact of <italic toggle=\"yes\">Montgomery</italic> in the six years since the Supreme Court’s landmark decision. See I Le Gallez and others, ‘<italic toggle=\"yes\">Montgomery</italic>'s Legal and Practical Impact: A Systematic Review at 6 Years’ (2022) 28 Journal of Evaluation in Clinical Practice 690.</p></fn><fn id=\"fwad009-FN11\"><label>11</label><p>Liddell and others (n 2) 59; Le Gallez and others (n 10) 699.</p></fn><fn id=\"fwad009-FN12\"><label>12</label><p>Liddell and others (n 2).</p></fn><fn id=\"fwad009-FN13\"><label>13</label><p>ibid 52–54.</p></fn><fn id=\"fwad009-FN14\"><label>14</label><p>ibid 58.</p></fn><fn id=\"fwad009-FN15\"><label>15</label><p>J Ritchie and J Lewis (eds), <italic toggle=\"yes\">Qualitative Research Practice: A Guide for Social Science Students and Researchers</italic> (Sage 2003).</p></fn><fn id=\"fwad009-FN16\"><label>16</label><p>ibid; J Ritchie and L Spencer, ‘Analyzing Qualitative Data’ in A Bryman and R Burgess (eds), <italic toggle=\"yes\">Qualitative Data Analysis for Applied Policy Research</italic> (Routledge 1994).</p></fn><fn id=\"fwad009-FN17\"><label>17</label><p>\n<italic toggle=\"yes\">Montgomery</italic> (n 8) [86].</p></fn><fn id=\"fwad009-FN18\"><label>18</label><p>The different types of standards and their origins is discussed in Liddell and others (n 2) 37–40.</p></fn><fn id=\"fwad009-FN19\"><label>19</label><p>\n<italic toggle=\"yes\">Montgomery</italic> (n 8) [84].</p></fn><fn id=\"fwad009-FN20\"><label>20</label><p>This view is described and evaluated in Le Gallez and others (n 10) 692. Prior to <italic toggle=\"yes\">Montgomery</italic>, the legal standard for disclosure of medical risk was unsettled. On one view, the majority in <italic toggle=\"yes\">Sidaway v Board of Governors of the Bethlam Royal Hospital</italic> [1985] AC 871 considered the matter to fall within the scope of <italic toggle=\"yes\">Bolam</italic>, subject to two qualifications. However, courts had departed from this view in various cases. <italic toggle=\"yes\">Montgomery</italic> (n 8) [86].</p></fn><fn id=\"fwad009-FN21\"><label>21</label><p>Le Gallez and others (n 10) 6–7.</p></fn><fn id=\"fwad009-FN22\"><label>22</label><p>Liddell and others (n 2) 52.</p></fn><fn id=\"fwad009-FN23\"><label>23</label><p>Similar concerns have been repeatedly expressed about Montgomery’s impact on treatment practices: Le Gallez and others (n 10) 7–9.</p></fn><fn id=\"fwad009-FN24\"><label>24</label><p>Liddell and others (n 2) 49–52.</p></fn><fn id=\"fwad009-FN25\"><label>25</label><p>\n<italic toggle=\"yes\">Taylor v Dailly Health Centre and others</italic> [2018] CSOH 91. In this case, the court held that <italic toggle=\"yes\">Montgomery</italic> did not require the disclosure of diagnostic uncertainty on the grounds that there is a crucial distinction between: (a) considering investigatory or treatment options and (b) discussing a recommended treatment and possible alternatives with the patient. [40].</p></fn><fn id=\"fwad009-FN26\"><label>26</label><p>\n<italic toggle=\"yes\">Hii Chii Kok v Ooi Peng Jin London Lucien</italic> [2017] SGCA 38. This decision introduced a modified <italic toggle=\"yes\">Montgomery</italic> standard. It held that a doctor was required to disclose information which a reasonable patient in the patient’s position would wish to know (in line with <italic toggle=\"yes\">Montgomery</italic>). Unlike the decision in <italic toggle=\"yes\">Montgomery</italic> (which was silent on this point), the Singaporean Court expressly highlighted information pertaining to other possible diagnoses such as the degree of certainty, the reasons for the lack of certainty and whether more can be done to clarify the uncertainty. However, whether a doctor was negligent in failing to possess that information and in failing to disclose it remained to be assessed by reference to the <italic toggle=\"yes\">Bolam/Bolitho</italic> standard. The decision is discussed in more detail in Liddell and others (n 2) 50–51. Since then, the Singapore Parliament enacted legislation responding to <italic toggle=\"yes\">Hii Chii Kok.</italic> Section 37 of the Singaporean Civil Law Act now provides, in brief, that a doctor providing advice to a patient meets the standard if he acts in a manner accepted by a responsible body of logical medical opinion (seemingly reintroducing <italic toggle=\"yes\">Bolam/Bolitho</italic>). It also provides, however, that medical opinion must require the provision of the information that a person in the same circumstances as the patient would reasonably require to make an informed decision, and information that ought to be known to be material to the patient in question based on questions asked by the patient or information gleaned from their medical records (seemingly retaining the elements of <italic toggle=\"yes\">Montgomery</italic> which were adopted in <italic toggle=\"yes\">Hii Chii Kok</italic>). The meaning and effects of this provision have yet to be determined. See generally, K Amirthalingam, ‘Upending the Medical Duty to Advise: Legislating the Standard in Singapore’ (2022) 22 <italic toggle=\"yes\">Medical Law International</italic> 189.</p></fn><fn id=\"fwad009-FN27\"><label>27</label><p>\n<italic toggle=\"yes\">Jandre v Wisconsin Injured Patients & Families Compensation Fund</italic> 813 NW2d 627 (Wis 2012). The Wisconsin Supreme Court held that a physician could have a duty to disclose information regarding diagnostic uncertainty under the ‘reasonable patient’ standard that was in place at the time. The decision and the legislation that followed is discussed in more detail in Liddell and others (n 2) 50–51.</p></fn><fn id=\"fwad009-FN28\"><label>28</label><p>They supported the decision in <italic toggle=\"yes\">Hi Chii Kok.</italic></p></fn><fn id=\"fwad009-FN29\"><label>29</label><p>SOL 60968.</p></fn><fn id=\"fwad009-FN30\"><label>30</label><p>BAR 59949.</p></fn><fn id=\"fwad009-FN31\"><label>31</label><p>BAR 58982.</p></fn><fn id=\"fwad009-FN32\"><label>32</label><p>BAR 60433.</p></fn><fn id=\"fwad009-FN33\"><label>33</label><p>See also Liddell and others (n 2) 52–54.</p></fn><fn id=\"fwad009-FN34\"><label>34</label><p>BAR 60244.</p></fn><fn id=\"fwad009-FN35\"><label>35</label><p>BAR 59820.</p></fn><fn id=\"fwad009-FN36\"><label>36</label><p>BAR 59820.</p></fn><fn id=\"fwad009-FN37\"><label>37</label><p>For a brief overview, see Liddell and others (n 2) 37–39.</p></fn><fn id=\"fwad009-FN38\"><label>38</label><p>Of course, some judges may nevertheless do so: R Mulheron, <italic toggle=\"yes\">Principles of Tort Law</italic> (CUP 2020) 365–66.</p></fn><fn id=\"fwad009-FN39\"><label>39</label><p>\n<italic toggle=\"yes\">Bolitho v City and Hackney HA</italic> [1998] AC 232 (HL), 243.</p></fn><fn id=\"fwad009-FN40\"><label>40</label><p>\n<italic toggle=\"yes\">Muller v King’s College Hospital NHS Foundation Trust</italic> [2017] EWHC 128 (QB), [48], [62]. It seems that some have suggested that ‘pure diagnosis’ cases could also include situations where no further action is taken after the diagnosis; for example, the claimant’s lawyers in <italic toggle=\"yes\">Brady</italic> suggested that it was a case of pure diagnosis. This was rejected by the judge. See <italic toggle=\"yes\">Brady</italic> (n 7).</p></fn><fn id=\"fwad009-FN41\"><label>41</label><p>E Jackson, <italic toggle=\"yes\">Medical Law: Text, Cases and Materials</italic> (5th edn, OUP 2019), 134 (citing <italic toggle=\"yes\">Muller</italic> [75]).</p></fn><fn id=\"fwad009-FN42\"><label>42</label><p>[1999] EWCA Civ 3005.</p></fn><fn id=\"fwad009-FN43\"><label>43</label><p>[2017] EWHC 128 (QB).</p></fn><fn id=\"fwad009-FN44\"><label>44</label><p>\n<italic toggle=\"yes\">Muller</italic> (n 40) [72].</p></fn><fn id=\"fwad009-FN45\"><label>45</label><p>ibid [97].</p></fn><fn id=\"fwad009-FN46\"><label>46</label><p>\n<italic toggle=\"yes\">Brady</italic> (n 7).</p></fn><fn id=\"fwad009-FN47\"><label>47</label><p>ibid, at [23].</p></fn><fn id=\"fwad009-FN48\"><label>48</label><p>ibid.</p></fn><fn id=\"fwad009-FN49\"><label>49</label><p>ibid.</p></fn><fn id=\"fwad009-FN50\"><label>50</label><p>ibid, at [20]. The case involved the misdiagnosis of gastrointestinal infection. Unlike a ‘pure diagnosis’ case, the doctors made decisions on the basis of the diagnosis (for example, to treat with a basic course of IV and oral antibiotics, and to discharge home without urgent gastroscopy). [6]–[14]. Furthermore, the claimant’s argument was that the doctors should have performed a test to confirm a specific diagnosis. See Liddell and others (n 2) 41–44, and <italic toggle=\"yes\">Brady</italic> (n 7) [20].</p></fn><fn id=\"fwad009-FN51\"><label>51</label><p>BAR 61460.</p></fn><fn id=\"fwad009-FN52\"><label>52</label><p>SOL 59953.</p></fn><fn id=\"fwad009-FN53\"><label>53</label><p>The extent to which the <italic toggle=\"yes\">Bolitho</italic> exception reduces judicial deference is also questioned in literature. See generally, Mulheron (n 38) 369–75; M Brazier and J Miola, ‘Bye-bye Bolam: A Medical Litigation Revolution?’ (2000) 8 Medical Law Review 85, 88.</p></fn><fn id=\"fwad009-FN54\"><label>54</label><p>BAR 59823.</p></fn><fn id=\"fwad009-FN55\"><label>55</label><p>For example, if a child has encephalopathy when they are born, they also had it when they were a foetus at 20 weeks gestation. At the time of a prenatal scan, however, the scan would require interpretation and there might be room for reasonable disagreement about whether the fetus had encephalopathy. At birth, when the child is older and outside the womb, the condition is clearer.</p></fn><fn id=\"fwad009-FN56\"><label>56</label><p>BAR 61332.</p></fn><fn id=\"fwad009-FN57\"><label>57</label><p>BAR 59716.</p></fn><fn id=\"fwad009-FN58\"><label>58</label><p>This is not to say that it has been applied in all types of case. See generally Mulheron (n 38) 376–81. For example, <italic toggle=\"yes\">Bolam/Bolitho</italic> does not apply in: disclosure of risk cases (where <italic toggle=\"yes\">Montgomery</italic> now applies, and prior cases applied versions of a patient-led perspective); matters that the court considers to be questions of ‘fact’ (where the court’s view on the balance of probabilities is determinative); cases where the crucial issue does not involve matters of expert or clinical judgement (for example, providing administrative information about waiting times, as in <italic toggle=\"yes\">Darnley v Croydon Health Services NHS Trust</italic> [2019] AC 831); and cases where there is no body of professional opinion.</p></fn><fn id=\"fwad009-FN59\"><label>59</label><p>Liddell and others (n 2) 34.</p></fn><fn id=\"fwad009-FN60\"><label>60</label><p>\n<italic toggle=\"yes\">Bolitho v City & Hackney Health Authority</italic> [1998] AC 232 (HL), 243.</p></fn><fn id=\"fwad009-FN61\"><label>61</label><p>\n<italic toggle=\"yes\">Hunter v Hanley</italic> [1955] SC 200, 204 (emphasis added).</p></fn><fn id=\"fwad009-FN62\"><label>62</label><p>BAR 59823.</p></fn><fn id=\"fwad009-FN63\"><label>63</label><p>Liddell and others (n 2).</p></fn></fn-group>" ]	[]	[]	[]	{ "acronym": [], "definition": [] }	0	CC BY	no	2024-01-13 23:36:46	Med Law Rev. 2023 May 30; 31(4):485-500	oa_package/cd/1d/PMC10681357.tar.gz
PMC10693530	38041704	[ "<title>Introduction</title>", "<p id=\"Par2\">Atmospheric deposition has caused a serious decline in forest health in Europe and Japan (Sase et al., ##UREF##34##1998##; Schütt & Cowling, ##UREF##37##1985##; Takamatsu et al., ##UREF##41##2001##) and the acidification of water and damage to fish and other aquatic life in lakes and rivers in Europe and North America (Baker, ##UREF##5##1991##; Rodhe, ##UREF##31##1972##). However, emissions of SO<sub>2</sub> have decreased due to regulation and controls implemented in the 1970s (Smith et al., ##UREF##38##2011##), and emissions of NO<sub>x</sub> have decreased since the 1990s in Europe and since the 2000s in North America and Japan (Akimoto, ##REF##14657488##2003##; EPA, ##UREF##10##2022##; Kopáček & Posch, ##UREF##22##2011##). Initial signs of the recovery from forest soil acidification, lake and river acidification, and biotic diversity have been reported in those regions due to the recovery of atmospheric conditions (Eimers et al., ##UREF##9##2004##; McHale et al., ##UREF##26##2017##; Sase et al., ##UREF##35##2019##; Wright et al., ##REF##16616318##2006##). Therefore, correct and wide area estimation for values of atmospheric input to the forest is important to evaluate the recovery potential of the forest by reducing atmospheric deposition.</p>", "<p id=\"Par3\">Stand deposition (SD) to the forest floor represents the total deposition supplied by throughfall (TF) and stemflow (SF). SD can be classified as wet deposition (WD; mainly precipitation), dry deposition (DD; gases and particles during dry periods), and canopy exchange (CE; canopy leaching or uptake) (Parker, ##UREF##30##1983##). WD is impacted by the strength and proximity of emission sources and meteorological factors, such as precipitation and wind speed. DD is affected by emission sources, meteorological factors, and vegetation factors such as the canopy’s ability to capture pollutants (Andersen & Hovmand, ##UREF##2##1999##; Lovett et al., ##UREF##24##1996##). CE encompasses the exchange of gases, such as nitrogen compounds (e.g., NH<sub>3</sub>, NO, and NO<sub>2</sub>), SO<sub>2</sub>, HNO<sub>3</sub>, and dissolved compounds (e.g., SO<sub>4</sub><sup>2−</sup>, NO<sub>3</sub><sup>−</sup>, NH<sub>4</sub><sup>+</sup>). The CE of gases occurs mainly via the stomata of vegetation (Sparks, ##REF##18975011##2009##) and is controlled by stomatal conductance and gas concentrations. The CE of dissolved compounds is controlled by ion concentrations in leaves and precipitation characteristics (Lovett et al., ##UREF##24##1996##; Parker, ##UREF##30##1983##). Thus, the input of dissolved ions to the forest floor is influenced by both physical factors (e.g., the strength and proximity of emission sources and meteorological conditions) and vegetation factors (e.g., the canopy form and leaf ion concentrations). Understanding the influence of these physical and vegetation factors on dissolved ion input processes is necessary to clarify the differences in inputs to forests according to composition.</p>", "<p id=\"Par4\">Physical factors can be investigated by comparing deposition trends in stands of the same species among different areas. For example, Imamura et al. (##UREF##19##2020a##) explained how physical factors (e.g., the distance from the center of Tokyo and elevation) affected the DD process in forests by comparing the WD and DD around Japanese cedar trees (<italic>Cryptomeria japonica</italic> (L.f.) D.Don) at seven sites within the Tokyo Metropolis. By contrast, to clarify vegetation factors, researchers have compared seasonal changes in DD and CE between coniferous and deciduous species at neighboring or nearby locations. Studies have performed seasonal comparisons of deciduous forests dominated by sugar maple (<italic>Acer saccharum</italic> Marsh.) and coniferous forests dominated by white pine (<italic>Pinus strobus</italic> L.) in Ontario, Canada (Neary & Gizyn, ##UREF##29##1994##); deciduous forests dominated by sugar maple and coniferous forests dominated by balsam fir (<italic>Abies balsamea</italic> (L.) Mill.) in Quebec, Canada (Houle et al., ##UREF##16##1999##); and deciduous forests dominated by silver birch (<italic>Betula pendula</italic> Roth) and coniferous forests dominated by Corsican pine (<italic>Pinus nigra</italic> ssp. <italic>laricio</italic> Maire) in Merksplas, Belgium (De Schrijver et al., ##REF##15210279##2004##; Table ##TAB##0##1##). From these previous studies, the influence of vegetation factors (e.g., leaf capture efficiency, physiological activity, and leafless period in deciduous species) on the processes governing dissolved element inputs to the forest floor could be investigated by comparing seasonality between coniferous and deciduous species at neighboring locations. However, reported vegetation factors differed among previous studies.\n</p>", "<p id=\"Par5\">De Schrijver et al. (##REF##17629749##2007##) summarized the differences in annual SD between coniferous and deciduous stands reported in 38 case studies of sites with different atmospheric conditions. They found that, among stands, the Na<sup>+</sup> SD increased with open field deposition; there were no relationships of the variations in the SDs of K<sup>+</sup>, Ca<sup>2+</sup>, and Mg<sup>2+</sup> with open field deposition; moreover, the NH<sub>4</sub><sup>+</sup> SD had a stronger correlation with open field deposition than did the NO<sub>3</sub><sup>−</sup> SD (De Schrijver et al., ##REF##17629749##2007##). From these results, we hypothesized that open field deposition, which is driven by physical factors, also affects the differences in DD and CE between coniferous and deciduous species, which are influenced by vegetation factors. The difference in atmospheric deposition could affect the different results about vegetation factors among previous studies. The present study aimed to identify factors influencing the differences in annual SDs between coniferous evergreen and broad-leaved deciduous species by comparing DD and CE between species during different phenological phases at sites that experience high and low atmospheric deposition values.</p>" ]	[ "<title>Materials and methods</title>", "<title>Site description</title>", "<p id=\"Par6\">We established forest sites in Kanto, Japan, experiencing either lower atmospheric deposition (Chichibu) or higher atmospheric deposition (Tanashi) (Fig. ##FIG##0##1## and Table ##TAB##0##1##). The Chichibu site was located at The University of Tokyo Chichibu Forest, 83.7 km from the center of Tokyo (Imamura et al., ##UREF##19##2020a##) and about 100 km from Tokyo Bay. The site hosts a natural deciduous mixed forest (35°56′N, 138°48′E; 1264 m a.s.l.) and coniferous Japanese cedar (<italic>C. japonica</italic>) plantation (35°56′N, 138°49′E; 1040 m a.s.l.) (Fig. ##FIG##0##1##) (Imamura et al., ##UREF##20##2020b##). The deciduous mixed forest is dominated by Japanese beech (<italic>Fagus japonica</italic> Maxim.), Siebold’s beech (<italic>Fagus crenata</italic> Blume), and Hemlock fir (<italic>Tsuga sieboldii</italic> Carrière). The Tanashi site was established in The University of Tokyo Tanashi Forest (35°44′N, 139°32′E) (Fig. ##FIG##0##1##) (Shi et al., ##REF##25366401##2014##). The site is 14.3 km from the center of Tokyo and 22.6 km from Tokyo Bay (Imamura et al., ##UREF##19##2020a##). The present study focused on naturally seriated secondary deciduous stands of Sawtooth oak (<italic>Quercus acutissima</italic> Carruth.) and Japanese cedar (<italic>C. japonica</italic>) evergreen plantations at the Tanashi site.</p>", "<title>Precipitation, throughfall, and stemflow measurements</title>", "<p id=\"Par7\">Wet-only precipitation was collected using an automatic wet-only sampler at the First Nursery meteorological station at Tanashi (Imamura et al., ##UREF##18##2018##). Bulk precipitation was collected using a bulk sampler at the Koakasawa meteorological station at Chichibu and at the meteorological station at Tanashi. At Chichibu, six throughfall collectors arranged in two parallel lines of three samplers each were installed 1 m from broad-leaved deciduous species (<italic>F. crenata</italic>) (Fig. ##FIG##1##2##) (Imamura et al., ##UREF##17##2012##). Under the stand of coniferous evergreen species (<italic>C. japonica</italic>), throughfall samplers were placed at random, with six per site. Water samples were collected from the same three collectors to take into account the distance from the trunks (Fig. ##FIG##1##2##). SF was collected at each study plot. At Tanashi, under a broad-leaved deciduous (<italic>Q. acutissima</italic>) tree and <italic>C. japonica</italic> tree, TF samples were collected using five bulk samplers (Fig. ##FIG##1##2##). <italic>F. crenata</italic> and <italic>Q. acutissima</italic> belong to Fagaceae (the Beech family). Water samples were collected from all collectors. SF collectors were installed in three individuals of each tree type. Bulk precipitation, TF, and SF were measured and sampled at least once a month from October 2010 to September 2012 at Chichibu and Tanashi. Stemflow volumes were calculated by dividing the volume of collected water by the canopy projection area at each site. Table ##TAB##0##1## summarizes the study plot characteristics, including tree age, tree height, basal area, and leaf area index (LAI).</p>", "<p id=\"Par8\">The pH and electrical conductivity of the samples were measured during each sampling period. The concentrations of dissolved inorganic ions (Na<sup>+</sup>, Cl<sup>−</sup>, SO<sub>4</sub><sup>2−</sup>, K<sup>+</sup>, Mg<sup>2+</sup>, Ca<sup>2+</sup>, NH<sub>4</sub><sup>+</sup>, and NO<sub>3</sub><sup>−</sup>) were measured using ion chromatography (LC-10A; Shimadzu Corp., Kyoto, Japan) and flame emission spectrometry (Z-2310; Hitachi High-Tech Science Corp., Tokyo, Japan). For quality control, each sample was assessed by comparing the measured and calculated conductivities of the water samples and the ion balances.</p>", "<title>Meteorological and air quality measurements</title>", "<p id=\"Par9\">Meteorological observations of air temperature and relative humidity were conducted atop a 23-m-high meteorological tower at the deciduous forest site in Chichibu and a 26-m-high meteorological tower at the <italic>C. japonica</italic> plantation in Tanashi. Air temperature and relative humidity were measured using a thermo-hygrograph at Chichibu (CS500; Campbell Scientific, Inc., Logan, USA) and Tanashi (Hobo U23-002; Onset Computer Corp., Bourne, MA, USA).</p>", "<p id=\"Par10\">NO<sub>2</sub> and NO<sub>x</sub> (NO plus NO<sub>2</sub>) filter samples were collected monthly from July 26, 2011, to July 5, 2012, on the meteorological tower in Chichibu using a passive sampler (OG-SN-S; Ogawa & Co., Ltd, Kobe, Japan). NO was calculated by subtraction. Water extracted from the exposed filter and blank filter was analyzed using the Saltzman method with a spectrophotometer (U-1800; Hitachi High-Tech Corporation, Tokyo, Japan). The limit of quantitation (LOQ) was calculated as ten times the standard deviation of the blanks (MacDougall et al., ##UREF##25##1980##). At Tanashi, these concentrations were obtained from national monitoring data obtained from July 14, 2011, to July 3, 2012, at the nearest monitoring site (located 1.2 km from Tanashi) (National Institute for Environmental Studies, ##UREF##28##2022##).</p>", "<title>Estimation of dry deposition and canopy exchange</title>", "<p id=\"Par11\">The TF and SF volumes were averaged across all collector samples at each site. The volume-weighted mean ion concentrations in TF and SF were then calculated. TF and SF depositions (mmol m<sup>−2</sup>) were calculated using the above datasets. During periods without observations, WD was calculated using bulk deposition and the bulk:wet-only concentration ratio at Tanashi (Imamura et al., ##UREF##18##2018##). Bulk deposition was used as a proxy for WD at Chichibu during all sampling periods. DD and CE were calculated with the canopy budget model (CBM) using WD, TF, and SF (Adriaenssens et al., ##UREF##1##2013##; Staelens et al., ##UREF##40##2008##). The DDs of K<sup>+</sup>, Mg<sup>2+</sup>, and Ca<sup>2+</sup> were estimated assuming that aerosols containing K<sup>+</sup>, Mg<sup>2+</sup>, and Ca<sup>2+</sup> were deposited onto the forest canopy at a rate equal to that of particulate Na<sup>+</sup>. Using the net throughfall (NTF):WD ratio of the Na<sup>+</sup> tracer ion, the DD rates of K<sup>+</sup>, Mg<sup>2+</sup>, and Ca<sup>2+</sup> were calculated as follows:where <sub><italic>X</italic></sub> is K<sup>+</sup>, Mg<sup>2+</sup>, or Ca<sup>2+</sup>.</p>", "<p id=\"Par12\">The CL values of K<sup>+</sup>, Mg<sup>2+</sup>, and Ca<sup>2+</sup> were calculated by subtracting DD from NTF. The CL of basic cations (BC; K<sup>+</sup> + Mg<sup>2+</sup> + Ca<sup>2+</sup>) should equal the CU of H<sup>+</sup> (Cronan & Reiners, ##REF##28310235##1983##) and NH<sub>4</sub><sup>+</sup> (Roelofs et al., ##UREF##32##1985##) based on the ion charge balance of the canopy (Eq. ##FORMU##1##2.2##):</p>", "<p id=\"Par13\">H<sup>+</sup> has an exchange capacity six times larger than that of NH<sub>4</sub><sup>+</sup> (Draaijers et al., ##UREF##8##1998##), which is accounted for by the relative uptake efficiency factor (<italic>xH</italic> = 6) in Eq. ##FORMU##2##2.3## to calculate the CU of NH<sub>4</sub><sup>+</sup> (De Schrijver et al., ##REF##15210279##2004##):</p>", "<p id=\"Par14\">The CU of H<sup>+</sup> was calculated by subtracting NH<sub>4</sub> from CU<sub>NH4+H</sub>. The DDs of NH<sub>4</sub><sup>+</sup> and H<sup>+</sup> were calculated by subtracting CU from NTF.</p>", "<p id=\"Par15\">The CU of NO<sub>3</sub><sup>−</sup> was calculated based on the TF fluxes of NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup>, using an efficiency factor of NH<sub>4</sub><sup>+</sup> versus NO<sub>3</sub><sup>−</sup> uptake (xNH<sub>4</sub>) with a value of six (de Vries et al., ##UREF##7##2001##; Eq. ##FORMU##3##2.4##).</p>", "<p id=\"Par16\">Na<sup>+</sup>, Cl<sup>−</sup>, and SO<sub>4</sub><sup>2−</sup> were defined only in terms of DD, i.e., not in terms of CL or CU.</p>", "<title>Definition of seasons</title>", "<p id=\"Par17\">At Chichibu, long-term video data indicate that the leaf-out period for the <italic>F. crenata</italic> canopy lasts from May to November (Fujiwara & Saito, ##UREF##11##2005##); these 7 months were considered the growing season, and the remaining 5 months were considered the dormant season (Fig. ##FIG##2##3##). At Tanashi, the leaf-out period for <italic>Q. acutissima</italic> lasted from April until November based on visual observations; these 8 months were defined as the growing season, and the remaining 4 months were considered the dormant season (Fig. ##FIG##2##3##).</p>", "<p id=\"Par18\">The 2-year average annual DD and CE values were separated into four phenological phases (Staelens et al., ##UREF##39##2007##; Van Stan et al., ##REF##22621811##2012##). The leaf emergence and leaf senescence periods were defined as the first and last 2 months of the growing season, respectively, for all species (Fig. ##FIG##2##3##). The other months of the growing season were defined as the fully leafed period. The leafless period was equal to the duration of the dormant season (Fig. ##FIG##2##3##).</p>", "<title>Data analysis</title>", "<p id=\"Par19\">To elucidate the differences in annual SDs between coniferous and deciduous species, annual SDs between coniferous and deciduous stands were compared at original study sites (Chichibu and Tanashi) and previous study sites (Ontario; Neary & Gizyn, ##UREF##29##1994##, Quebec; Houle et al., ##UREF##16##1999##, Merksplas; De Schrijver et al., ##REF##15210279##2004##). Previous studies have performed seasonal comparisons of deciduous and coniferous forests. A low atmospheric deposition site was defined as a lower wet deposition site compared to that at Chichibu. By contrast, a higher atmospheric deposition site was defined as a higher wet deposition site compared to that at Tanashi. DD and CE in annual, growing, and dormant seasons were calculated by the CBM at Chichibu, Tanashi, Ontario, Quebec, and Merksplas. In addition, only at Chichibu and Tanashi, monthly averaged DD and CE were calculated by the same method in the leaf emergence, fully leafed, leaf senescence, and leafless periods. A paired <italic>t</italic>-test was used to test the significant difference in annual and seasonal SD, DD, and CE between coniferous and deciduous stands.</p>" ]	[ "<title>Results</title>", "<title>Meteorology and air quality</title>", "<p id=\"Par20\">Figure ##FIG##3##4## presents the seasonal variations in meteorological parameters of the canopies at Chichibu and Tanashi from October 2010 to September 2012. The annual mean humidity was 79% and 70% at Chichibu and Tanashi, respectively. The relative humidity was higher at Chichibu than Tanashi throughout the year, particularly in summer when the relative humidity at Chichibu exceeded 80% from June to September.</p>", "<p id=\"Par21\">At Chichibu, the average absorption of the field blank for NO<sub>2</sub> and NO<sub>x</sub> was 0.16 (<italic>n</italic> = 4) and 0.21 (<italic>n</italic> = 4), respectively. The LOQ of absorption was 0.02 and 0.57 for NO<sub>2</sub> and NO<sub>x</sub>. Whereas all values of absorption for NO<sub>2</sub> were above the LOQ, those for NO<sub>x</sub> were below LOQ. Therefore, the average NO and NO<sub>2</sub> concentrations were below the LOQ and 1.2 ppb, respectively, at Chichibu. At Tanashi, the average NO and NO<sub>2</sub> concentrations were 5.5 ppb and 16.6 ppb, respectively. The NO<sub>2</sub> concentrations were > 10 times higher at Tanashi than Chichibu.</p>", "<title>Differences in stand deposition between deciduous and coniferous species</title>", "<p id=\"Par22\">At Chichibu, there were no differences in the 2-year average annual SD and DD values for Na<sup>+</sup> (<italic>p</italic> = 0.05) and SO<sub>4</sub><sup>2−</sup> (<italic>p</italic> = 0.61) between deciduous and coniferous species (Tables ##TAB##1##2## and ##TAB##2##3##). By contrast, the average annual SD and DD values of Cl<sup>−</sup> were significantly higher for coniferous than deciduous species (<italic>p</italic> < 0.05) (Tables ##TAB##1##2## and ##TAB##2##3##). At Tanashi, the average annual SD and DD values of Na<sup>+</sup>, Cl<sup>−</sup>, and SO<sub>4</sub><sup>2−</sup> were significantly higher for coniferous than deciduous species (<italic>p</italic> < 0.001) (Tables ##TAB##1##2## and ##TAB##2##3##). At Chichibu, the DD values were significantly higher for coniferous than deciduous species for Na<sup>+</sup> and Cl<sup>−</sup> in the leaf senescence period (<italic>p</italic> < 0.05) and Cl<sup>−</sup> and SO<sub>4</sub><sup>2−</sup> in the leafless period (<italic>p</italic> < 0.05) (Fig. ##FIG##4##5##). The SO<sub>4</sub><sup>2−</sup> DD value was significantly higher for deciduous than coniferous species in the fully leafed and leaf senescence periods (<italic>p</italic> < 0.05) (Fig. ##FIG##4##5##). At Tanashi, the DD values were significantly higher for coniferous than deciduous species during all phenological periods except the leaf senescence period for Na<sup>+</sup> (<italic>p</italic> < 0.05) and Cl<sup>−</sup> (<italic>p</italic> < 0.01) and the fully leafed and leafless periods for SO<sub>4</sub><sup>2−</sup> (<italic>p</italic> < 0.01) (Fig. ##FIG##4##5##).\n</p>", "<p id=\"Par23\">The annual K<sup>+</sup> SD value was non-significantly higher for deciduous than coniferous species at Chichibu (<italic>p</italic> = 0.50) and significantly at Tanashi (<italic>p</italic> < 0.01) (Table ##TAB##1##2##). The annual Mg<sup>2+</sup> SD value did not differ between deciduous and coniferous species at Chichibu (<italic>p</italic> = 0.09) but was significantly higher for coniferous than deciduous species at Tanashi (<italic>p</italic> < 0.01) (Table ##TAB##1##2##). The annual SD value of Ca<sup>2+</sup> was significantly higher for coniferous than deciduous species at both Chichibu and Tanashi (<italic>p</italic> < 0.01) (Table ##TAB##1##2##). At Chichibu, the annual CL values of K<sup>+</sup>, Mg<sup>2+</sup>, and Ca<sup>2+</sup> were > 20 times higher than the DD values for both coniferous and deciduous species (Tables ##TAB##2##3## and ##TAB##3##4##). At Tanashi, the annual K<sup>+</sup> DD value was about one-tenth the CL value for coniferous species, and the Mg<sup>2+</sup> and Ca<sup>2+</sup> DD values were about half the respective CL values (Tables ##TAB##2##3## and ##TAB##3##4##). The Mg<sup>2+</sup> CL value was significantly higher for deciduous than coniferous species in the leaf emergence period at Chichibu (<italic>p</italic> < 0.01) (Fig. ##FIG##5##6##). At Tanashi, the CL values of K<sup>+</sup> (<italic>p</italic> < 0.01) and Mg<sup>2+</sup> (<italic>p</italic> < 0.05) were significantly higher for deciduous than coniferous species in the leaf emergence and fully leafed periods (Fig. ##FIG##5##6##). By contrast, the Mg<sup>2+</sup> CL value was significantly higher for coniferous than deciduous species in the leafless period at Chichibu (<italic>p</italic> < 0.05) and Tanashi (<italic>p</italic> < 0.001) (Fig. ##FIG##5##6##). The Ca<sup>2+</sup> CL value was significantly higher for coniferous than deciduous species in the fully leafed, leaf senescence, and leafless periods at Chichibu (<italic>p</italic> < 0.05) and in the leaf emergence and leafless periods at Tanashi (<italic>p</italic> < 0.05) (Fig. ##FIG##5##6##). Coniferous species showed significantly higher DD values of Mg<sup>2+</sup> (<italic>p</italic> < 0.01) and Ca<sup>2+</sup> (<italic>p</italic> < 0.01) than deciduous species during all phenological periods except the leaf senescence period at Tanashi (Fig. ##FIG##4##5##).\n</p>", "<p id=\"Par24\">The annual H<sup>+</sup> SD value was significantly higher for coniferous than deciduous species at Chichibu and Tanashi (<italic>p</italic> < 0.001) (Table ##TAB##1##2##). At Chichibu and Tanashi, SF represented 78% and 83%, respectively, of the annual H<sup>+</sup> SD value for coniferous species and 5% and 6%, respectively, for deciduous species (Table ##TAB##1##2##).</p>", "<p id=\"Par25\">The annual NH<sub>4</sub><sup>+</sup> SD value was significantly higher for deciduous than coniferous species at Chichibu (<italic>p</italic> < 0.01) (Table ##TAB##1##2##). By contrast, coniferous species showed significantly higher annual SD values of NH<sub>4</sub><sup>+</sup> (<italic>p</italic> < 0.01) and NO<sub>3</sub><sup>−</sup> (<italic>p</italic> < 0.001) than deciduous species at Tanashi (Table ##TAB##1##2##). At Chichibu, the annual NH<sub>4</sub><sup>+</sup> DD value was non-significantly higher than the CU value for deciduous species (<italic>p</italic> = 0.54) (Tables ##TAB##2##3## and ##TAB##4##5##). At Tanashi, the annual DD values of NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> were significantly higher than the respective CU values for coniferous and deciduous species (<italic>p</italic> < 0.001 and <italic>p</italic> < 0.05, respectively), and the DD values were significantly higher for coniferous than deciduous species (<italic>p</italic> < 0.01 and <italic>p</italic> < 0.001, respectively) (Tables ##TAB##2##3## and ##TAB##4##5##). The NH<sub>4</sub><sup>+</sup> CU value was significantly higher for deciduous than coniferous species in the leaf emergence and fully leafed periods at Chichibu and Tanashi (<italic>p</italic> < 0.05) (Fig. ##FIG##6##7##). The NH<sub>4</sub><sup>+</sup> DD value was significantly higher for deciduous than coniferous species in the leaf emergence, fully leafed, and leaf senescence periods at Chichibu (<italic>p</italic> < 0.05) (Fig. ##FIG##4##5##). By contrast, the NH<sub>4</sub><sup>+</sup> DD value was significantly higher for coniferous than deciduous species in the fully leafed and leafless periods at Tanashi (<italic>p</italic> < 0.01), while the NH<sub>4</sub><sup>+</sup> DD value was significantly higher for deciduous than coniferous species in the leaf emergence period (<italic>p</italic> < 0.01) (Fig. ##FIG##4##5##). In addition, at Chichibu, the NO<sub>3</sub><sup>−</sup> DD and CU values were significantly higher for deciduous than coniferous species in the leaf emergence period (<italic>p</italic> < 0.05) (Figs. ##FIG##4##5## and ##FIG##6##7##). At Tanashi, the NO<sub>3</sub><sup>−</sup> DD value was higher for coniferous than deciduous species during all phenological periods except the leaf senescence period (<italic>p</italic> < 0.01) (Fig. ##FIG##4##5##).\n</p>" ]	[ "<title>Discussion</title>", "<title>Sodium and chloride ions</title>", "<p id=\"Par26\">At the low-atmospheric-deposition site (Chichibu), there were no differences in the annual Na<sup>+</sup> DD or SD values between coniferous and deciduous species (Tables ##TAB##1##2## and ##TAB##2##3##) because significant differences were observed only in the leaf senescence period (Fig. ##FIG##4##5##). Similarly, in Ontario, Canada, where the Na<sup>+</sup> WD value was lower than that at Chichibu (Table ##TAB##0##1##), the annual SD value did not differ significantly between species (Neary & Gizyn, ##UREF##29##1994##) (Table ##TAB##1##2##) because the DD values did not differ between species in either the growing or dormant seasons (Table ##TAB##2##3##). In addition, at a low-atmospheric-deposition site in Quebec, Canada (Table ##TAB##0##1##), the Na<sup>+</sup> SD and DD values were similar between coniferous and deciduous species (Houle et al., ##UREF##16##1999##) (Tables ##TAB##1##2## and ##TAB##2##3##). These results suggest that differences in the annual SD values of Na<sup>+</sup> between coniferous and deciduous species are minimally impacted by vegetation factors such as capture efficiency at low-deposition sites.</p>", "<p id=\"Par27\">The annual Cl<sup>−</sup> SD value was higher for coniferous than deciduous species at Chichibu (Table ##TAB##1##2##). This resulted from the significantly higher Cl<sup>−</sup> DD value for coniferous than deciduous species during the leaf senescence and leafless periods (Fig. ##FIG##4##5##), which could be influenced by HCl gas concentrations at Chichibu. In Ontario and Quebec, where the Cl<sup>−</sup> WD values were lower than that at Chichibu (Table ##TAB##0##1##), there were no significant differences in annual Cl<sup>−</sup> SD values between species (Houle et al., ##UREF##16##1999##; Neary & Gizyn, ##UREF##29##1994##) (Table ##TAB##1##2##) because there were no differences in the DD values between species in the growing and dormant seasons (Table ##TAB##2##3##). Similar to Na<sup>+</sup>, the differences in annual Cl<sup>−</sup> SD values between coniferous and deciduous species are minimally influenced by vegetation factors such as capture efficiency at low-deposition sites.</p>", "<p id=\"Par28\">At the high-atmospheric-deposition site (Tanashi), the annual Na<sup>+</sup> and Cl<sup>−</sup> SD values were significantly higher for coniferous than deciduous species (Table ##TAB##1##2##) as a result of the higher DD values for the former species in the fully leafed and leafless periods (Fig. ##FIG##4##5##). In Merksplas, Belgium, where the Na<sup>+</sup> WD value was higher than that at Tanashi (Table ##TAB##0##1##), the annual Na<sup>+</sup> SD value was significantly higher for coniferous than deciduous species (De Schrijver et al., ##REF##15210279##2004##) (Table ##TAB##1##2##) because the DD value was significantly higher for the former species in both the growing and dormant seasons (Table ##TAB##2##3##). Vegetation factors impacting DD include tree height (Griffith et al., ##UREF##12##2015##; Lovett & Reiners, ##UREF##23##1986##), LAI (Augusto et al., ##UREF##4##2002##), basal area (Zhang et al., ##UREF##46##2022##), vegetation type (evergreen vs. deciduous) (Erisman & Draaijers, ##REF##12758019##2003##), and leaf shape (Woodcock, ##UREF##45##1953##). Tree height was higher for deciduous than coniferous species, and the difference in LAI was small between species at Tanashi and Quebec (Table ##TAB##0##1##). These results suggest that higher stand capture efficiency based on wide basal area and spiral leaf shape of coniferous canopies drive the differences in Na<sup>+</sup> and Cl<sup>−</sup> SD values between species in the growing (i.e., leafed) season. In the dormant season, the absence of leaves on deciduous species and differences in tree basal area drive the differences in the annual Na<sup>+</sup> and Cl<sup>−</sup> SD values between deciduous and coniferous species.</p>", "<title>Potassium, magnesium, and calcium ions</title>", "<p id=\"Par29\">The annual K<sup>+</sup> SD value was significantly higher for deciduous than coniferous species at Tanashi (Table ##TAB##1##2##) as a result of the low K<sup>+</sup> DD value (Table ##TAB##2##3##) and increased K<sup>+</sup> CL value for deciduous species in the leaf emergence and fully leafed periods (Fig. ##FIG##5##6##). Although not significant, the same trend was observed at Chichibu (Fig. ##FIG##5##6##, Tables ##TAB##1##2## and ##TAB##2##3##). Similarly, three other studies found higher annual K<sup>+</sup> SD values for deciduous than coniferous species because the K<sup>+</sup> CL values were higher for deciduous than coniferous species in the growing season, even though these correlations were not significant (De Schrijver et al., ##REF##15210279##2004##; Houle et al., ##UREF##16##1999##; Neary & Gizyn, ##UREF##29##1994##) (Tables ##TAB##1##2## and ##TAB##3##4##). Similar to Chichibu and Tanashi, the previous studies also reported lower annual K<sup>+</sup> DD than CL values (Tables ##TAB##2##3## and ##TAB##3##4##). These trends indicate that differences in the annual K<sup>+</sup> SD value between coniferous and deciduous species are influenced by the CL value of deciduous species in the growing season, especially the leaf emergence and fully leafed periods, even at sites with different atmospheric deposition values. In Japan, deciduous broad-leaved species generally have higher K<sup>+</sup> levels in their leaves than <italic>C. japonica</italic> (Table ##TAB##5##6##). In addition, broad leaves are susceptible to the leaching of K<sup>+</sup> (Rothe et al., ##UREF##33##2002##). The higher K<sup>+</sup> CL value in deciduous than coniferous species in the leaf emergence and fully leafed periods was assumed to be due to differences in leaf K<sup>+</sup> concentrations between deciduous and coniferous species. Therefore, differences in the K<sup>+</sup> SD value between coniferous and deciduous species are influenced by the physiological state and leaf K<sup>+</sup> concentration of tree species, regardless of the atmospheric deposition value.\n</p>", "<p id=\"Par30\">At Chichibu, the Mg<sup>2+</sup> CL value was higher for deciduous species in the leaf emergence period and coniferous species in the leafless period; meanwhile, the Ca<sup>2+</sup> CL was significantly higher for coniferous than deciduous species in the fully leafed and leafless periods (Fig. ##FIG##5##6##). Moreover, the annual Mg<sup>2+</sup> SD value did not differ between tree species, and the Ca<sup>2+</sup> SD value was significantly higher for coniferous than deciduous species (Table ##TAB##1##2##). The same trends were observed at low-deposition sites in Ontario and Quebec, Canada (Houle et al., ##UREF##16##1999##; Neary & Gizyn, ##UREF##29##1994##) (Table ##TAB##1##2##). This resulted from the higher Mg<sup>2+</sup> CL value for deciduous species in the growing period and coniferous species in the dormant season (Table ##TAB##3##4##). In Ontario, the Ca<sup>2+</sup> CL value was non-significantly higher for coniferous than deciduous species in the growing or dormant season; in Quebec, the Ca<sup>2+</sup> CL value was significantly higher for coniferous species in the dormant season (Table ##TAB##3##4##). Leaf Mg<sup>2+</sup> and Ca<sup>2+</sup> concentrations did not differ between deciduous species and <italic>C. japonica</italic> (Table ##TAB##5##6##); however, broad leaves are more susceptible to leaching of Mg<sup>2+</sup> than Ca<sup>2+</sup> (Rothe et al., ##UREF##33##2002##). The lack of differences in annual Mg<sup>2+</sup> SD values between coniferous and deciduous species resulted from differences in the Mg<sup>2+</sup> CL values of each species between the growing and dormant seasons at low-deposition sites. By contrast, the higher annual Ca<sup>2+</sup> SD value for coniferous than deciduous species resulted from higher CL from coniferous than deciduous species throughout the year. These results indicate that differences in annual Mg<sup>2+</sup> and Ca<sup>2+</sup> SD values between coniferous and deciduous species are influenced by the physiological characteristics of leaves at low-deposition sites.</p>", "<p id=\"Par31\">The annual Mg<sup>2+</sup> and Ca<sup>2+</sup> DD values were > 20-fold lower than the respective CL values at the low-deposition site, Chichibu, but were only half the respective CL values at the high-deposition site (Tanashi; Tables ##TAB##2##3## and ##TAB##3##4##). In addition, the Mg<sup>2+</sup> and Ca<sup>2+</sup> DD values were higher for coniferous than deciduous species during all phenological periods, except the leaf senescence period at Tanashi (Fig. ##FIG##4##5##). These trends indicate that Mg<sup>2+</sup> and Ca<sup>2+</sup> DD values also influence the differences in annual Mg<sup>2+</sup> and Ca<sup>2+</sup> SD values between coniferous and deciduous species at high-deposition sites. At a high-deposition site in Merksplas, Belgium (Table ##TAB##0##1##), the annual Mg<sup>2+</sup> and Ca<sup>2+</sup> SD values were higher for coniferous than deciduous species, although not significantly (De Schrijver et al., ##REF##15210279##2004##) (Table ##TAB##1##2##); the Mg<sup>2+</sup> and Ca<sup>2+</sup> DD values were higher than the respective CL values and were also higher for coniferous than deciduous species throughout the year (Tables ##TAB##2##3## and ##TAB##3##4##). These findings indicate that differences in annual Mg<sup>2+</sup> and Ca<sup>2+</sup> SD values between coniferous and deciduous species are affected by the CL and DD values at high-deposition sites. Mg<sup>2+</sup> and Ca<sup>2+</sup> CL and DD values between coniferous and deciduous species are influenced by the physiological characteristics of leaves and by stand capture efficiency, respectively.</p>", "<title>Hydrogen ion</title>", "<p id=\"Par32\">The higher annual H<sup>+</sup> SD for coniferous than deciduous species was the result of higher H<sup>+</sup> SF for coniferous than deciduous species (Table ##TAB##1##2##). Generally, conifers supply high amounts of H<sup>+</sup> via SF, due to the low pH of SF resulting from the comparatively higher dissolved organic concentrations of conifers (Inagaki et al., ##UREF##21##1995##; Parker, ##UREF##30##1983##; Thieme et al., ##UREF##43##2019##) and lower bark pH (Asplund et al., ##UREF##3##2015##) compared to deciduous species. Measurements in Ontario, Canada, revealed lower H<sup>+</sup> SF values for conifers than in this study (Table ##TAB##1##2##) because the five most dominant species were selected for SF sampling in the former study (Table ##TAB##0##1##), which also found higher H<sup>+</sup> SF levels for coniferous than deciduous species (Neary & Gizyn, ##UREF##29##1994##) (Table ##TAB##1##2##). Other studies conducted in Quebec, Canada, and Merksplas, Belgium, did not consider inputs of H<sup>+</sup> from SF in the evaluation of H<sup>+</sup> SD values, and the SD of conifers was not greater than that of deciduous species (De Schrijver et al., ##REF##15210279##2004##; Houle et al., ##UREF##16##1999##) (Table ##TAB##1##2##). Overall, the findings indicate that differences in the annual H<sup>+</sup> SD value between coniferous and deciduous species are caused by differences in H<sup>+</sup> SF between species, regardless of atmospheric deposition values.</p>", "<title>Sulfur, ammonium, and nitrate ions</title>", "<p id=\"Par33\">The CU of nitrogen is controlled by leaf physiological activities (e.g., stomatal opening and photosynthesis rates) (Krupa, ##REF##12713921##2003##; Lovett et al., ##UREF##24##1996##; Parker, ##UREF##30##1983##) and passive diffusion processes from water film into leaves (Hansen, ##UREF##15##1996##; Lovett et al., ##UREF##24##1996##; Schaefer et al., ##UREF##36##1988##). In addition, some studies reported canopy nitrification by using a dual isotope approach (Guerrieri et al., ##UREF##13##2015##; Templer et al., ##UREF##42##2015##; Watanabe et al., ##UREF##44##2016##). However, CBM does not account for possible nitrogen transformations occurring in tree canopies by epiphytes and/or microbes associated with foliage (Guerrieri et al., ##UREF##14##2021##). Therefore, this chapter is just focused on leaf physiological activities and passive diffusion processes for CU of nitrogen.</p>", "<p id=\"Par34\">Birch showed the highest uptake rates in the leaf developing stage by the <sup>15</sup>NH<sub>4</sub><sup>+</sup>-labelled test (Adriaenssens et al., ##UREF##0##2011##). In addition, Adriaenssens et al. (##REF##22325986##2012##) reported a strong negative net TF flux for NO<sub>3</sub><sup>−</sup> in a beech canopy during the leaf development period, which was related to NO<sub>3</sub><sup>−</sup>-N assimilation. At both Chichibu and Tanashi, we found that the NH<sub>4</sub><sup>+</sup> CU value was significantly higher for deciduous than coniferous species during the leaf emergence period (Fig. ##FIG##6##7##). This trend is considered the result of increased CU by leaf physiological activities of deciduous species in the leaf emergence period. In addition, water films on leaves, which form when particles are dry-deposited under relatively humid conditions, reduce cuticular resistance (Burkhardt & Eiden, ##UREF##6##1994##). Gaseous deposition of NH<sub>3</sub>, NO<sub>y</sub>, and SO<sub>2</sub> from the atmosphere to the plant surface is increased in the presence of such films; as the gases dissolve into the water in the film, their concentrations rise, thereby enhancing passive diffusion from water film into the needle (Adriaenssens et al., ##REF##22325986##2012##; Sase et al., ##REF##17658672##2008##). De Schrijver et al. (##REF##15210279##2004##) suggested that CU by deciduous species increases in the growing season when cuticles are thinner and wettability is greater. At the low-deposition site (Chichibu), we found that the SO<sub>4</sub><sup>2−</sup> and NH<sub>4</sub><sup>+</sup> DD values were significantly higher for deciduous than coniferous species in the fully leafed and leaf senescence periods (Fig. ##FIG##4##5##). The relative humidity during summer was higher at Chichibu than Tanashi because a large area around Chichibu is forested (Fig. ##FIG##3##4##). In addition, fog occurs frequently at Chichibu (Imamura et al., ##UREF##20##2020b##). Therefore, the increased SO<sub>4</sub><sup>2−</sup> and NH<sub>4</sub><sup>+</sup> DD values for deciduous species in the growing season are attributable to the result of the presence of water films on leaves. In addition, the NH<sub>4</sub><sup>+</sup> CU value for deciduous species also could be increased in the growing season via passive diffusion from water film into leaves (Fig. ##FIG##6##7##).</p>", "<p id=\"Par35\">While the NH<sub>4</sub><sup>+</sup> CU value was significantly higher for deciduous than coniferous species in the leaf emergence period, the NH<sub>4</sub><sup>+</sup> DD value was significantly higher for deciduous than coniferous species during the growing season (Figs. ##FIG##4##5## and ##FIG##6##7##). Therefore, the annual NH<sub>4</sub><sup>+</sup> SD value has been higher for deciduous than coniferous species because the annual NH<sub>4</sub><sup>+</sup> DD value was higher than the annual NH<sub>4</sub><sup>+</sup> CU value for deciduous species. The annual SO<sub>4</sub><sup>2−</sup> SD value did not differ between coniferous and deciduous species (Table ##TAB##1##2##); this was the result of a higher SO<sub>4</sub><sup>2−</sup> DD value for deciduous species in the fully leafed and leaf senescence periods and higher value for coniferous species in the leafless period (Fig. ##FIG##4##5##). At a low-deposition site in Quebec, Canada (Table ##TAB##0##1##), the significantly higher annual NH<sub>4</sub><sup>+</sup> SD value for deciduous than coniferous species resulted from a higher NH<sub>4</sub><sup>+</sup> DD value for the former species throughout the year (Houle et al., ##UREF##16##1999##) (Tables ##TAB##1##2## and ##TAB##2##3##). Differences in the annual SO<sub>4</sub><sup>2−</sup> SD value between deciduous and coniferous species were influenced by leaf wettability, and those of NH<sub>4</sub><sup>+</sup> were influenced by leaf uptake (a phenological factor), as well as the DD and CU driven by leaf wettability and diffusion processes from water film into leaves at the low-deposition site.</p>", "<p id=\"Par36\">The NO<sub>3</sub><sup>−</sup> CU value was higher for deciduous than coniferous species in the leaf emergence period at Chichibu (Fig. ##FIG##6##7##). However, there was no difference between species in the NO<sub>3</sub><sup>−</sup> DD value during other periods (Fig. ##FIG##4##5##). While the NH<sub>4</sub><sup>+</sup> DD value for deciduous species increased in fully leafed and leaf senescence periods (relatively humid conditions), the NO<sub>3</sub><sup>−</sup> DD value did not increase during same periods at Chichibu (Fig. ##FIG##4##5##). This is because water films had no impact on the diffusion processes, possibly due to low gas concentrations (NO: below the LOQ; NO<sub>2</sub>: 1.2 ppb). In Quebec, CU of NO<sub>3</sub><sup>−</sup> was reported in the leaf senescence period. In addition, the annual NO<sub>3</sub><sup>−</sup> SD value was significantly higher for deciduous than coniferous species because the NO<sub>3</sub><sup>−</sup> DD value was higher for the former species throughout the year (Houle et al., ##UREF##16##1999##) (Tables ##TAB##1##2## and ##TAB##2##3##). The gas concentrations in 1999 in Quebec (NO: 2.3 ppb; NO<sub>2</sub>: 8.0 ppb; National Air Pollution Surveillance Program, ##UREF##27##2022##) were higher than those at Chichibu during the present study; thus, water film formation increased the DD of NO<sub>3</sub><sup>−</sup> for deciduous species. Overall, differences in the annual NO<sub>3</sub><sup>−</sup> SD value between deciduous and coniferous species were influenced by both phenological factors and diffusion processes, although atmospheric gas concentrations also impact diffusion.</p>", "<p id=\"Par37\">At Tanashi, the significantly higher annual SO<sub>4</sub><sup>2−</sup> SD value for coniferous than deciduous species (Table ##TAB##1##2##) resulted from the higher SO<sub>4</sub><sup>2−</sup> DD values for coniferous than deciduous species in the fully leafed and leafless periods (Fig. ##FIG##4##5##). The NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> CU values were higher in the leaf emergence period (Fig. ##FIG##4##5##), and the annual NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> DD values were significantly higher than the respective CU values for both species (Tables ##TAB##2##3## and ##TAB##4##5##). In addition, the NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> DD values were higher for coniferous than deciduous species in the fully leafed and leafless periods (Fig. ##FIG##4##5##). Therefore, the annual NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> SD values were significantly higher for coniferous than deciduous species (Table ##TAB##1##2##). In Ontario, Canada, where the SO<sub>4</sub><sup>2−</sup> WD value was higher than that at Tanashi (Table ##TAB##0##1##), the annual SO<sub>4</sub><sup>2−</sup> SD value was significantly higher for coniferous than deciduous species (Neary & Gizyn, ##UREF##29##1994##) (Table ##TAB##1##2##) because DD was significantly higher for coniferous than deciduous species in the growing season (Table ##TAB##2##3##). Similarly, the annual SO<sub>4</sub><sup>2−</sup> SD value was non-significantly higher for coniferous than deciduous species in Quebec (Houle et al., ##UREF##16##1999##) (Table ##TAB##1##2##) because the DD was higher for the former species in the growing and dormant seasons (Table ##TAB##2##3##). In Merksplas, Belgium, where the NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> WD values were higher than those in Tanashi (Table ##TAB##0##1##), the annual NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> DD values were higher than the respective CU values (Tables ##TAB##2##3## and ##TAB##4##5##). In addition, the annual NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> DD and SD values were higher for coniferous than deciduous species (De Schrijver et al., ##REF##15210279##2004##) (Tables ##TAB##1##2## and ##TAB##2##3##). These results indicate that the annual SO<sub>4</sub><sup>2−</sup>, NH<sub>4</sub><sup>+</sup>, and NO<sub>3</sub><sup>−</sup> SD values are higher for coniferous than deciduous species as a result of increased DD (due to a higher capture efficiency) for coniferous species in the growing season, as well as the absence of leaves on deciduous species in the dormant season at high-deposition sites.</p>" ]	[ "<title>Conclusion</title>", "<p id=\"Par38\">This research explained the factors affecting the difference of dissolved ion inputs to the forest floor between coniferous and deciduous species by comparing seasonal variations of dry deposition and canopy exchange at two different atmospheric deposition conditions. Whereas this research is regional and based on limited observation data, this research cleared that the atmospheric deposition affected to vegetation factor, especially the capture efficiency of coniferous trees for Na<sup>+</sup>, Cl<sup>−</sup>, Mg<sup>2+</sup>, Ca<sup>2+</sup>, SO<sub>4</sub><sup>2−</sup>, NH<sub>4</sub><sup>+</sup>, and NO<sub>3</sub><sup>−</sup>. In contrast, atmospheric deposition had no impact on canopy leaching of K<sup>+</sup>, Mg<sup>2+</sup>, and Ca<sup>2+</sup> and neutralization between species. This suggests that information on atmospheric depositions in the study area could be important to estimate correctly different values of dissolved ion inputs to forest floor between deciduous and coniferous forests.</p>" ]	[ "<p id=\"Par1\">It is necessary to clear the relationship between physical and vegetation factors on the processes governing dissolved ion inputs to the forest floor to estimate correctly the values of atmospheric input to the forest. This study identified the factors influencing the differences in dissolved ion inputs to the forest floor between coniferous evergreen and broad-leaved deciduous species by analyzing the phenological variations of dry deposition and canopy exchange calculated by the canopy budget model under a high-deposition site near the city of Tokyo and a low-deposition site 84 km further away. At low-deposition site, vegetation factors such as capture efficiency did not explain the differences in Na<sup>+</sup> or Cl<sup>−</sup> dry deposition. Leaf physiological characteristics influenced the differences in the Mg<sup>2+</sup> and Ca<sup>2+</sup> canopy leaching values, and phenology, leaf wettability, and diffusion processes from water film into leaves influenced the differences in NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>−</sup> input processes between tree types. At the high-deposition site, differences in the dry deposition of Na<sup>+</sup>, SO<sub>4</sub><sup>2−</sup>, Cl<sup>−</sup>, Mg<sup>2+</sup>, Ca<sup>2+</sup>, NH<sub>4</sub><sup>+</sup>, and NO<sub>3</sub><sup>−</sup> between tree types were influenced by differences in capture efficiency between coniferous and broad-leaved canopies in the leafed period and by the absence of leaves in deciduous species after leaf fall. These results indicated that atmospheric deposition affected the capture efficiency of coniferous trees for dry deposition and enhanced the difference of dissolved ion inputs to the forest floor between coniferous and deciduous species.</p>", "<title>Supplementary Information</title>", "<p>The online version contains supplementary material available at 10.1007/s10661-023-12132-6.</p>", "<title>Keywords</title>" ]	[ "<title>Supplementary Information</title>", "<p>Below is the link to the electronic supplementary material.</p>" ]	[ "<title>Acknowledgements</title>", "<p>We gratefully acknowledge suggestions from Dr. Masakazu Suzuki (Emeritus Professor, The University of Tokyo). The authors thank to technical staffs in The University of Tokyo Chichibu forest and Tanashi forest for supporting observation works. The authors also wish to thank Ms. Chiai Kosaku and Dr. Jun Shi for their support in field observation at Tanashi.</p>", "<title>Author contribution</title>", "<p>Conceptualization: Naohiro Imamura, and Nobuhito Ohte; methodology: Naohiro Imamura, Nobuhito Ohte, and Nobuaki Tanaka.; formal analysis and investigation: Naohiro Imamura, Nobuhito Ohte, and Nobuaki Tanaka.; writing—original draft preparation: Naohiro Imamura; writing—review and editing: Naohiro Imamura, Nobuhito Ohte, and Nobuaki Tanaka; funding acquisition: Naohiro Imamura, Nobuhito Ohte, and Nobuaki Tanaka.</p>", "<title>Funding</title>", "<p>This work was supported by the Japan Society for the Promotion of Science: JSPS KAKENHI (grant nos. 22780139, 24658133, and 20K15563).</p>", "<title>Data availability</title>", "<p>Data is supplied by supplementary file.</p>", "<title>Declarations</title>", "<title>Ethics approval</title>", "<p id=\"Par39\">All authors have read, understood, and have complied as applicable with the statement on “Ethical responsibilities of Authors” as found in the Instructions for Authors.</p>", "<title>Competing interests</title>", "<p id=\"Par40\">The authors declare no competing interests.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><p>Location of the Chichibu and Tanashi forest sites. The satellite image was obtained from Google Maps</p></caption></fig>", "<fig id=\"Fig2\"><label>Fig. 2</label><caption><p>Canopy projection and locations of bulk throughfall samplers at the observation sites at (<bold>a</bold>) Chichibu and (<bold>b</bold>) Tanashi. Individual <italic>Fagus crenata</italic>, <italic>Quercus acutissima</italic>, and <italic>Cryptomeria japonica</italic> trees are denoted as Fc, Qa, and Cj, respectively. Stemflow water was collected from Cj1, Cj2, and Cj3 and from Qa1, Qa2, and Qa3, respectively, at Tanashi</p></caption></fig>", "<fig id=\"Fig3\"><label>Fig. 3</label><caption><p>Phenological periods at (<bold>a</bold>) Chichibu and (<bold>b</bold>) Tanashi. The leaf emergence period lasted 1 month (May at Chichibu and April at Tanashi). The fully leafed period was 4 months (June–September) at Chichibu and 5 months (May–September) at Tanashi. The leaf senescence period was 2 months (October–November) at both sites. The leafless period was 5 months (December–April) at Chichibu and 4 months (December–March) at Tanashi</p></caption></fig>", "<fig id=\"Fig4\"><label>Fig. 4</label><caption><p>Monthly air temperature (°C) and relative humidity (%) by canopy height from October 2010 to September 2012 at (<bold>a</bold>) Chichibu and (<bold>b</bold>) Tanashi</p></caption></fig>", "<fig id=\"Fig5\"><label>Fig. 5</label><caption><p>The 2-year average dry deposition values (mmol m<sup>−2</sup> month<sup>−1</sup>) of Na<sup>+</sup>, Cl<sup>−</sup>, SO<sub>4</sub><sup>2−</sup>, K<sup>+</sup>, Mg<sup>2+</sup>, Ca<sup>2+</sup>, H<sup>+</sup>, NH<sub>4</sub><sup>+</sup>, and NO<sub>3</sub><sup>−</sup> during each canopy phenological phase for deciduous species and coniferous species (<italic>Cryptomeria japonica</italic>) at Chichibu and Tanashi. The leaf emergence, fully leafed, leaf senescence, and leafless periods are defined in Fig. ##FIG##2##3##. A paired <italic>t</italic>-test, <italic>p</italic> < 0.05, <italic>t</italic>-test, <italic>p</italic> < 0.01, *<italic>t</italic>-test, <italic>p</italic> < 0.001</p></caption></fig>", "<fig id=\"Fig6\"><label>Fig. 6</label><caption><p>The 2-year average canopy leaching values (mmol m<sup>−2</sup> month<sup>−1</sup>) of K<sup>+</sup>, Mg<sup>2+</sup> and Ca<sup>2+</sup> during each canopy phenological phase for deciduous species and coniferous species (<italic>Cryptomeria japonica</italic>) at Chichibu and Tanashi. The leaf emergence, fully leafed, leaf senescence, and leafless periods are defined in Fig. ##FIG##2##3##. A paired <italic>t</italic>-test, <italic>p</italic> < 0.05, <italic>t</italic>-test, <italic>p</italic> < 0.01, <italic>t</italic>-test, <italic>p</italic> < 0.001</p></caption></fig>", "<fig id=\"Fig7\"><label>Fig. 7</label><caption><p>The 2-year average canopy uptake values (mmol m<sup>−2</sup> month<sup>−1</sup>) of H<sup>+</sup>, NH<sub>4</sub><sup>+</sup>, and NO<sub>3</sub><sup>−</sup> during each canopy phenological phase for deciduous species and coniferous species (<italic>Cryptomeria japonica</italic>) at Chichibu and Tanashi. The leaf emergence, fully leafed, leaf senescence, and leafless periods are defined in Fig. ##FIG##2##3##. A paired <italic>t</italic>-test, <italic>p</italic> < 0.05, <italic>t</italic>-test, <italic>p</italic> < 0.01, *<italic>t</italic>-test, <italic>p</italic> < 0.001</p></caption></fig>" ]	[ "<table-wrap id=\"Tab1\"><label>Table 1</label><caption><p>Comparison of deposition values and study site characteristics between this and previous studies</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\" colspan=\"2\">Site locations</th><th align=\"left\">Ontario, Canada</th><th align=\"left\">Quebec, Canada</th><th align=\"left\">Merksplas, Belgium</th><th align=\"left\">Chichibu, Japan</th><th align=\"left\">Tanashi, Japan</th></tr></thead><tbody><tr><td align=\"left\" rowspan=\"9\"><p>Wet deposition</p><p>(mmol m<sup>–2</sup> year<sup>–1</sup>)</p></td><td align=\"left\">Na<sup>+</sup></td><td align=\"left\">4.1</td><td align=\"left\">2.2</td><td align=\"left\">132.0</td><td align=\"left\">10.1</td><td align=\"left\">36.8</td></tr><tr><td align=\"left\">Cl<sup>−</sup></td><td align=\"left\">5.6</td><td align=\"left\">3.1</td><td align=\"left\">-</td><td align=\"left\">11.8</td><td align=\"left\">47.2</td></tr><tr><td align=\"left\">SO<sub>4</sub><sup>2−</sup></td><td align=\"left\">30.5</td><td align=\"left\">23.6</td><td align=\"left\">-</td><td align=\"left\">9.4</td><td align=\"left\">19.5</td></tr><tr><td align=\"left\">K<sup>+</sup></td><td align=\"left\">3.0</td><td align=\"left\">0.9</td><td align=\"left\">9.6</td><td align=\"left\">11.3</td><td align=\"left\">10.5</td></tr><tr><td align=\"left\">Mg<sup>2+</sup></td><td align=\"left\">2.1</td><td align=\"left\">0.7</td><td align=\"left\">19.2</td><td align=\"left\">2.5</td><td align=\"left\">8.0</td></tr><tr><td align=\"left\">Ca<sup>2+</sup></td><td align=\"left\">8.1</td><td align=\"left\">2.8</td><td align=\"left\">38.4</td><td align=\"left\">8.3</td><td align=\"left\">17.6</td></tr><tr><td align=\"left\">H<sup>+</sup></td><td align=\"left\">62.8</td><td align=\"left\">55.9</td><td align=\"left\">6.0</td><td align=\"left\">8.5</td><td align=\"left\">25.8</td></tr><tr><td align=\"left\">NH<sub>4</sub><sup>+</sup></td><td align=\"left\">25.8</td><td align=\"left\">23.4</td><td align=\"left\">143.5</td><td align=\"left\">13.6</td><td align=\"left\">27.6</td></tr><tr><td align=\"left\">NO<sub>3</sub><sup>−</sup></td><td align=\"left\">38.3</td><td align=\"left\">30.4</td><td align=\"left\">111.6</td><td align=\"left\">16.3</td><td align=\"left\">36.2</td></tr><tr><td align=\"left\" rowspan=\"2\">Tree species</td><td align=\"left\">Deciduous</td><td align=\"left\"><p><italic>Acer saccharum</italic>,</p><p><italic>Acer rubrum</italic>,</p><p><italic>Fagus grandifolia</italic>,</p><p><italic>Betula alleghaniensis</italic>,</p><p><italic>Populus grandidentata</italic></p><p><italic>Betula papyrifera</italic></p></td><td align=\"left\"><italic>Acer saccharum</italic></td><td align=\"left\"><italic>Betula pendula</italic></td><td align=\"left\"><p><italic>Fagus crenata</italic></p><p><italic>Fagus japonica</italic></p><p><italic>Tsuga sieboldii</italic></p></td><td align=\"left\"><p><italic>Quercus acutissima</italic></p><p><italic>Pinus densiflora</italic></p><p><italic>Quercus rubra</italic></p></td></tr><tr><td align=\"left\">Coniferous</td><td align=\"left\"><p><italic>Pinus strobus</italic>,</p><p><italic>Tsuga canadensis</italic>,</p><p><italic>Acer rubrum</italic>,</p><p><italic>Quercus rubra</italic>,</p><p><italic>Betula papyrifera</italic></p></td><td align=\"left\"><p><italic>Abies balsamea</italic>,</p><p><italic>Picea rubens</italic></p></td><td align=\"left\"><italic>Pinus nigra</italic></td><td align=\"left\"><italic>Cryptomeria japonica</italic></td><td align=\"left\"><italic>Cryptomeria japonica</italic></td></tr><tr><td align=\"left\" rowspan=\"2\">Tree age</td><td align=\"left\">Deciduous</td><td align=\"left\"/><td align=\"left\">80–120</td><td align=\"left\">40</td><td align=\"left\">210–250<sup>‡</sup></td><td align=\"left\">80</td></tr><tr><td align=\"left\">Coniferous</td><td align=\"left\">87</td><td align=\"left\">50</td><td align=\"left\">40</td><td align=\"left\">47–57</td><td align=\"left\">51</td></tr><tr><td align=\"left\" rowspan=\"2\"><p>Tree height</p><p>(m)</p></td><td align=\"left\">Deciduous</td><td align=\"left\"/><td align=\"left\">20.2</td><td align=\"left\">14.4</td><td align=\"left\">24.5</td><td align=\"left\">18.5</td></tr><tr><td align=\"left\">Coniferous</td><td align=\"left\"/><td align=\"left\">12.6</td><td align=\"left\">16.1</td><td align=\"left\">30.5</td><td align=\"left\">16.3</td></tr><tr><td align=\"left\" rowspan=\"2\"><p>Basal area</p><p>(m<sup>2</sup> ha<sup>−1</sup>)</p></td><td align=\"left\">Deciduous</td><td align=\"left\">23.5<sup>†</sup></td><td align=\"left\">24.3</td><td align=\"left\">16</td><td align=\"left\">33.2 (> 5 cm)<sup>‡</sup></td><td align=\"left\">25.6 (> 5 cm)</td></tr><tr><td align=\"left\">Coniferous</td><td align=\"left\">31.3<sup>†</sup></td><td align=\"left\">32.6 (> 9 cm)</td><td align=\"left\">45</td><td align=\"left\">88.6</td><td align=\"left\">40.0 (> 5 cm)</td></tr><tr><td align=\"left\" rowspan=\"2\">LAI (m<sup>2</sup> m<sup>−2</sup>)</td><td align=\"left\">Deciduous</td><td align=\"left\"/><td align=\"left\">5.5</td><td align=\"left\" rowspan=\"2\">Three times higher at Evergreen site than Deciduous site</td><td align=\"left\">2.86</td><td align=\"left\">1.92</td></tr><tr><td align=\"left\">Coniferous</td><td align=\"left\"/><td align=\"left\">5</td><td align=\"left\">1.81</td><td align=\"left\">1.92</td></tr><tr><td align=\"left\" colspan=\"2\">Reference</td><td align=\"left\">Neary and Gizyn (##UREF##29##1994##)</td><td align=\"left\">Houle et al. (##UREF##15##1999##)</td><td align=\"left\">De Schrijver et al. (##REF##28310235##2004##)</td><td align=\"left\">This study</td><td align=\"left\">This study</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab2\"><label>Table 2</label><caption><p>Comparison of the average annual water and ion throughfall deposition (TF), stemflow deposition (SF), and stand deposition (SD) values between deciduous (Dec) and coniferous (Con) trees in this and previous studies</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\" colspan=\"2\"/><th align=\"left\" colspan=\"6\">Flux (mmol m<sup>–2</sup> year<sup>–1</sup>)</th><th align=\"left\" rowspan=\"3\">Reference</th></tr><tr><th align=\"left\" colspan=\"2\">Flux</th><th align=\"left\">TF</th><th align=\"left\"/><th align=\"left\">SF</th><th align=\"left\"/><th align=\"left\">SD</th><th align=\"left\"/></tr><tr><th align=\"left\" colspan=\"2\">Species</th><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\">Dec</th><th align=\"left\">Con</th></tr></thead><tbody><tr><td align=\"left\" rowspan=\"10\">Ontario</td><td align=\"left\">Water</td><td align=\"left\">929.0</td><td align=\"left\">819.3</td><td align=\"left\">32.0</td><td align=\"left\">20.0</td><td align=\"left\">950.3 (145.8)</td><td align=\"left\">832.7 (82.4)</td><td align=\"left\" rowspan=\"10\">Neary and Gizyn (##UREF##29##1994##)</td></tr><tr><td align=\"left\">Na<sup>+</sup></td><td align=\"left\">4.2</td><td align=\"left\">4.8</td><td align=\"left\">0.2</td><td align=\"left\">0.1</td><td align=\"left\">4.3 (1.2)</td><td align=\"left\">4.9 (0.4)</td></tr><tr><td align=\"left\">Cl<sup>–</sup></td><td align=\"left\">8.6</td><td align=\"left\">9.2</td><td align=\"left\">0.6</td><td align=\"left\">0.4</td><td align=\"left\">9.0 (1.4)</td><td align=\"left\">9.5 (1.5)</td></tr><tr><td align=\"left\">SO<sub>4</sub><sup>2–</sup></td><td align=\"left\">34.2</td><td align=\"left\">42.8</td><td align=\"left\">3.5</td><td align=\"left\">3.6</td><td align=\"left\">36.5 (0.9)</td><td align=\"left\">45.2 (4.6)</td></tr><tr><td align=\"left\">K<sup>+</sup></td><td align=\"left\">27.7</td><td align=\"left\">25.3</td><td align=\"left\">5.2</td><td align=\"left\">2.2</td><td align=\"left\">31.1 (8.4)</td><td align=\"left\">26.8 (2.3)</td></tr><tr><td align=\"left\">Mg<sup>2+</sup></td><td align=\"left\">6.8</td><td align=\"left\">7.2</td><td align=\"left\">0.7</td><td align=\"left\">0.4</td><td align=\"left\">7.3 (0.4)</td><td align=\"left\">7.4 (0.6)</td></tr><tr><td align=\"left\">Ca<sup>2+</sup></td><td align=\"left\">18.8</td><td align=\"left\">23.3</td><td align=\"left\">2.3</td><td align=\"left\">1.9</td><td align=\"left\">20.4 (0.6)</td><td align=\"left\">24.6 (2.6)</td></tr><tr><td align=\"left\">H<sup>+</sup></td><td align=\"left\">42.3</td><td align=\"left\">61.3</td><td align=\"left\">0.9</td><td align=\"left\">3.2</td><td align=\"left\">42.9 (7.9)</td><td align=\"left\">63.4 (8.8)</td></tr><tr><td align=\"left\">NH<sub>4</sub><sup>+</sup></td><td align=\"left\">19.0</td><td align=\"left\">15.0</td><td align=\"left\">0.3</td><td align=\"left\">0.1</td><td align=\"left\">19.2 (3.6)</td><td align=\"left\">15.0 (2.7)</td></tr><tr><td align=\"left\">NO<sub>3</sub><sup>–</sup></td><td align=\"left\">39.3</td><td align=\"left\">45.3</td><td align=\"left\">1.3</td><td align=\"left\">0.5</td><td align=\"left\">40.2 (3.8)</td><td align=\"left\">45.6 (7.3)</td></tr><tr><td align=\"left\" rowspan=\"10\">Quebec</td><td align=\"left\">Water</td><td align=\"left\">1165.0</td><td align=\"left\">1074.0</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">1165.0 (94.0)</td><td align=\"left\">1074.0 (100.0)</td><td align=\"left\" rowspan=\"10\">Houle et al. (##UREF##16##1999##)</td></tr><tr><td align=\"left\">Na<sup>+</sup></td><td align=\"left\">3.5</td><td align=\"left\">3.7</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">3.5 (1.1)</td><td align=\"left\">3.7 (1.0)</td></tr><tr><td align=\"left\">Cl<sup>−</sup></td><td align=\"left\">6.8</td><td align=\"left\">8.6</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">6.8 (1.4)</td><td align=\"left\">8.6 (1.7)</td></tr><tr><td align=\"left\">SO<sub>4</sub><sup>2−</sup></td><td align=\"left\">28.2</td><td align=\"left\">33.8</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">28.2 (3.6)</td><td align=\"left\">33.8 (5.7)</td></tr><tr><td align=\"left\">K<sup>+</sup></td><td align=\"left\">41.0</td><td align=\"left\">27.7</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">41.0(10.1)</td><td align=\"left\">27.7 (5.4)</td></tr><tr><td align=\"left\">Mg<sup>2+</sup></td><td align=\"left\">4.4</td><td align=\"left\">5.3</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">4.4 (0.5)</td><td align=\"left\">5.3 (0.7)</td></tr><tr><td align=\"left\">Ca<sup>2+</sup></td><td align=\"left\">12.6</td><td align=\"left\">13.6</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">12.6 (1.1)</td><td align=\"left\">13.6 (2.0)</td></tr><tr><td align=\"left\">H<sup>+</sup></td><td align=\"left\">34.7</td><td align=\"left\">46.7</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">34.7 (7.9)</td><td align=\"left\">46.7 (9.8)</td></tr><tr><td align=\"left\">NH<sub>4</sub><sup>+</sup></td><td align=\"left\">18.2</td><td align=\"left\">9.8</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">18.2 (2.9)</td><td align=\"left\">9.8 (1.9)</td></tr><tr><td align=\"left\">NO<sub>3</sub><sup>−</sup></td><td align=\"left\">33.8</td><td align=\"left\">25.8</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">33.8 (2.9)</td><td align=\"left\">25.8 (2.4)</td></tr><tr><td align=\"left\" rowspan=\"10\">Merksplas</td><td align=\"left\">Water</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\" rowspan=\"10\">De Schrijver et al. (##REF##15210279##2004##)</td></tr><tr><td align=\"left\">Na<sup>+</sup></td><td align=\"left\">158.4</td><td align=\"left\">202.8</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">158.4 (121.2)</td><td align=\"left\">202.8 (163.2)</td></tr><tr><td align=\"left\">Cl<sup>−</sup></td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td></tr><tr><td align=\"left\">SO<sub>4</sub><sup>2−</sup></td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td></tr><tr><td align=\"left\">K<sup>+</sup></td><td align=\"left\">44.4</td><td align=\"left\">36.0</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">44.4 (45.6)</td><td align=\"left\">36.0 (28.8)</td></tr><tr><td align=\"left\">Mg<sup>2+</sup></td><td align=\"left\">14.4</td><td align=\"left\">18.0</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">14.4 (12.0)</td><td align=\"left\">18.0 (14.4)</td></tr><tr><td align=\"left\">Ca<sup>2+</sup></td><td align=\"left\">22.8</td><td align=\"left\">26.4</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">22.8 (14.4)</td><td align=\"left\">26.4 (20.4)</td></tr><tr><td align=\"left\">H<sup>+</sup></td><td align=\"left\">4.8</td><td align=\"left\">0.0</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">4.8 (4.8)</td><td align=\"left\">0.0 (1.2)</td></tr><tr><td align=\"left\">NH<sub>4</sub><sup>+</sup></td><td align=\"left\">194.4</td><td align=\"left\">569.3</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">194.4(125.0)</td><td align=\"left\">569.3(371.8)</td></tr><tr><td align=\"left\">NO<sub>3</sub><sup>−</sup></td><td align=\"left\">170.1</td><td align=\"left\">356.1</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">170.1 (95.7)</td><td align=\"left\">356.1(196.6)</td></tr><tr><td align=\"left\" rowspan=\"10\">Chichibu</td><td align=\"left\">Water</td><td align=\"left\">1422.2</td><td align=\"left\">1162.2</td><td align=\"left\">79.5</td><td align=\"left\">107.4</td><td align=\"left\">1501.7 (100.5)</td><td align=\"left\">1269.6 (58.8)</td><td align=\"left\" rowspan=\"10\">This study</td></tr><tr><td align=\"left\">Na<sup>+</sup></td><td align=\"left\">8.6</td><td align=\"left\">9.4</td><td align=\"left\">0.5</td><td align=\"left\">1.1</td><td align=\"left\">9.0 (1.3)</td><td align=\"left\">10.6 (0.9)</td></tr><tr><td align=\"left\">Cl<sup>–</sup></td><td align=\"left\">16.5</td><td align=\"left\">28.6</td><td align=\"left\">1.0</td><td align=\"left\">5.9</td><td align=\"left\">17.5 (2.7)</td><td align=\"left\">34.5 (7.1)</td></tr><tr><td align=\"left\">SO<sub>4</sub><sup>2–</sup></td><td align=\"left\">10.4</td><td align=\"left\">9.2</td><td align=\"left\">0.8</td><td align=\"left\">1.1</td><td align=\"left\">11.3 (1.3)</td><td align=\"left\">10.4 (0.4)</td></tr><tr><td align=\"left\">K<sup>+</sup></td><td align=\"left\">83.1</td><td align=\"left\">66.7</td><td align=\"left\">6.7</td><td align=\"left\">7.3</td><td align=\"left\">89.8 (26.6)</td><td align=\"left\">74.0 (12.3)</td></tr><tr><td align=\"left\">Mg<sup>2+</sup></td><td align=\"left\">6.0</td><td align=\"left\">8.6</td><td align=\"left\">0.6</td><td align=\"left\">0.5</td><td align=\"left\">6.6 (0.6)</td><td align=\"left\">9.1 (1.1)</td></tr><tr><td align=\"left\">Ca<sup>2+</sup></td><td align=\"left\">14.6</td><td align=\"left\">35.7</td><td align=\"left\">1.4</td><td align=\"left\">2.6</td><td align=\"left\">16.1 (2.2)</td><td align=\"left\">38.3 (2.8)</td></tr><tr><td align=\"left\">H<sup>+</sup></td><td align=\"left\">1.7</td><td align=\"left\">2.5</td><td align=\"left\">0.1</td><td align=\"left\">8.9</td><td align=\"left\">1.8 (0.2)</td><td align=\"left\">11.4 (1.7)</td></tr><tr><td align=\"left\">NH<sub>4</sub><sup>+</sup></td><td align=\"left\">17.8</td><td align=\"left\">3.9</td><td align=\"left\">1.3</td><td align=\"left\">0.6</td><td align=\"left\">19.1 (1.6)</td><td align=\"left\">4.5 (2.2)</td></tr><tr><td align=\"left\">NO<sub>3</sub><sup>–</sup></td><td align=\"left\">16.5</td><td align=\"left\">13.2</td><td align=\"left\">0.3</td><td align=\"left\">0.1</td><td align=\"left\">16.8 (1.7)</td><td align=\"left\">13.3 (1.4)</td></tr><tr><td align=\"left\" rowspan=\"10\">Tanashi</td><td align=\"left\">Water</td><td align=\"left\">1331.4</td><td align=\"left\">1328.8</td><td align=\"left\">22.7</td><td align=\"left\">134.1</td><td align=\"left\">1354.1 (86.8)</td><td align=\"left\">1462.8 (164.8)</td><td align=\"left\" rowspan=\"10\">This study</td></tr><tr><td align=\"left\">Na<sup>+</sup></td><td align=\"left\">39.4</td><td align=\"left\">62.0</td><td align=\"left\">1.0</td><td align=\"left\">9.5</td><td align=\"left\">40.4 (5.0)</td><td align=\"left\">71.5 (8.5)</td></tr><tr><td align=\"left\">Cl<sup>−</sup></td><td align=\"left\">58.9</td><td align=\"left\">120.1</td><td align=\"left\">1.7</td><td align=\"left\">29.9</td><td align=\"left\">60.6 (8.1)</td><td align=\"left\">150.0 (16.3)</td></tr><tr><td align=\"left\">SO<sub>4</sub><sup>2−</sup></td><td align=\"left\">28.1</td><td align=\"left\">36.0</td><td align=\"left\">0.6</td><td align=\"left\">7.9</td><td align=\"left\">28.7 (3.2)</td><td align=\"left\">43.9 (4.2)</td></tr><tr><td align=\"left\">K<sup>+</sup></td><td align=\"left\">119.3</td><td align=\"left\">79.1</td><td align=\"left\">6.1</td><td align=\"left\">17.7</td><td align=\"left\">125.4 (9.1)</td><td align=\"left\">96.8 (6.5)</td></tr><tr><td align=\"left\">Mg<sup>2+</sup></td><td align=\"left\">20.4</td><td align=\"left\">24.7</td><td align=\"left\">0.4</td><td align=\"left\">3.1</td><td align=\"left\">20.7 (2.0)</td><td align=\"left\">27.8 (5.1)</td></tr><tr><td align=\"left\">Ca<sup>2+</sup></td><td align=\"left\">39.5</td><td align=\"left\">57.7</td><td align=\"left\">0.8</td><td align=\"left\">5.5</td><td align=\"left\">40.2 (4.1)</td><td align=\"left\">63.1 (10.7)</td></tr><tr><td align=\"left\">H<sup>+</sup></td><td align=\"left\">9.6</td><td align=\"left\">4.6</td><td align=\"left\">0.6</td><td align=\"left\">23.1</td><td align=\"left\">10.2 (3.2)</td><td align=\"left\">27.7 (1.6)</td></tr><tr><td align=\"left\">NH<sub>4</sub><sup>+</sup></td><td align=\"left\">72.9</td><td align=\"left\">112.1</td><td align=\"left\">0.7</td><td align=\"left\">16.7</td><td align=\"left\">73.5 (9.5)</td><td align=\"left\">128.8 (19.4)</td></tr><tr><td align=\"left\">NO<sub>3</sub><sup>−</sup></td><td align=\"left\">50.7</td><td align=\"left\">110.0</td><td align=\"left\">1.0</td><td align=\"left\">24.0</td><td align=\"left\">51.7 (7.7)</td><td align=\"left\">134.0 (19.7)</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab3\"><label>Table 3</label><caption><p>Comparison of the dry deposition values (mmol m<sup>−2</sup> year<sup>−1</sup>) of Na<sup>+</sup>, Cl<sup>−</sup>, SO<sub>4</sub><sup>2−</sup>, K<sup>+</sup>, Mg<sup>2+</sup>, Ca<sup>2+</sup>, H<sup>+</sup>, NH<sub>4</sub><sup>+</sup>, and NO<sub>3</sub><sup>−</sup> between deciduous (Dec) and coniferous (Con) species during the annual, growing, and dormant periods in this and previous studies</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\" colspan=\"8\">Dry deposition (mmol m<sup>–2</sup> year<sup>–1</sup>)</th></tr><tr><th align=\"left\">Elements</th><th align=\"left\">Annual</th><th align=\"left\"/><th align=\"left\">Growing</th><th align=\"left\"/><th align=\"left\">Dormant</th><th align=\"left\"/><th align=\"left\">Site</th></tr><tr><th align=\"left\"/><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\"/></tr></thead><tbody><tr><td align=\"left\">Na<sup>+</sup></td><td align=\"left\">0.4 (0.6)</td><td align=\"left\">0.7 (0.2)</td><td align=\"left\"> − 0.2 (0.2)</td><td align=\"left\"> − 0.3 (0.2)</td><td align=\"left\">0.6 (0.6)</td><td align=\"left\">0.9 (0.1)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">1.3</td><td align=\"left\">1.6</td><td align=\"left\">0.6</td><td align=\"left\">0.5</td><td align=\"left\">0.8</td><td align=\"left\">1.0</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">26.4</td><td align=\"left\">70.8</td><td align=\"left\">14.0</td><td align=\"left\">33.6</td><td align=\"left\">12.5</td><td align=\"left\">31.0</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\"> − 1.0 (1.3)</td><td align=\"left\">0.5 (0.8)</td><td align=\"left\">0.8 (1.8)</td><td align=\"left\">1.4 (0.4)</td><td align=\"left\"> − 1.8 (1.3)</td><td align=\"left\"> − 0.9 (0.5)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">3.6 (5.6)</td><td align=\"left\">34.7 (8.5)</td><td align=\"left\">2.9 (3.5)</td><td align=\"left\">25.3 (6.0)</td><td align=\"left\">0.8 (2.3)</td><td align=\"left\">9.4 (3.7)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">Cl<sup>−</sup></td><td align=\"left\">3.7 (0.8)</td><td align=\"left\">3.7 (0.7)</td><td align=\"left\">2.9 (0.5)</td><td align=\"left\">1.8 (0.2)</td><td align=\"left\">0.9 (0.3)</td><td align=\"left\">1.7 (0.9)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">3.7</td><td align=\"left\">5.4</td><td align=\"left\">2.5</td><td align=\"left\">3.4</td><td align=\"left\">1.2</td><td align=\"left\">2.1</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">5.7 (2.7)</td><td align=\"left\">22.7 (7.0)</td><td align=\"left\">6.8 (5.1)</td><td align=\"left\">17.9 (5.7)</td><td align=\"left\"> − 1.1 (1.4)</td><td align=\"left\">4.8 (2.1)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">13.4 (9.0)</td><td align=\"left\">102.8 (16.3)</td><td align=\"left\">10.7 (5.3)</td><td align=\"left\">70.0 (11.5)</td><td align=\"left\">2.8 (3.9)</td><td align=\"left\">32.8 (7.0)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">SO<sub>4</sub><sup>2−</sup></td><td align=\"left\">5.0 (4.4)</td><td align=\"left\">15.7 (4.9)</td><td align=\"left\">3.0 (1.3)</td><td align=\"left\">5.9 (0.6)</td><td align=\"left\">2.3 (3.5)</td><td align=\"left\">9.9 (5.5)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">4.6</td><td align=\"left\">10.1</td><td align=\"left\">2.7</td><td align=\"left\">3.4</td><td align=\"left\">1.9</td><td align=\"left\">6.7</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">-</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">1.8 (1.2)</td><td align=\"left\">0.9 (0.7)</td><td align=\"left\">1.6 (1.2)</td><td align=\"left\"> − 0.1 (0.6)</td><td align=\"left\">0.3 (1.1)</td><td align=\"left\">1.0 (0.5)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">9.2 (3.5)</td><td align=\"left\">24.3 (4.2)</td><td align=\"left\">8.0 (2.2)</td><td align=\"left\">16.0 (2.9)</td><td align=\"left\">1.2 (1.6)</td><td align=\"left\">8.3 (2.5)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">K<sup>+</sup></td><td align=\"left\">0.3 (0.5)</td><td align=\"left\">0.4 (0.1)</td><td align=\"left\"> − 0.3 (0.2)</td><td align=\"left\"> − 0.3 (0.3)</td><td align=\"left\">0.2 (0.1)</td><td align=\"left\">0.3 (0.0)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">0.5</td><td align=\"left\">0.6</td><td align=\"left\">0.3</td><td align=\"left\">0.2</td><td align=\"left\">0.3</td><td align=\"left\">0.3</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">1.9</td><td align=\"left\">5.1</td><td align=\"left\">1.4</td><td align=\"left\">3.3</td><td align=\"left\">0.5</td><td align=\"left\">1.1</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\"> − 1.5 (1.4)</td><td align=\"left\">0.4 (0.9)</td><td align=\"left\">0.5 (2.4)</td><td align=\"left\">2.7 (0.6)</td><td align=\"left\"> − 1.2 (1.2)</td><td align=\"left\"> − 0.4 (0.4)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">0.4 (1.7)</td><td align=\"left\">8.5 (2.4)</td><td align=\"left\">0.4 (0.9)</td><td align=\"left\">5.7 (1.5)</td><td align=\"left\">0.0 (1.2)</td><td align=\"left\">3.6 (2.1)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">Mg<sup>2+</sup></td><td align=\"left\">0.2(0.3)</td><td align=\"left\">0.3 (0.1)</td><td align=\"left\"> − 0.2 (0.1)</td><td align=\"left\"> − 0.2 (0.2)</td><td align=\"left\">0.2 (0.1)</td><td align=\"left\">0.3 (0.0)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">0.4</td><td align=\"left\">0.5</td><td align=\"left\">0.3</td><td align=\"left\">0.2</td><td align=\"left\">0.1</td><td align=\"left\">0.2</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">1.9</td><td align=\"left\">5.1</td><td align=\"left\">0.9</td><td align=\"left\">2.1</td><td align=\"left\">1.0</td><td align=\"left\">2.6</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\"> − 0.2 (0.3)</td><td align=\"left\">0.2 (0.2)</td><td align=\"left\">0.2 (0.4)</td><td align=\"left\">0.4 (0.1)</td><td align=\"left\"> − 0.3 (0.4)</td><td align=\"left\"> − 0.1 (0.1)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">0.9 (1.2)</td><td align=\"left\">7.8 (1.9)</td><td align=\"left\">0.6 (0.8)</td><td align=\"left\">5.5 (1.3)</td><td align=\"left\">0.2 (0.4)</td><td align=\"left\">2.1 (0.7)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">Ca<sup>2+</sup></td><td align=\"left\">0.9 (1.6)</td><td align=\"left\">1.3 (0.6)</td><td align=\"left\"> − 0.5 (0.5)</td><td align=\"left\"> − 0.6 (0.6)</td><td align=\"left\">0.8 (0.7)</td><td align=\"left\">1.1 (0.2)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">1.7</td><td align=\"left\">2.0</td><td align=\"left\">1.0</td><td align=\"left\">0.9</td><td align=\"left\">0.6</td><td align=\"left\">0.8</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">3.8</td><td align=\"left\">10.3</td><td align=\"left\">1.9</td><td align=\"left\">4.5</td><td align=\"left\">2.1</td><td align=\"left\">5.2</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\"> − 0.4 (1.1)</td><td align=\"left\">0.6 (0.7)</td><td align=\"left\">0.6 (1.4)</td><td align=\"left\">1.3 (0.4)</td><td align=\"left\"> − 1.0 (1.4)</td><td align=\"left\">0.0 (0.4)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">1.8 (2.7)</td><td align=\"left\">16.9 (4.1)</td><td align=\"left\">1.2 (1.6)</td><td align=\"left\">11.4 (2.7)</td><td align=\"left\">0.5 (1.2)</td><td align=\"left\">5.6 (2.0)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">H<sup>+</sup></td><td align=\"left\">33.2 (17.8)</td><td align=\"left\">64.5 (18.7)</td><td align=\"left\">24.8 (6.9)</td><td align=\"left\">35.0 (1.0)</td><td align=\"left\">9.4 (9.3)</td><td align=\"left\">31.1 (18.8)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">36.7</td><td align=\"left\">40.2</td><td align=\"left\">28.2</td><td align=\"left\">22.6</td><td align=\"left\">7.7</td><td align=\"left\">18.1</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">4.9</td><td align=\"left\"> − 5.0</td><td align=\"left\">2.4</td><td align=\"left\"> − 1.3</td><td align=\"left\"> − 0.7</td><td align=\"left\"> − 2.5</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">62.0 (16.5)</td><td align=\"left\">119.2 (20.2)</td><td align=\"left\">47.9 (17.5)</td><td align=\"left\">79.3 (14.5)</td><td align=\"left\">12.5 (6.0)</td><td align=\"left\">36.9 (8.3)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">105.8 (15.2)</td><td align=\"left\">108.6 (14.9)</td><td align=\"left\">96.7 (14.1)</td><td align=\"left\">77.6 (12.3)</td><td align=\"left\">9.2 (3.9)</td><td align=\"left\">30.5 (5.2)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">NH<sub>4</sub><sup>+</sup></td><td align=\"left\"> − 2.8 (5.4)</td><td align=\"left\"> − 7.2 (1.9)</td><td align=\"left\"> − 0.1 (4.5)</td><td align=\"left\"> − 3.7 (0.7)</td><td align=\"left\"> − 1.7 (1.9)</td><td align=\"left\"> − 2.5 (2.5)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\"> − 0.8</td><td align=\"left\"> − 11.0</td><td align=\"left\"> − 1.2</td><td align=\"left\"> − 10.0</td><td align=\"left\">0.9</td><td align=\"left\"> − 0.8</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">82.9</td><td align=\"left\">446.3</td><td align=\"left\">57.1</td><td align=\"left\">301.9</td><td align=\"left\">26.7</td><td align=\"left\">148.2</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">41.8 (7.3)</td><td align=\"left\">8.6 (5.0)</td><td align=\"left\">37.5 (15.5)</td><td align=\"left\">5.1 (3.9)</td><td align=\"left\">5.1 (3.3)</td><td align=\"left\">3.1 (2.6)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">104.2 (16.2)</td><td align=\"left\">153.6 (23.0)</td><td align=\"left\">94.2 (14.6)</td><td align=\"left\">112.3 (14.0)</td><td align=\"left\">10.0 (5.9)</td><td align=\"left\">40.9 (11.6)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">NO<sub>3</sub><sup>−</sup></td><td align=\"left\">2.2 (2.9)</td><td align=\"left\">10.0 (6.8)</td><td align=\"left\"> − 0.1 (0.6)</td><td align=\"left\">3.2 (0.9)</td><td align=\"left\">2.3 (2.9)</td><td align=\"left\">7.2 (7.2)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">4.7</td><td align=\"left\"> − 3.5</td><td align=\"left\"> − 0.4</td><td align=\"left\"> − 6.2</td><td align=\"left\">5.1</td><td align=\"left\">2.8</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">63.1</td><td align=\"left\">246.6</td><td align=\"left\">45.9</td><td align=\"left\">166.3</td><td align=\"left\">26.7</td><td align=\"left\">82.4</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">5.9 (1.9)</td><td align=\"left\">6.6 (0.6)</td><td align=\"left\">1.8 (2.0)</td><td align=\"left\">2.6 (1.4)</td><td align=\"left\">3.6 (2.2)</td><td align=\"left\">3.6 (1.1)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">22.3 (9.3)</td><td align=\"left\">107.1 (20.9)</td><td align=\"left\">19.0 (6.7)</td><td align=\"left\">83.0 (16.7)</td><td align=\"left\">3.2 (3.7)</td><td align=\"left\">24.0 (8.2)</td><td align=\"left\">Tanashi</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab4\"><label>Table 4</label><caption><p>Comparison of the canopy leaching values (mmol m<sup>−2</sup> year<sup>−1</sup>) of K<sup>+</sup>, Mg<sup>2+</sup>, and Ca<sup>2+</sup> between deciduous (Dec) and coniferous (Con) species during the annual, growing, and dormant periods in this and previous studies</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\" colspan=\"8\">Canopy leaching (mmol m<sup>–2</sup> year<sup>–1</sup>)</th></tr><tr><th align=\"left\">Elements</th><th align=\"left\">Annual</th><th align=\"left\"/><th align=\"left\">Growing</th><th align=\"left\"/><th align=\"left\">Dormant</th><th align=\"left\"/><th align=\"left\">Site</th></tr><tr><th align=\"left\"/><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\"/></tr></thead><tbody><tr><td align=\"left\">K<sup>+</sup></td><td align=\"left\">27.8 (8.6)</td><td align=\"left\">23.5 (1.9)</td><td align=\"left\">22.8 (5.6)</td><td align=\"left\">18.9 (1.5)</td><td align=\"left\">5.2 (2.8)</td><td align=\"left\">5.0 (1.2)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">39.6</td><td align=\"left\">26.2</td><td align=\"left\">37.0</td><td align=\"left\">20.8</td><td align=\"left\">2.1</td><td align=\"left\">5.4</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">32.9</td><td align=\"left\">21.3</td><td align=\"left\">28.0</td><td align=\"left\">14.2</td><td align=\"left\">4.5</td><td align=\"left\">7.9</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">80.0 (25.3)</td><td align=\"left\">62.4 (12.2)</td><td align=\"left\">67.7 (31.2)</td><td align=\"left\">40.1 (8.0)</td><td align=\"left\">11.5 (6.3)</td><td align=\"left\">20.3 (5.2)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">114.4 (10.1)</td><td align=\"left\">77.8 (7.6)</td><td align=\"left\">107.3 (10.5)</td><td align=\"left\">55.5 (6.4)</td><td align=\"left\">7.1 (2.7)</td><td align=\"left\">21.5 (4.3)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">Mg<sup>2+</sup></td><td align=\"left\">5.0 (0.9)</td><td align=\"left\">5.0 (0.4)</td><td align=\"left\">4.1 (0.2)</td><td align=\"left\">3.4 (0.3)</td><td align=\"left\">1.0 (0.6)</td><td align=\"left\">1.9 (0.6)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">3.2</td><td align=\"left\">4.0</td><td align=\"left\">2.9</td><td align=\"left\">2.6</td><td align=\"left\">0.4</td><td align=\"left\">1.5</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">2.8</td><td align=\"left\">3.3</td><td align=\"left\">2.6</td><td align=\"left\">2.8</td><td align=\"left\">0.5</td><td align=\"left\">0.9</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">4.3 (0.5)</td><td align=\"left\">6.5 (2.2)</td><td align=\"left\">3.1 (0.9)</td><td align=\"left\">3.8 (1.4)</td><td align=\"left\">1.1 (0.5)</td><td align=\"left\">2.5 (1.0)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">11.8 (1.2)</td><td align=\"left\">12.0 (3.6)</td><td align=\"left\">10.9 (1.1)</td><td align=\"left\">9.1 (3.1)</td><td align=\"left\">1.0 (0.4)</td><td align=\"left\">3.1 (0.6)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">Ca<sup>2+</sup></td><td align=\"left\">11.1 (3.8)</td><td align=\"left\">15.5 (3.0)</td><td align=\"left\">8.6 (1.3)</td><td align=\"left\">9.2 (0.3)</td><td align=\"left\">3.3 (2.4)</td><td align=\"left\">7.3 (3.3)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">8.1</td><td align=\"left\">8.9</td><td align=\"left\">6.9</td><td align=\"left\">5.7</td><td align=\"left\">1.2</td><td align=\"left\">3.4</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\"> − 0.5</td><td align=\"left\"> − 3.1</td><td align=\"left\">1.6</td><td align=\"left\"> − 0.3</td><td align=\"left\"> − 2.1</td><td align=\"left\"> − 2.2</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">8.2 (2.1)</td><td align=\"left\">29.3 (4.9)</td><td align=\"left\">5.3 (2.4)</td><td align=\"left\">20.4 (4.1)</td><td align=\"left\">3.0 (1.3)</td><td align=\"left\">8.4 (2.0)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">20.8 (3.2)</td><td align=\"left\">28.6 (4.9)</td><td align=\"left\">16.1 (2.1)</td><td align=\"left\">21.1 (4.2)</td><td align=\"left\">4.7 (1.4)</td><td align=\"left\">7.4 (1.6)</td><td align=\"left\">Tanashi</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab5\"><label>Table 5</label><caption><p>Comparison of the canopy uptake values (mmol m<sup>−2</sup> year<sup>−1</sup>) of H<sup>+</sup>, NH<sub>4</sub><sup>+</sup>, and NO<sub>3</sub><sup>−</sup> between deciduous (Dec) and coniferous (Con) species during the annual, growing, and dormant periods in this and previous studies</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\" colspan=\"8\">Canopy uptake (mmol m<sup>–2</sup> year<sup>–1</sup>)</th></tr><tr><th align=\"left\">Elements</th><th align=\"left\">Annual</th><th align=\"left\"/><th align=\"left\">Growing</th><th align=\"left\"/><th align=\"left\">Dormant</th><th align=\"left\"/><th align=\"left\">Site</th></tr><tr><th align=\"left\"/><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\">Dec</th><th align=\"left\">Con</th><th align=\"left\"/></tr></thead><tbody><tr><td align=\"left\">H<sup>+</sup></td><td align=\"left\">55.9 (14.2)</td><td align=\"left\">61.0 (7.9)</td><td align=\"left\">43.9 (4.2)</td><td align=\"left\">41.0 (2.3)</td><td align=\"left\">13.0 (8.2)</td><td align=\"left\">22.4 (8.6)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">57.9</td><td align=\"left\">49.4</td><td align=\"left\">52.0</td><td align=\"left\">35.5</td><td align=\"left\">4.9</td><td align=\"left\">14.3</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">6.1</td><td align=\"left\">1.0</td><td align=\"left\">3.8</td><td align=\"left\">0.8</td><td align=\"left\">0.3</td><td align=\"left\">0.5</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">68.6 (15.7)</td><td align=\"left\">116.3 (19.4)</td><td align=\"left\">53.2 (29.4)</td><td align=\"left\">76.7 (13.4)</td><td align=\"left\">13.8 (7.6)</td><td align=\"left\">35.6 (8.3)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">121.4 (12.1)</td><td align=\"left\">106.7 (14.7)</td><td align=\"left\">108.1 (11.0)</td><td align=\"left\">78.0 (11.7)</td><td align=\"left\">13.4 (3.6)</td><td align=\"left\">28.3 (4.9)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">NH<sub>4</sub><sup>+</sup></td><td align=\"left\">4.1 (1.8)</td><td align=\"left\">3.4 (0.8)</td><td align=\"left\">4.4 (1.9)</td><td align=\"left\">3.1 (0.8)</td><td align=\"left\">0.7 (0.5)</td><td align=\"left\">0.9 (0.3)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">4.4</td><td align=\"left\">2.7</td><td align=\"left\">4.7</td><td align=\"left\">2.0</td><td align=\"left\">0.3</td><td align=\"left\">0.7</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">32.0</td><td align=\"left\">20.5</td><td align=\"left\">32.8</td><td align=\"left\">18.4</td><td align=\"left\">1.0</td><td align=\"left\">4.9</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">36.3 (7.6)</td><td align=\"left\">17.7 (3.2)</td><td align=\"left\">31.2 (14.7)</td><td align=\"left\">10.7 (2.7)</td><td align=\"left\">5.8 (3.0)</td><td align=\"left\">6.4 (1.8)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">58.2 (7.0)</td><td align=\"left\">52.4 (6.4)</td><td align=\"left\">53.1 (6.7)</td><td align=\"left\">37.9 (5.4)</td><td align=\"left\">5.1 (1.7)</td><td align=\"left\">14.1 (2.2)</td><td align=\"left\">Tanashi</td></tr><tr><td align=\"left\">NO<sub>3</sub><sup>−</sup></td><td align=\"left\">1.4 (0.4)</td><td align=\"left\">1.7 (0.3)</td><td align=\"left\">1.0 (0.0)</td><td align=\"left\">1.1 (0.0)</td><td align=\"left\">0.3 (0.2)</td><td align=\"left\">0.6 (0.3)</td><td align=\"left\">Ontario</td></tr><tr><td align=\"left\"/><td align=\"left\">1.4</td><td align=\"left\">1.2</td><td align=\"left\">1.1</td><td align=\"left\">0.8</td><td align=\"left\">0.1</td><td align=\"left\">0.3</td><td align=\"left\">Quebec</td></tr><tr><td align=\"left\"/><td align=\"left\">4.7</td><td align=\"left\">2.1</td><td align=\"left\">5.6</td><td align=\"left\">2.0</td><td align=\"left\">1.1</td><td align=\"left\">0.5</td><td align=\"left\">Merksplas</td></tr><tr><td align=\"left\"/><td align=\"left\">5.4 (1.2)</td><td align=\"left\">9.6 (1.3)</td><td align=\"left\">3.0 (1.1)</td><td align=\"left\">4.8 (1.5)</td><td align=\"left\">2.0 (1.1)</td><td align=\"left\">4.2 (1.7)</td><td align=\"left\">Chichibu</td></tr><tr><td align=\"left\"/><td align=\"left\">6.9 (0.9)</td><td align=\"left\">9.3 (1.3)</td><td align=\"left\">5.9 (0.8)</td><td align=\"left\">7.0 (1.3)</td><td align=\"left\">0.9 (0.3)</td><td align=\"left\">2.2 (0.3)</td><td align=\"left\">Tanashi</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab6\"><label>Table 6</label><caption><p>Average nutrient contents of leaves in Japan reported by previous studies</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th align=\"left\" rowspan=\"2\">Family</th><th align=\"left\" rowspan=\"2\">Species</th><th align=\"left\" rowspan=\"2\">Location<break/>(Prefecture)</th><th align=\"left\" colspan=\"3\">Nutrient content of leaves (%)</th><th align=\"left\" rowspan=\"2\">Reference</th></tr><tr><th align=\"left\">K<sup>+</sup></th><th align=\"left\">Mg<sup>2+</sup></th><th align=\"left\">Ca<sup>2+</sup></th></tr></thead><tbody><tr><td align=\"left\" rowspan=\"6\">Fagaceae</td><td align=\"left\"><italic>Quercus serrata</italic></td><td align=\"left\" rowspan=\"3\">Kyoto</td><td align=\"left\">0.90</td><td align=\"left\">0.17</td><td align=\"left\">0.90</td><td align=\"left\" rowspan=\"3\">Katagiri (1996)</td></tr><tr><td align=\"left\"><italic>Quercus crispula</italic></td><td align=\"left\">1.11</td><td align=\"left\">0.21</td><td align=\"left\">1.68</td></tr><tr><td align=\"left\"><italic>Fagus crenata</italic></td><td align=\"left\">0.73</td><td align=\"left\">0.21</td><td align=\"left\">0.86</td></tr><tr><td align=\"left\"><italic>Castanea crenata</italic></td><td align=\"left\" rowspan=\"2\">Shimane</td><td align=\"left\">0.93</td><td align=\"left\">0.34</td><td align=\"left\">0.85</td><td align=\"left\" rowspan=\"2\">†Katagiri (1977)</td></tr><tr><td align=\"left\"><italic>Quercus serrata</italic></td><td align=\"left\">0.66</td><td align=\"left\">0.37</td><td align=\"left\">1.46</td></tr><tr><td align=\"left\"/><td align=\"left\"/><td align=\"left\">0.87 (0.18)</td><td align=\"left\">0.26 (0.09)</td><td align=\"left\">1.15 (0.39)</td><td align=\"left\"/></tr><tr><td align=\"left\" rowspan=\"7\">Cupressaceae</td><td align=\"left\" rowspan=\"6\"><italic>Cryptomeria japonica</italic></td><td align=\"left\">Akita</td><td align=\"left\">0.48</td><td align=\"left\">0.21</td><td align=\"left\">1.39</td><td align=\"left\" rowspan=\"6\">‡Tsutsumi (1965)</td></tr><tr><td align=\"left\" rowspan=\"5\">Nara</td><td align=\"left\">0.58</td><td align=\"left\">0.14</td><td align=\"left\">0.69</td></tr><tr><td align=\"left\">0.42</td><td align=\"left\">0.17</td><td align=\"left\">0.95</td></tr><tr><td align=\"left\">0.70</td><td align=\"left\">0.28</td><td align=\"left\">0.56</td></tr><tr><td align=\"left\">0.50</td><td align=\"left\">0.24</td><td align=\"left\">0.88</td></tr><tr><td align=\"left\">0.35</td><td align=\"left\">0.20</td><td align=\"left\">0.58</td></tr><tr><td align=\"left\"/><td align=\"left\"/><td align=\"left\">0.51 (0.12)</td><td align=\"left\">0.21 (0.05)</td><td align=\"left\">0.84 (0.05)</td><td align=\"left\"/></tr></tbody></table></table-wrap>" ]	[ "<disp-formula id=\"Equ1\"><label>2.1</label><alternatives><tex-math id=\"M1\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${DD}_{X}=\\frac{{(TF+SF-WD)}_{Na}}{{WD}_{Na}}\\bullet {WD}_{X}$$\\end{document}</tex-math><mml:math id=\"M2\" display=\"block\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">DD</mml:mi></mml:mrow><mml:mi>X</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>T</mml:mi><mml:mi>F</mml:mi><mml:mo>+</mml:mo><mml:mi>S</mml:mi><mml:mi>F</mml:mi><mml:mo>-</mml:mo><mml:mi>W</mml:mi><mml:mi>D</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">Na</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">WD</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">Na</mml:mi></mml:mrow></mml:msub></mml:mfrac><mml:mo>∙</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">WD</mml:mi></mml:mrow><mml:mi>X</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ2\"><label>2.2</label><alternatives><tex-math id=\"M3\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${CU}_{{NH}_{4}+H}={CL}_{BC}$$\\end{document}</tex-math><mml:math id=\"M4\" display=\"block\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">CU</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub><mml:mo>+</mml:mo><mml:mi>H</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">CL</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">BC</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ3\"><label>2.3</label><alternatives><tex-math id=\"M5\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${CU}_{{NH}_{4}}=\\frac{{(PD+TF+SF)}_{{NH}_{4}}}{{(PD+TF+SF)}_{{NH}_{4}}+xH\\bullet {(PD+TF+SF)}_{H}}\\bullet {CL}_{BC}$$\\end{document}</tex-math><mml:math id=\"M6\" display=\"block\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">CU</mml:mi></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>P</mml:mi><mml:mi>D</mml:mi><mml:mo>+</mml:mo><mml:mi>T</mml:mi><mml:mi>F</mml:mi><mml:mo>+</mml:mo><mml:mi>S</mml:mi><mml:mi>F</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub></mml:msub><mml:mrow><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>P</mml:mi><mml:mi>D</mml:mi><mml:mo>+</mml:mo><mml:mi>T</mml:mi><mml:mi>F</mml:mi><mml:mo>+</mml:mo><mml:mi>S</mml:mi><mml:mi>F</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub></mml:msub><mml:mo>+</mml:mo><mml:mi>x</mml:mi><mml:mi>H</mml:mi><mml:mo>∙</mml:mo><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>P</mml:mi><mml:mi>D</mml:mi><mml:mo>+</mml:mo><mml:mi>T</mml:mi><mml:mi>F</mml:mi><mml:mo>+</mml:mo><mml:mi>S</mml:mi><mml:mi>F</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>H</mml:mi></mml:msub></mml:mrow></mml:mfrac><mml:mo>∙</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">CL</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">BC</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ4\"><label>2.4</label><alternatives><tex-math id=\"M7\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${CU}_{({NO}_{3}+{NH}_{4})}=\\frac{{xNH}_{4}\\bullet {\\left(TF+SF\\right)}_{{NH}_{4}}+{(TF+SF)}_{{NO}_{3}}}{{xNH}_{4}\\bullet {(TF+SF)}_{{NH}_{4}}}\\bullet {CU}_{{NH}_{4}}$$\\end{document}</tex-math><mml:math id=\"M8\" display=\"block\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">CU</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NO</mml:mi></mml:mrow><mml:mn>3</mml:mn></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">xNH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub><mml:mo>∙</mml:mo><mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mi>T</mml:mi><mml:mi>F</mml:mi><mml:mo>+</mml:mo><mml:mi>S</mml:mi><mml:mi>F</mml:mi></mml:mfenced><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>T</mml:mi><mml:mi>F</mml:mi><mml:mo>+</mml:mo><mml:mi>S</mml:mi><mml:mi>F</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NO</mml:mi></mml:mrow><mml:mn>3</mml:mn></mml:msub></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">xNH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub><mml:mo>∙</mml:mo><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>T</mml:mi><mml:mi>F</mml:mi><mml:mo>+</mml:mo><mml:mi>S</mml:mi><mml:mi>F</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub></mml:msub></mml:mrow></mml:mfrac><mml:mo>∙</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">CU</mml:mi></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"italic\">NH</mml:mi></mml:mrow><mml:mn>4</mml:mn></mml:msub></mml:msub></mml:mrow></mml:math></alternatives></disp-formula>" ]	[]	[]	[]	[]	[ "<supplementary-material content-type=\"local-data\" id=\"MOESM1\"></supplementary-material>" ]	[ "<table-wrap-foot><p><sup></sup>Watmough, S.A., & Dillon, P.J. (2004). Major element fluxes from a coniferous catchment in central Ontario, 1983–1999. <italic>Biogeochemistry</italic>. <italic>67</italic>, 369–398</p><p><sup>†</sup>Watmough, S.A., & Dillon, P.J. (2003). Base cation and nitrogen budgets for seven forested catchments in central Ontario, 1983–1999. <italic>Forest Ecology and Management</italic>. <italic>177</italic>, 155–177</p><p><sup>‡</sup>Sawada, H., Kaji, M., Oomura, K., & Ohkubo, T. (2008). Age structure and regeneration characteristic in a natural beech (<italic>Fagus japonica</italic> Maxim. And <italic>F. crenata</italic> Blume) forest in the Chichibu mountains, central Japan. <italic>Bulletin of the Tokyo University Forests</italic>, <italic>119</italic>, 1–23</p></table-wrap-foot>", "<table-wrap-foot><p>Values in parentheses are standard deviations</p></table-wrap-foot>", "<table-wrap-foot><p>Values in parentheses are standard deviations</p></table-wrap-foot>", "<table-wrap-foot><p>Values in parentheses are standard deviations</p></table-wrap-foot>", "<table-wrap-foot><p>Values in parentheses are standard deviations</p></table-wrap-foot>", "<table-wrap-foot><p>Values in parentheses are standard deviations</p><p><sup></sup>Katagiri, S. (1996). V. Material production and nutrient cycling in various forest ecosystems. In Iwatsubo, G (Ed.), <italic>Modern Forestry </italic><italic> 12 Forest ecology</italic>, (pp. 189–293). Tokyo: Buneido Publishing Co., Ltd</p><p><sup>†</sup>Katagiri, S. (1977). Studies on mineral cycling in a deciduous broad-leaved forest at Sanbe forest of Shimane university (IV) Concentration of nutrient elements of trees. <italic>Bulletin of the Faculty of Agriculture, Shimane University</italic>, <italic>11</italic>, 60–72</p><p><sup>‡</sup>Tsutsumi, T. (1965). Amount of nutrients in trees of <italic>Cryptomeria japonica</italic>. <italic>Transactions of the meeting of the Japanese Forestry Society</italic>, <italic>47</italic>, 105–108</p></table-wrap-foot>", "<fn-group><fn><p><bold>Publisher's Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"10661_2023_12132_Fig1_HTML\" id=\"MO1\"/>", "<graphic xlink:href=\"10661_2023_12132_Fig2_HTML\" id=\"MO2\"/>", "<graphic xlink:href=\"10661_2023_12132_Article_Equ1.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"10661_2023_12132_Article_Equ2.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"10661_2023_12132_Article_Equ3.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"10661_2023_12132_Article_Equ4.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"10661_2023_12132_Fig3_HTML\" id=\"MO3\"/>", "<graphic xlink:href=\"10661_2023_12132_Fig4_HTML\" id=\"MO4\"/>", "<graphic xlink:href=\"10661_2023_12132_Fig5_HTML\" id=\"MO5\"/>", "<graphic xlink:href=\"10661_2023_12132_Fig6_HTML\" id=\"MO6\"/>", "<graphic xlink:href=\"10661_2023_12132_Fig7_HTML\" id=\"MO7\"/>" ]	[ "<media xlink:href=\"10661_2023_12132_MOESM1_ESM.xlsx\"><caption><p>Supplementary file1 (XLSX 139 KB)</p></caption></media>" ]	[{"mixed-citation": ["Adriaenssens, S., Staelens, J., Wuyts, K., De Schrijver, A., Van Wittenberghe, S., Wuytack, T., Kardel, F., Verheyen, K., Samson, R., & Boeckx, P. (2011). Foliar nitrogen uptake from wet deposition and the relation with leaf wettability and water storage capacity. "], "italic": ["Water, Air, and Soil Pollution,", "219"]}, {"mixed-citation": ["Adriaenssens, S., Staelens, J., Baeten, L., Verstraeten, A., Boeckx, P., Samson, R., & Verheyen, K. (2013). Influence of canopy budget model approaches on atmospheric deposition estimates to forests. "], "italic": ["Biogeochemistry,", "116"]}, {"surname": ["Andersen", "Hovmand"], "given-names": ["HV", "MF"], "article-title": ["Review of dry deposition measurements of ammonia and nitric acid to forest"], "source": ["Forest Ecology and Management"], "year": ["1999"], "volume": ["114"], "fpage": ["5"], "lpage": ["18"], "pub-id": ["10.1016/S0378-1127(98)00378-8"]}, {"surname": ["Asplund", "Ohlson", "Gauslaa"], "given-names": ["J", "M", "Y"], "article-title": ["Tree species shape the elemental composition in the lichen "], "italic": ["Hypogymnia physodes"], "source": ["Fungal Ecology"], "year": ["2015"], "volume": ["16"], "fpage": ["1"], "lpage": ["5"], "pub-id": ["10.1016/j.funeco.2015.03.006"]}, {"surname": ["Augusto", "Ranger", "Binkley", "Rothe"], "given-names": ["L", "J", "D", "A"], "article-title": ["Impact of several common tree species of European temperate forests on soil fertility"], "source": ["Annals of Forest Science"], "year": ["2002"], "volume": ["59"], "fpage": ["233"], "lpage": ["253"], "pub-id": ["10.1051/forest:2002020"]}, {"surname": ["Baker", "Irving"], "given-names": ["JP", "PM"], "article-title": ["Biological effects of changes in surface water acid-base chemistry"], "source": ["Acidic deposition: State of science and technology"], "year": ["1991"], "publisher-name": ["The U.S. National Acid Precipitation Assessment Program"], "fpage": ["119"], "lpage": ["123"]}, {"surname": ["Burkhardt", "Eiden"], "given-names": ["J", "R"], "article-title": ["Thin water films on coniferous needles. A new device for the study of water vapour condensation and gaseous deposition to plant surfaces and particle samples"], "source": ["Atmospheric Environment"], "year": ["1994"], "volume": ["28"], "fpage": ["2001"], "lpage": ["2011"], "pub-id": ["10.1016/1352-2310(94)90469-3"]}, {"mixed-citation": ["de Vries, W., Reinds, G. J., van der Salm, C., Draaijers, G. P. J., Bleeker, A., Erisman, J. W., Au\u00e9e, J., Gundersen, P., Kristensen, H. L., van Dobben, H., de Zwart, D., Derome, J., Voogd, J. C. H., & Vel, E. M. (2001). Intensive monitoring of forest ecosystems in Europe Technical Report 2001. In "], "italic": ["Forest Intensive Monitoring Coordinating Institute, 2001"], "ext-link": ["https://www.icp-forests.org/pdf/TRLII2001.pdf"]}, {"mixed-citation": ["Draaijers, G. P. J., Erisman, J. W., L\u00f6vblad, G., Spranger, T., & Vel, E. (1998). "], "italic": ["Quality and uncertainty aspects ot torest deposition estimation using throughfall, stemflow and precipitation measurements"], "ext-link": ["https://publications.tno.nl/publication/34641023/vuCqh6/MEP-R-1998-093.pdf"]}, {"surname": ["Eimers", "Dillon", "Watmough"], "given-names": ["MC", "PJ", "SA"], "article-title": ["Long-term (18-year) changes in sulphate concentrations in two Ontario headwater lakes and their inflows in response to decreasing deposition and climate variations"], "source": ["Hydrological Processes"], "year": ["2004"], "volume": ["18"], "fpage": ["2617"], "lpage": ["2630"], "pub-id": ["10.1002/hyp.5570"]}, {"mixed-citation": ["EPA. (2022). "], "italic": ["Air pollutant emissions trends data. National Tier 1 CAPS Trends (xlsx). Criteria pollutants National Tier 1 for 1970 - 2021"], "ext-link": ["https://www.epa.gov/air-emissions-inventories/air-pollutant-emissions-trends-data"]}, {"surname": ["Fujiwara", "Saito"], "given-names": ["A", "K"], "article-title": ["Analysis of long term fixed point daily video recordings using a robot camera for observing tree phenology"], "source": ["Journal of the Japanese Institute of Landscape Architecture"], "year": ["2005"], "volume": ["68"], "fpage": ["927"], "lpage": ["930"], "pub-id": ["10.5632/jila.68.927"]}, {"mixed-citation": ["Griffith, K. T., Ponette-Gonz\u00e1lez, A. G., Curran, L. M., & Weathers, K. C. (2015). Assessing the influence of topography and canopy structure on Douglas fir throughfall with LiDAR and empirical data in the Santa Cruz mountains, USA. "], "italic": ["Environmental Monitoring and Assessment", "187, 270"]}, {"mixed-citation": ["Guerrieri, R., Vanguelova, E. I., Michalski, G., Heaton, T. H. E., & Mencuccini, M. (2015). Isotopic evidence for the occurrence of biological nitrification and nitrogen deposition processing in forest canopies. "], "italic": ["Global Change Biology,", "21"]}, {"mixed-citation": ["Guerrieri, R., Templer, P., & Magnani, F. (2021). Canopy exchange and modification of nitrogen fluxes in forest ecosystems. "], "italic": ["Current Forestry Reports,", "7"]}, {"surname": ["Hansen"], "given-names": ["K"], "article-title": ["In-canopy throughfall measurements of ion fluxes in Norway spruce"], "source": ["Atmospheric Environment"], "year": ["1996"], "volume": ["30"], "fpage": ["4065"], "lpage": ["4076"], "pub-id": ["10.1016/1352-2310(95)00444-0"]}, {"surname": ["Houle", "Ouimet", "Paquin", "Laflamme"], "given-names": ["D", "R", "R", "J-G"], "article-title": ["Interactions of atmospheric deposition with a mixed hardwood and a coniferous forest canopy at the Lake Clair Watershed (Duchesnay, Quebec)"], "source": ["Canadian Journal of Forest Research"], "year": ["1999"], "volume": ["29"], "fpage": ["1944"], "lpage": ["1957"], "pub-id": ["10.1139/x99-212"]}, {"surname": ["Imamura", "Tanaka", "Ohte", "Yamamoto"], "given-names": ["N", "N", "N", "H"], "article-title": ["Nutrient transfer with rainfall in the canopies of a broad-leaved deciduous forest in Okuchichibu"], "source": ["Journal of the Japanese Forestry Society"], "year": ["2012"], "volume": ["94"], "fpage": ["74"], "lpage": ["83"], "pub-id": ["10.4005/jjfs.94.74"]}, {"surname": ["Imamura", "Iwai", "Tanaka", "Ohte"], "given-names": ["N", "N", "N", "N"], "article-title": ["A comparison between wet-only and bulk deposition at two forest sites in Japan"], "source": ["Asian Journal of Atmospheric Environment"], "year": ["2018"], "volume": ["12"], "fpage": ["67"], "lpage": ["77"], "pub-id": ["10.5572/ajae.2018.12.1.067"]}, {"mixed-citation": ["Imamura, N., Katata, G., Kajino, M., Kobayashi, M., Itoh, Y., & Akama, A. (2020b). Fogwater deposition of radiocesium in the forested mountains of East Japan during the Fukushima Daiichi Nuclear Power Plant accident: A key process in regional radioactive contamination. "], "italic": ["Atmospheric Environment,", "224"]}, {"mixed-citation": ["Imamura, N., Levia, D. F., Nanko, K., Tanaka, N., & Ohte, N. (2020a). Geographic factors explain the variability of atmospheric deposition of sulfur and nitrogen onto coniferous forests within and beyond the Tokyo metropolis. "], "italic": ["Water, Air, & Soil Pollution,", "231"]}, {"mixed-citation": ["Inagaki, M., Sakai, M., & Ohnuki, Y. (1995). The effects of organic carbon on acid rain in a temperate forest in Japan. "], "italic": ["Water, Air, & Soil Pollution,", "85"]}, {"surname": ["Kop\u00e1\u010dek", "Posch"], "given-names": ["J", "M"], "article-title": ["Anthropogenic nitrogen emissions during the Holocene and their possible effects on remote ecosystems"], "source": ["Global Biogeochemical Cycles"], "year": ["2011"], "volume": ["25"], "fpage": ["1"], "lpage": ["16"], "pub-id": ["10.1029/2010GB003779"]}, {"surname": ["Lovett", "Reiners"], "given-names": ["GM", "WA"], "article-title": ["Canopy structure and cloud water deposition in subalpine coniferous forests"], "source": ["Tellus"], "year": ["1986"], "volume": ["38B"], "fpage": ["319"], "lpage": ["327"], "pub-id": ["10.1111/j.1600-0889.1986.tb00257.x"]}, {"surname": ["Lovett", "Nolan", "Driscoll", "Fahey"], "given-names": ["GM", "SS", "CT", "TJ"], "article-title": ["Factors regulating throughfall flux in a New Hampshire forested landscape"], "source": ["Canadian Journal of Forest Research"], "year": ["1996"], "volume": ["26"], "fpage": ["2134"], "lpage": ["2144"], "pub-id": ["10.1139/x26-242"]}, {"mixed-citation": ["MacDougall, D., Crummett, W. B., et al. (1980). Guidelines for data acquisition and data quality evaluation in environmental chemistry. "], "italic": ["Analytical Chemistry,", "52"]}, {"mixed-citation": ["McHale, M. R., Burns, D. A., Siemion, J., & Antidormi, M. R. (2017). The response of soil and stream chemistry to decreases in acid deposition in the Catskill Mountains, New York, USA. "], "italic": ["Environmental Pollution,", "229"]}, {"mixed-citation": ["National Air Pollution Surveillance Program. (2022). "], "italic": ["Available from the Government of Canada Open Data Portal at open.canada.ca.\u00a0"], "ext-link": ["https://open.canada.ca/data/en/dataset/1b36a356-defd-4813-acea-47bc3abd859b"]}, {"mixed-citation": ["National Institute for Environmental Studies. (2022). "], "italic": ["Environmental observatory data of continuous monitoring of air pollution"], "ext-link": ["https://tenbou.nies.go.jp/download"]}, {"surname": ["Neary", "Gizyn"], "given-names": ["AJ", "WI"], "article-title": ["Throughfall and stemflow chemistry under deciduous and coniferous forest canopies in south central Ontario"], "source": ["Canadian Journal of Forest Research"], "year": ["1994"], "volume": ["24"], "fpage": ["1089"], "lpage": ["1100"], "pub-id": ["10.1139/x94-145"]}, {"surname": ["Parker"], "given-names": ["GG"], "article-title": ["Throughfall and stemflow in the forest nutrient cycle"], "source": ["Advances in Ecological Research"], "year": ["1983"], "volume": ["13"], "fpage": ["57"], "lpage": ["133"], "pub-id": ["10.1016/S0065-2504(08)60108-7"]}, {"mixed-citation": ["Rodhe, H. (1972). A study of the sulfur budget for the atmosphere over Northern Europe. "], "italic": ["Tellus a: Dynamic Meteorology and Oceanography,", "24"]}, {"surname": ["Roelofs", "Kempers", "Houdijk", "Jansen"], "given-names": ["JGM", "AJ", "ALFM", "J"], "article-title": ["The effect of air-borne ammonium sulphate on "], "italic": ["Pinus nigra", "maritima"], "source": ["Plant and Soil"], "year": ["1985"], "volume": ["84"], "fpage": ["45"], "lpage": ["56"], "pub-id": ["10.1007/BF02197866"]}, {"mixed-citation": ["Rothe, A., Huber, C., Kreutzer, K., & Weis, W. (2002). Deposition and soil leaching in stands of Norway spruce and European Beech: Results from the Hoglwald research in comparison with other European case studies. "], "italic": ["Plant and Soil,", "240"]}, {"surname": ["Sase", "Takamatsu", "Yoshida", "Inubushi"], "given-names": ["H", "T", "T", "K"], "article-title": ["Changes in properties of epicuticular wax and the related water loss in Japanese cedar ("], "italic": ["Cryptomeria japonica"], "source": ["Canadian Journal of Forest Research"], "year": ["1998"], "volume": ["28"], "fpage": ["546"], "lpage": ["556"], "pub-id": ["10.1139/x98-021"]}, {"mixed-citation": ["Sase, H, Takahashi, M., Matsuda, K., Sato, K., Tanikawa, T., Yamashita, N., Ohizumi, T., Ishida, T., Kamisako, M., Kobayashi, R., Uchiyama, S., Saito, T., Morohashi, M., Fukuhara, H., Kaneko, S., Inoue, T., Yamada, T., Takenaka, C., Tayasu, I., \u2026 Ohta, S. (2019). Response of river water chemistry to changing atmospheric environment and sulfur dynamics in a forested catchment in central Japan. "], "italic": ["Biogeochemistry", "142"]}, {"surname": ["Schaefer", "Reiners", "Olson"], "given-names": ["DA", "WA", "RK"], "article-title": ["Factors controlling the chemical alteration of throughfall in a subalpine balsam fir canopy"], "source": ["Environmental and Experimental Botany"], "year": ["1988"], "volume": ["28"], "fpage": ["175"], "lpage": ["189"], "pub-id": ["10.1016/0098-8472(88)90027-5"]}, {"surname": ["Sch\u00fctt", "Cowling"], "given-names": ["P", "E"], "article-title": ["Waldsterben, a general decline of forests in central Europe: Symptoms, deveropment, and possible causes"], "source": ["Plant Disease"], "year": ["1985"], "volume": ["69"], "fpage": ["548"], "lpage": ["558"]}, {"surname": ["Smith", "Van Aardenne", "Klimont", "Andres", "Volke", "Delgado Arias"], "given-names": ["SJ", "J", "Z", "RJ", "A", "S"], "article-title": ["Anthropogenic sulfur dioxide emissions: 1850\u20132005"], "source": ["Atmospheric Chemistry and Physics"], "year": ["2011"], "volume": ["11"], "fpage": ["1101"], "lpage": ["1116"], "pub-id": ["10.5194/acp-11-1101-2011"]}, {"surname": ["Staelens", "De Schrijver", "Verheyen"], "given-names": ["J", "A", "K"], "article-title": ["Seasonal variation in throughfall and stemflow chemistry beneath a European beech ("], "italic": ["Fagus sylvatica"], "source": ["Canadian Journal of Forest Research"], "year": ["2007"], "volume": ["37"], "fpage": ["1359"], "lpage": ["1372"], "pub-id": ["10.1139/X07-003"]}, {"surname": ["Staelens", "Houle", "De Schrijver", "Neirynck", "Verheyen"], "given-names": ["J", "D", "A", "J", "K"], "article-title": ["Calculating dry deposition and canopy exchange with the canopy budget model: Review of assumptions and application to two deciduous forests"], "source": ["Water, Air, and Soil Pollution"], "year": ["2008"], "volume": ["191"], "fpage": ["149"], "lpage": ["169"], "pub-id": ["10.1007/s11270-008-9614-2"]}, {"surname": ["Takamatsu", "Sase", "Takada"], "given-names": ["T", "H", "J"], "article-title": ["Some physiological properties of "], "italic": ["Cryptomeria japonica"], "source": ["Canadian Journal of Forest Research"], "year": ["2001"], "volume": ["31"], "fpage": ["663"], "lpage": ["672"], "pub-id": ["10.1139/cjfr-31-4-663"]}, {"mixed-citation": ["Templer, P. H., Weathers, K. C., Lindsey, A., Lenoir, K., & Scott, L. (2015). Atmospheric inputs and nitrogen saturation status in and adjacent to Class I wilderness areas of the northeastern US. "], "italic": ["Oecologia,", "177"]}, {"mixed-citation": ["Thieme, L., Graeber, D., Hofmann, D., Bischoff, S., Schwarz, M. T., Steffen, B., Meyer, U. N., Kaupenjohann, M., Wilcke, W., Michalzik, B., & Siemens, J. (2019). Dissolved organic matter characteristics of deciduous and coniferous forests with variable management: Different at the source, aligned in the soil. "], "italic": ["Biogeosciences,", "16"]}, {"mixed-citation": ["Watanabe, K., Kohzu, A., Suda, W., Yamamura, S., Takamatsu, T., Takenaka, A., Koshikawa, M. K., Hayashi, S., & Watanabe, M. (2016). Microbial nitrification in throughfall of a Japanese cedar associated with archaea from the tree canopy. "], "italic": ["SpringerPlus", "5, 1596"]}, {"surname": ["Woodcock"], "given-names": ["AH"], "article-title": ["Salt nuclei in marine air as a function of altitude and wind force"], "source": ["Journal of Meteorology"], "year": ["1953"], "volume": ["10"], "fpage": ["362"], "lpage": ["371"], "pub-id": ["10.1175/1520-0469(1953)010<0366:SNIMAA>2.0.CO;2"]}, {"mixed-citation": ["Zhang, S., De Frenne, P., Landuyt, D., & Verheyen, K. (2022). Impact of tree species diversity on throughfall deposition in a young temperate forest plantation. "], "italic": ["Science of the Total Environment,", "842"]}]	{ "acronym": [], "definition": [] }	59	CC BY	no	2024-01-13 23:36:43	Environ Monit Assess. 2024 Dec 2; 196(1):1	oa_package/7f/0e/PMC10693530.tar.gz
PMC10698164	38052884	[ "<title>Introduction</title>", "<p id=\"Par3\">Identifying and characterizing the origin of wines on the basis of their chemical content is a challenging yet fundamental problem in wine science. Wines are shaped by multiple factors such as the soil, the climate<sup>##UREF##0##1##,##UREF##1##2##</sup>, the varietals, the microbiology and the wine-maker’s practices. If we are to understand how these factors influence the taste of a wine, we need to uncover what part of the chemical composition determines its quality, origin, and typicity. Wine typicity and authenticity are indeed at the center of the wine industry’s preoccupations<sup>##REF##32949040##3##–##REF##32750629##7##</sup>.</p>", "<p id=\"Par4\">One approach to address these questions consists in measuring the concentration of specific targeted molecules that are thought to be particularly informative with regard to wine origin and flavor. This approach has led to the identification of several key compounds but it is akin to finding a needle in a haystack<sup>##REF##26365759##8##–##UREF##6##14##</sup>. Unlike industrial beverages, wines are complex mixtures of molecules and their taste often depends on molecules present only in remarkably small concentrations. Also, it is quite possible that the chemical typicity of wine is not defined by the concentration of a handful of molecules but depends instead on the overall pattern of concentrations over a wide range of molecules, possibly in a nonlinear way.</p>", "<p id=\"Par5\">Several groups have indeed abandoned the targeted approach in favor of a global perspective. They used statistical tools from machine learning (ML) to analyze the output of broad-spectrum chemical analysis. This approach has been applied for instance to wine classification using ICP MS<sup>##REF##24996361##15##</sup>, nuclear magnetic resonance<sup>##REF##31357002##16##</sup>, RP-HPLC/DAD<sup>##UREF##3##5##</sup> and UV-spectroscopy<sup>##REF##33375212##17##</sup> or to wine region classification using GC/QTOFMS<sup>##UREF##7##18##</sup>, isotopic ratio<sup>##REF##20872626##19##</sup>, absorbance-transmission and fluorescence excitation-emission matrix (A-TEEM) or climate data<sup>##UREF##8##20##</sup>. Other studies have also looked at sensorial properties and aroma profiles using gas chromatography (GC)<sup>##UREF##9##21##</sup> and wine quality using global chemical measurements (alcoholic contents or acidity as examples)<sup>##UREF##10##22##</sup> and the emergence of oxidative markers during aging with GC<sup>##REF##33677212##23##</sup>.</p>", "<p id=\"Par6\">Here we apply (ML) techniques to raw chromatograms obtained with GC. GC is a popular type of analysis for wine, which has led to seminal discoveries, but which is typically used within the targeted molecule approach, i.e., as a tool to identify molecules of interest. Yet, GC is a lot more amenable to global analysis because it can reveal the presence of a much wider range of molecules than, say, UV-spectroscopy. The problem, however, is to determine what class of chemicals to target with GC, since GC can be tuned to reveal specific families of molecules (e.g., esters) depending on the type of filter applied to the output of the chromatography column. Moreover, it is unclear which part of the chromatogram to focus on. Typically, researchers integrate peaks of the chromatograms to quantify the concentration of specific molecules, thus discarding the rest of the chromatograms. Using the raw, unprocessed chromatograms could in principle lead to better results but this requires using techniques that can automatically determine which parts of the chromatograms are most informative for a particular classification problem. This is precisely where ML can help since ML algorithms can automatically find the most informative parts of a chromatogram.</p>", "<p id=\"Par7\">Accordingly, we used a variety of ML techniques, including nonlinear dimensionality reduction, linear and nonlinear classifiers, and regression models to predict several features of wines from the Bordeaux regions from chromatograms. We focused in particular on the identity of estates and vintages. Our results indicate that raw chromatograms are highly informative about terroir and estate identity for the Bordeaux estates studied here. We also found that integrating peaks to estimate the concentration of specific chemical compounds leads to lower performance on all tasks. Finally, whether we use the raw chromatograms or a quantification table of specific compounds, we observed that wine chemical identity is defined by a large chemical spectrum rather than a few specific molecules.</p>" ]	[ "<title>Material and methods</title>", "<title>Wine samples</title>", "<p id=\"Par34\">Our study involved 80 Bordeaux red wines from 7 estates (a.k.a. chateaux): A, B, C, D, E, F, and G. Twelve vintages were available for each estate (1990, 1995, 1996, 1998, 1999, 2000, 2001, 2002, 2004, 2005, 2006, and 2007) except for estate F which is represented by only eight vintages (1995, 1998, 2000, 2001, 2002, 2005, 2006, and 2007). One single bottle of 75 cL per wine was studied and samples were analyzed in 2018 when the wines were aged between 11 and 28 years in the estates’ cellars. A, B, and C are right-bank wines from the Pomerol (A) and St-Emilion (B and C) appellations, while the others are left-bank wines from the Pauillac (D, E), Margaux (F) and Pessac-Léognan (G) appellations.</p>", "<title>Gas Chromatography data acquisition and post-acquisition treatment</title>", "<p id=\"Par35\">All the wines were analyzed in a single batch in August 2018 by three previously designed GC methods, one focused on the quantification of odorous esters<sup>##UREF##14##28##</sup>, the second one on oak-flavor compounds<sup>##REF##17993382##29##</sup> and the last one on off-flavor compounds<sup>##REF##19233369##30##</sup>. This data set was collected for another set of experiments, unrelated to the current project<sup>##UREF##11##24##</sup>.</p>", "<title>Analysis of off-flavor compounds using SBSE extraction</title>", "<p id=\"Par36\">The analytical procedure is based on the method developed by Franc et al.<sup>##REF##19233369##30##</sup>. The extraction of compounds was carried out using 10 mm × 1 mm (length × film thickness) polydimethylsiloxane stir bars (Twister®, 63 µL coating, Gerstel, Mülheim an der Ruhr, Germany). These were placed into the vial containing 10 mL of wine sample and 20 µL of an internal standard solution (hydro alcoholic solution 50% v/v at 112 µg L<sup>−1</sup> of d<sub>3</sub>-2-isobutyl-3-methoxypyrazine, 55.5 µg.L<sup>−1</sup> of d<sub>5</sub>-2,4,6-trichloroanisole 60 µg L<sup>−1</sup> of d<sub>5</sub>-4-ethylguaiacol and 300 µg./L<sup>−1</sup> of (±)-d<sub>5</sub>-geosmin). After 60 min of stirring at 900 rpm, the stir bars were removed, rinsed with Milli-Q quality water (18.2 MΩ cm<sup>−1</sup>), dried carefully with a paper towel, and transferred into a desorption tube for chromatographic analysis. Analyses were performed using an Agilent 6890 gas chromatograph system, fit with an Agilent HP-5MS capillary column (30 m × 0.25 mm i.d. 0.25 µm film thickness). The GC was combined into an Agilent 5975 mass spectrometric detector (Agilent Technologies, Massy, France). The system was equipped with a Gerstel MPS 2 autosampler, a Twister Thermal Desorption Unit (TDU), and a Gerstel Cooled Injection System Programmable Temperature Vaporization (PTV) inlet (Gerstel, Mülheim an der Ruhr, Germany).The compounds adsorbed on stir bars were thermally desorbed in the TDU with a helium flow at 50 mL min<sup>−1</sup> in splitless mode and a temperature rate program of 60 °C.min<sup>−1</sup> from 30 °C to 280 °C (held for 10 min). TDU transfer line was kept at 300 °C and the desorbed compounds were cryofocused in the CIS maintained at −100 °C using liquid nitrogen. PTV injector was then heated at 12 °C.s<sup>−1</sup> from −100 °C to 290 °C (held for 5 min) to inject the trapped compounds onto the capillary column. The injection was performed in splitless mode at 1.5 min (helium purge flow of 50 mL.min<sup>−1</sup>). The program for the oven temperature was as follows: 40 °C for initial temperature, increasing to 120 °C at a rate of 2 °C min<sup>−1</sup> and then to 290 °C (held for 9 min) at a rate of 10 °C min<sup>−1</sup>. Electronic ionization was performed at 70 eV with a detector temperature at 230 °C. The selected ions monitored with a dwell time of 50 ms and distributed in time windows were the following: Window 1—after solvent delay (15 min) to 30.5 min, ions 122, 124, 137, 139, 152, 157; Window 2 - From 30.5 to 34.5 min, ions 195, 197, 210, 212, 215, 217; Window 3 - From 34.5 to 39 min, ions 112, 114, 128, 149, 182, 186; Window 4—From 39 to 43 min, ions 231, 244, 246; Window 5—From 43 to 46 min, ions 265, 278, 280, 329, 331, 346. Run time was 66 min. The method allows the quantification of: 2-Isobutyl-3-methoxypyrazine (IBMP); 2,4,6-trichloroanisole (TCA); 2,4,6-tribromoanisole; 2,3,5,6-tetrachloroanisole; 2,3,4,5,6-pentachloroanisole; 4-ethylphenol (EP); 4-ethylguaiacol (EG); (±)-geosmin. Only, IBMP (in 2 samples at the levels of 4 and 17 ng L<sup>−1</sup>), EP and EG (in all the samples but 3 at levels between 8 and 7000 µg L<sup>−1</sup>) have been detected and quantified.</p>", "<title>Analysis of oak-flavor compounds using liquid/liquid extraction</title>", "<p id=\"Par37\">Oak-flavour compounds were extracted according to the method described by Bloem<sup>##REF##19233369##30##</sup>: 200 µL of 1-dodecanol (45 mg L<sup>−1</sup> in hydroalcoholic solution 50% v/v) was added as an internal standard to 50 mL of wine. The sample was extracted three times by 4, 2, and 2 mL of dichloromethane HPLC Grade during 5 min at 700 rpm. The resulting organic extracts were dried with anhydrous sodium sulfate (Na<sub>2</sub>SO<sub>4</sub>) and concentrated to 0.25 mL under nitrogen gentle flow. An Agilent 7890 A gas chromatograph coupled with an Agilent 5975 C mass spectrometric detector (Agilent Technologies, Massy, France) and equipped with a Gerstel MPS2 autosampler (Gerstel, Mülheim an der Ruhr, Germany) and a SGE BP21 capillary column (50 m × 0.32 mm i.d., 0.25 µm film thickness) was used (SGE Trajan, Ringwood Victoria, Australia). 2 µL of the extract was injected in splitless mode (30 s) in the injector at 250 °C. The program for the oven temperature was as follows: held 1 min at 60 °C, raised at 4 °C min<sup>−1</sup> to 220 °C and held for 30 min. MS grade helium was used as carrier gas with a debit of 1 mL min<sup>−1</sup>. Electron ionization was performed at 70 eV with a detector temperature at 180 °C. The selected ions monitored with a dwell time of 20 ms and distributed in time windows were the following: Window 1—after solvent delay (10 min) to 19 min, ions 71, 87, 99, 109, 124; Window 2—From 19 to 28 min, ions 71, 83, 87, 97, 99; Window 3—From 28 to 31 min, ions 111, 131, 139, 149, 154, 164; Window 4—From 31 to 41 min, ions 91, 123, 151, 152, 179, 194; Window 5—From 41 to 43.5 min, ions 123, 151, 166; Window 6—From 43.5 to 50 min, ions 153, 167, 181, 182, 196. Run time was 71 min. The method allows the quantification of: oak-lactone (Whiskylactone; <italic>cis</italic> and <italic>trans</italic>); eugenol; gaiacol; vanillin; acetovanillone; syringaldehyde; isoeugenol (<italic>cis</italic> and <italic>trans</italic>); furfural; 5-methylfurfural; acetosynringaldehyde and syringol.</p>", "<title>Analysis of esters using SPME extraction</title>", "<p id=\"Par38\">We used the method developed by Antalick et al.<sup>##UREF##14##28##</sup> to obtain a chromatogram that was originally designed to analyze 32 specific esters in wine. In the wines we study here, 16 esters were present at significant concentration, i.e., above the limit of quantification of the method in all the wines<sup>##UREF##11##24##</sup>. The compounds were extracted by solid-phase micro-extraction (SPME). Ten milliliters of wine and 10 µL of the internal standard solution (mixture of 4,4,4-ethyl-d3-butanoate at 178 mg L<sup>−1</sup>, ethyl-d11-hexanoate at 209 mg L<sup>−1</sup>, ethyl-d15-octanoate at 223 mg L<sup>−1</sup> and ethyl-d5-<italic>trans</italic>-cinnamate at 325 mg L<sup>−1</sup> in 100% ethanol v/v) were added to a vial containing 3.5 g of sodium chloride. SPME fiber (polydimethylsiloxane, 100 µm film thickness, 1 cm length) from Supelco (Bellefonte, Palo Alto, USA) was used as absorbent. Extraction of compounds was performed at 40 °C for 30 min with agitation speed at 500 rpm. Following desorption for 15 min at 250 °C, samples were injected in splitless mode (45 s). Gas chromatographic analysis was carried out on an Agilent 6890 N gas chromatograph coupled to an Agilent 5875 C mass spectrometer (Agilent technologies, Massy, France) and equipped with a Gerstel MPS2 autosampler (Gerstel, Mülheim an der Ruhr, Germany). An SGE BP21 capillary column (50 m × 0.32 mm i.d., 0.25 µm film thickness) was used (SGE Trajan, Ringwood Victoria, Australia), and the carrier gas used was MS grade helium at 1.2 mL min<sup>−1</sup>. The oven temperature was programmed at 40 °C for 5 min then raised at 3 °C min<sup>−1</sup> to 220 °C (held for 30 min). The mass spectrometer was operated in electron ionization mode at 70 eV with a detector temperature at 280 °C. The selected ions monitored with a dwell time of 20 ms were the following: 43, 55, 56, 57, 60, 61, 69, 70, 71, 74, 85, 87, 88, 89, 91, 97, 99, 101, 102, 104, 105, 106, 110, 114, 116, 122, 127, 131, 136, 142, 176, 178, and 181. They were monitored from after solvent delay (2 min) to 95 min final run time.</p>", "<title>Quantification of specific chemical compounds</title>", "<p id=\"Par39\">For quantification, the mass spectrometers were operated in selected-ion-monitoring mode. The 32 quantified compounds were identified using retention time associated with control and quantification ions (<italic>m/z</italic>) as described in previous studies<sup>##UREF##14##28##–##REF##19233369##30##</sup>. The internal standard used to convert area under the peak into concentration was identified using the specific ions as also described in previous studies<sup>##UREF##14##28##–##REF##19233369##30##</sup>. All the quantifications have been performed using an external calibration set up in an old red Bordeaux wine matrix.</p>", "<p id=\"Par40\">Chromatograms were extracted from Agilent Chemstation software (Agilent Technologies, Santa Clara, CA, USA) as a .csv file without any signal alignment nor baseline correction. These chromatograms specify the signal intensity (A.U.) as a function of retention time. We analyzed the chromatograms separately (“esters”, “oak”, “offFla”) or as a single large chromatogram obtained by concatenating all three chromatograms together along the retention time axis (“concat”).</p>", "<p id=\"Par41\">It is important to note that the TIC chromatogram includes peaks produced by the fragmentation of compounds of the wine extract which are not exclusively in the targeted classes. Examples of chromatograms are presented in Fig. ##SUPPL##1##S1##.</p>", "<title>Data analysis</title>", "<title>Dimensionality reduction</title>", "<p id=\"Par42\">We used the t-SNE<sup>##UREF##15##31##</sup> and uniform manifold approximation (UMAP)<sup>##UREF##16##32##</sup> algorithms to reduce the thousands of dimensions of the chromatograms (corresponding to the retention times) to two (or three dimensions, without any visible structure beyond that seen in two dimensions, Fig. ##SUPPL##1##S2##), constrained by the distance structure between the chromatograms. The analysis was performed with custom Python scripts, using the scikit-learn library<sup>##UREF##17##33##</sup> and a Python library for UMAP<sup>##UREF##16##32##</sup> with default parameters, except perplexity = 30 for tSNE and n_neigbors = 60 for UMAP. Before dimensionality reduction, we pre-processed the data by standard scaling, i.e., for a given chromatogram, each feature (dimension = retention time) was z-scored with respect to all chromatograms (wine samples) of a given type. That means the mean of this feature across samples was subtracted and then it was divided by the standard deviation of this feature across samples (see Fig. ##SUPPL##1##S1## for example chromatograms).</p>", "<title>Supervised decoding</title>", "<p id=\"Par43\">The supervised decoding of estate/vintage from chromatograms was performed with LR and linear discriminant analysis (LDA), implemented in Python, packaged in scikit-learn<sup>##UREF##17##33##</sup>, with default parameters; no hyper-parameter tuning was needed. We used leave-7-out cross-validation for the estate decoding, which consists in splitting the data set into 73 data points for training the classifier and 7 data points for determining generalization performance. The set of seven test wines was obtained by drawing one wine randomly from each of the seven estates. We repeated this split 50 times and reported the average performance over all spits. A similar procedure was used for vintages, but using leave-12-out cross-validation, where 12 is the number of distinct vintages.</p>", "<title>Binning and “survival of the fittest” algorithm</title>", "<p id=\"Par44\">We tested if sections of the chromatograms contained decodable estate/vintage information by first binning each chromatogram into <italic>N</italic> non-overlapping consecutive bins of equal size (<italic>N</italic> = 50 in Fig. ##FIG##2##3##, and <italic>N</italic> = 5, 10, 20 in Fig. ##SUPPL##1##S9##). For instance, the oak chromatogram has 30 k data points (ordered by retention time), then the first bin contains the first 600 data points, the second the next 600, and so on, and the 50th bin contains the last 600 data points.</p>", "<p id=\"Par45\">We then tested how the iterative removal of bins (sections of the chromatogram) prior to decoding impacted performance, keeping at each step the best bins. More specifically, the procedure is as follows: we started with all <italic>N</italic> bins and then systematically removed one bin at a time. Each time, we quantified the change in performance when removing one bin. We then selected the bin for which the change in performance was the most favorable (either the smallest drop or largest improvement in performance) and then removed this bin permanently from the chromatogram, resulting in a chromatogram with <italic>N</italic>-1 bins. We repeated this procedure <italic>N-1</italic> times until only one bin remained and reported performance each time a bin was removed. In other words, this procedure removes iteratively the most informative bins.</p>", "<p id=\"Par46\">We coined this procedure “survival of the fittest” in the sense that the last few bins to be removed are among the most informative ones.</p>", "<title>Statistics</title>", "<p id=\"Par47\">We used two different one-tailed significance tests. First, decoding estate or vintage resulted in a distribution of decoding accuracies for different train/test splits. Here, a <italic>t</italic> test implemented in Scipy (scipy.stats.ttest_1samp<sup>##REF##32015543##34##</sup>) was used to estimate the likelihood that the chance level is the mean of the distribution of decoding accuracies. We corrected p-values via Bonferroni’s method, multiplying them by the number of comparisons (8 for vintage and estate decoding, as there are three chromatogram types, their concatenation, and two classifiers).</p>" ]	[ "<title>Results</title>", "<p id=\"Par8\">Our results are based on three types of GC methods which, for simplicity, we refer to as esters, oak, and off-flavor (offFla) in the rest of the paper (see Fig. ##SUPPL##1##S1## for examples). However, these chromatograms correspond to different extraction strategies (see Methods), which are not exclusively sensitive to the targeted molecules from which the method names arise. It is, therefore important to keep in mind that the resulting chromatograms are not simply reflecting the wine content for these three selections of molecules. Also, we emphasize that this data set was not collected specifically for the present study but had been used previously for a different purpose<sup>##UREF##11##24##</sup>. Nonetheless, given its diversity, we thought that this data set has the potential of being informative about the estate and vintage of wine.</p>", "<title>Recovering terroir through dimensionality reduction</title>", "<p id=\"Par9\">We first applied nonlinear dimensionality reduction to the gas chromatograms, allowing us to visualize the distribution of the wines in 2-D. This first analysis was based on the concatenation of the three types of chromatograms (“esters”, “oak”, and “offFla”, see Methods) into a single meta-chromatogram per wine. Figure ##FIG##0##1a, b## shows the results for two different clustering techniques, t-distributed stochastic neighbor embedding (t-SNE) and UMAP, which project the data in such a way that wines with similar chromatograms remain close to one another in the projected 2-D space.</p>", "<p id=\"Par10\">Several organizational principles emerged from these projections. First, wines from the same estate (or ‘chateau’, as they are known in the Bordeaux region) tend to form distinct clusters regrouping all vintages, with very few outliers (e.g., A-1990 and C-1990). This suggests that the chromatograms reveal specific features of each estate independently of the vintage. Second, two large clusters are clearly visible in both Fig. ##FIG##0##1a, b##, regrouping the A, C and B in one cluster and D, E, F, and G in another. Within the second cluster, G and F tend to lie on one side, closer to the (A, C, B) cluster while D and E lie on the other side of the cluster. Strikingly, the spatial configuration of the projection reflects the geography of the Bordeaux region (Fig. ##FIG##0##1c##) in the following way. Wines (A, C, B) are all located on the right bank of the Garonne river in the Libourne region, while (G, F, E, D) are all left-bank estates from the Medoc. Furthermore, D and E are located in the northern part of Medoc, while G and F are further south, next to the city of Bordeaux, in between (A, C, B) and (E, D), as in Fig. ##FIG##0##1a, b##. In other words, spatial relations between wines in 2-D-embedded space are similar to the corresponding wine estates’ geographical relations.</p>", "<p id=\"Par11\">We note that this is not true within the right bank estates, which are not spatially arranged in a way consistent with their relative geographical locations, but which also happen to be particularly nearby (within 7 km, versus 40 km between C and G, the two closest right and left bank estates). We also tried principal component analysis (PCA), a linear dimensionality reduction technique, and found that the clusters were not as clear, though the right-left bank distinction was still evident (Fig. ##SUPPL##1##S2##). Further note that cluster spread and orientation depend on cluster algorithm parameters such as the random seed, though the above-described spatial relations remain invariant.</p>", "<p id=\"Par12\">Next, we applied this analysis to the three types of chromatograms separately (Fig. ##SUPPL##1##S2##). While right and left bank estates tend to cluster together for all three chromatograms, this separation is particularly clear with the “offFla” data. However, the “offFla” (SBSE-GC/MS) do not show clear estate clusters while these clusters are clearly visible for the oak (liquid extract) and esters (SPME-GC/MS). As to the north-south axis of the left bank, it is only observed in oak, where we can see that the estates G and F stand in between the right bank estates and the estates T and F, just as we observed for the concatenated chromatograms.</p>", "<p id=\"Par13\">We hypothesized that the following factors are likely to contribute to these results. First, these estates use different blends of four varietals: cabernet-sauvignon, cabernet franc, merlot, and petit verdot. The percentage of these varietals varies across estates and across vintages (Table ##SUPPL##1##S1##). To evaluate whether this variability in blends is sufficient to explain our results, we applied the same dimensionality reduction technique to the percentages in the blend (reducing 4 dimensions to 2). Figure ##FIG##0##1d, e## shows the resulting plots. While three estate clusters (C, G, F) are clearly separated, other estates are now indistinguishable (A and B, and E and D). Moreover, the distinction between right vs left bank is less marked (in particular for UMAP for which C tends to be closer to the left bank estates). Finally, the south-north axis in the Medoc region is no longer present (G and F are not next to each other and do not stand in between the E-D estates and the right bank estate). This indicates that while the blend plays a partial role, it is not the only contributing factor. Other factors are likely to contribute such as the composition of the soil, vine and climate, modulated by the wine-making practices of each estate.</p>", "<title>Estate and vintage identification</title>", "<p id=\"Par14\">Given the clear estate clusters generated by t-SNE and UMAP, one would predict that it should be possible to identify estates with high accuracy independently of vintage from the chromatograms. Conversely, we expected that vintage identification, independently of the estate, might be more challenging given that vintages do not seem to cluster together (Figs. ##FIG##0##1a, b## and ##SUPPL##1##S2##).</p>", "<p id=\"Par15\">This is indeed what we found, using LDA and logistic regression (LR). Fig. ##FIG##1##2## shows the histogram of test performance (i.e., generalization to unseen data) across multiple splits and for the three chromatograms independently or for the concatenated chromatograms. On average, the best performance was obtained with LDA applied to the concatenated chromatogram, leading to 99% correct estate classification. Interestingly, similar performance was observed using only the oak chromatogram, or the ester chromatogram, while the offFla chromatogram led to worse performance (87% correct).</p>", "<p id=\"Par16\">We used the same technique to decode vintages. In line with the results of t-SNE and UMAP, and in sharp contrast to estate decoding, we obtained relatively low decoding performance on vintages, with a best performance of 27% correct with LDA applied to the oak chromatogram. While small, this is still well above chance performance of 8% (<italic>p</italic> < 0.001, Bonferroni corrected). Decoding vintages from the esters and offFla chromatograms led to near-chance performance.</p>", "<title>Detailed analysis of chromatograms</title>", "<p id=\"Par17\">Wine chemical identity could be defined primarily by the concentration of a handful of molecules or, conversely, by the overall pattern of concentration over a large range of molecules. To explore this issue, we looked for the regions of the chromatograms that most contribute to classification performance. We did so by first binning the chromatogram into 50 bins and then removing one by one the least informative bins (a procedure we coined ‘survival of the fittest’). This procedure revealed that decoding performance remains stable (and sometimes even increases due to overfitting) after removing about 45 bins (Fig. ##FIG##2##3a##). This was observed for both estate and vintage classification. Figure ##FIG##2##3a## (lower panel) shows the location of the remaining 5 bins on the chromatogram. Interestingly, the most informative bins do not necessarily line up with the largest peaks of the chromatogram suggesting that classification performance is partly driven by molecules with very low average concentration (µg.L<sup>−1</sup> or less) (Fig. ##SUPPL##1##S1## shows examples of normalized chromatograms, revealing the presence of multiple small peaks).</p>", "<p id=\"Par18\">This also shows that only a small fraction of the chromatogram is sufficient to reach asymptotic classification performance. We verified this by training our classifier on the concatenation of the N most informative bins for each of the three chromatograms, where N was systematically varied from 1 to 4, for a total of 3xN bins. We found that keeping 2–3 bins per chromatogram is sufficient to match, and in some cases outperform, the classifier trained on the full concatenated chromatograms. Indeed, the LDA estate classifier performed perfectly, 100% correct, when trained on the concatenation of the top 3 bins for each chromatogram, compared to 99% correct for the full concatenated chromatogram (Fig. ##SUPPL##1##S3##).</p>", "<p id=\"Par19\">In the case of vintages, classification reached a performance of 34% correct when training on the concatenation of the top 3 bins for each chromatogram, compared to 27% for the full concatenated chromatograms. Performance reached up to 50% correct when using only the most informative bins of the oak chromatogram (Fig. ##FIG##2##3c##). We also observed that some vintages are easier to decode than others, with 2007 being clearly the easiest (Fig. ##SUPPL##1##S4##).</p>", "<p id=\"Par20\">These results can be slightly misleading in that they suggest that there are just a few informative bins in each chromatogram. It is possible instead that most bins are informative but also happen to be highly redundant. The PCA analysis of the chromatograms already points in that direction since 90% of the variance in our data set is explained by only 20 dimensions (Fig. ##SUPPL##1##S5##). In order to explore this issue further, we trained classifiers on each bin separately. The red histograms in Fig. ##FIG##2##3b## show the estate classification performance for the individual bins in all three chromatograms. Surprisingly, while some bins are more informative than others, the vast majority of the bins lead to similar estate classification performance, well above chance (14%), indicating that many parts of the chromatograms contain information about estate identity and vintage (Fig. ##FIG##2##3d##, chance level at 8%).</p>", "<p id=\"Par21\">This conclusion is consistent with the profile of the weights used by the LDA classifier (Fig. ##SUPPL##1##S6##). If only a few molecules mattered, one would expect the weight pattern to show a few prominent peaks, with smaller weights between the peaks. Instead, we see that the weights are homogeneously large throughout the chromatograms. Moreover, we ran an analysis in which we removed one by one the most informative bins while tracking classification performance (the opposite of the ‘survival of the fittest’ procedure above). We found that performance declines gradually, and drops sharply only when there is about 20% of the least informative bins left, thus revealing that the most informative bins do not play any specific role in encoding the chemical identity of the estate (Fig. ##SUPPL##1##S7##). Altogether, these results strongly suggest that the chemical identity of an estate does not rely on the concentration of a few molecules but rather on the whole chemical spectrum.</p>", "<title>Chemical-compounds based analysis</title>", "<p id=\"Par22\">To further explore whether wine chemical identity relies on a large ensemble of molecules or a small subset, we manually extracted the area under the peak for 32 chemical compounds from the chromatograms, converted these area measurements into concentrations, and repeated the same set of analyses (16 compounds from Ester, 13 from Oak and three from offFla, see Methods for a complete list of compounds, information on internal standards and calibration strategies). In these new analyses, each wine is now characterized by a 32-dimensional vector of compound concentrations.</p>", "<p id=\"Par23\">Dimensionality reduction using either tSNE or UMAP reveals estate-specific clusters though with significantly more overlap than was observed for the maps from the raw chromatograms (Fig. ##FIG##3##4a, b##). Moreover, the right/left bank distinction is less clear, particularly in the case of tSNE which does not group the right bank wines (A, B, C) together.</p>", "<p id=\"Par24\">With regard to wine estate classification, we found the performance was markedly reduced (Fig. ##FIG##3##4c##). For instance, performance for logistic regression using oak decreased from 95% correct with the chromatograms to 78% with the oak compounds. Likewise, performance decreased from 98% to 75% for ester and 85% to 27% for offFla. This suggests that many of the smaller peaks in the chromatograms strongly contribute to the estate identity. This also shows that the traditional approach of extracting the concentration of targeted compounds is not as good as working with the raw chromatograms, and has the disadvantage of requiring extensive manual pre-processing.</p>", "<p id=\"Par25\">The results for vintages on the other hand were mixed (Fig. ##FIG##3##4d##). Oak performance for logistic regression decreased from 27% with the chromatogram to 23% with the compounds. However, we observed the reverse for ester, for which performance increased from 7% to 23%. Still in all cases, performance remained below the best vintage performance of 27%, which was obtained with the oak chromatograms.</p>", "<p id=\"Par26\">We saw previously that vintage classification performance could be improved to 50% for the chromatogram when using our survival of the fittest procedure. The same approach applied to the compound concentrations also improves performance but only to 37% correct (Fig. ##SUPPL##1##S10##). Therefore, once again, using compounds does not improve vintage classification performance and, in this case, even results in lower performance.</p>", "<p id=\"Par27\">One advantage of working with compound concentrations is that we can measure the influence of any compound on classification performance by examining the classification weights. Interestingly, we found that the weights for estate classification tend to have similar values across all compounds, indicating that most chemical compounds contribute to the identity of the estate (Fig. ##SUPPL##1##S11##). We also trained classifiers based on the concentration of single compounds, similar to our analysis based on single chromatogram bins (Fig. ##FIG##2##3b##). Some compounds lead to up to 40% correct classification on their own (such as acetosyringaldehyde, ethylbutanoate-C4C2 and ethylhexanoate-C6C2) but, remarkably, estate identity can be significantly decoded from the concentration of any of the 32 compounds (Fig. ##SUPPL##1##S12##). This brings further support to our claim that estates are not defined by the presence of a few specific chemicals but instead by the overall chemical spectrum</p>" ]	[ "<title>Discussion</title>", "<p id=\"Par28\">Gas chromatography has a long history in wine science, dating back to the 1980s, but our results revealed that this analysis might be more powerful than had been suspected hitherto. The fact that nonlinear dimensionality reduction techniques recovered the geography of the Bordeaux wine regions showed in particular that the raw gas chromatograms provide a chemical signature of terroir, i.e., a combination of the soil, rootstock, varietal, location, blend, and winemaking practices. In addition, for the seven estates we considered, estate identity can be predicted perfectly from chromatograms, independent of vintage, while vintage could be recovered with 27% accuracy, and up to 50% correct when targeting a specific part of the chromatograms.</p>", "<p id=\"Par29\">Other groups have recently started to use ML approaches to classify estates or vintages from chemical measures. In particular, Ranaweera et al.<sup>##UREF##12##25##</sup> have reported nearly perfect performance in classifying three vintages and five subregions of Barossa valley shiraz based on absorbance-transmission and fluorescence excitation-emission matrix (A-TEEM). It is not clear whether this technique could identify estates independent of vintages as we report here, but the fact that their approach could clearly distinguish vintages suggests that a combination of A-TEEM and GC might improve joint classification of estate and vintage. The study of Li et al.<sup>##UREF##7##18##</sup> is also particularly relevant for our approach given that they analyzed Australian shiraz with GC, and more specifically GC/qTOF-MS. However, they used a set of wines that are separated by up to 1500 km and included only two vintages. Moreover, they did not use raw chromatograms but manually extracted features. In that respect, our analysis is simpler since it is based on raw chromatograms. It is also cheaper as GC is considerably less expensive than GC/qTOF-MS. Nonetheless, this study complements ours in that it confirms the potential of using GC for wine classification, even for single-varietal wines.</p>", "<p id=\"Par30\">Our results also suggest that wine’s chemical identity is not defined by the concentration of just a handful of molecules. Indeed, we have found that wine classification does not depend critically on specific regions of the chromatograms and, therefore, on the concentration of specific molecules. Instead, most bins of the chromatograms contain information about estate identity. However, classification does not require the entire chromatograms for near-perfect performance; 10–20% is typically sufficient. This indicates that the information about estate identity is distributed across the whole chromatogram and that there is a large degree of redundancy in the sense that the concentration of many molecules detected by GC must be strongly correlated across estates. This conclusion was also supported by the analysis of the concentrations of 32 chemical compounds extracted manually from the chromatogram (Fig. ##FIG##3##4##), which revealed that estate identity can be significantly decoded using the concentration of any of the 32 compounds in isolation.</p>", "<p id=\"Par31\">The fact that we could perfectly identify estates, independently of vintages, suggests that the estates we have analyzed here have distinct identities. While wine experts believe that some Bordeaux estates have indeed distinct profiles, this is, to our knowledge the first time that this is demonstrated with a purely chemical analysis of Bordeaux wines. This result was by no means a foregone conclusion. Indeed, one might have worried that GC does not have the required sensitivity for this type of analysis. Ultimately, however, our results reveal that this is not an issue probably because of the redundancy in the chromatograms. As we have seen, many regions can be used to identify estates. Therefore, even if some parts of the chromatograms may not be sensitive enough, the redundancy allows to compensate by looking at other, more sensitive, regions of the chromatogram.</p>", "<p id=\"Par32\">It would be interesting to compare the performance of our model to the one of expert human tasters on blind tasting of the 80 wines we have analyzed. Whether expert wine tasters would be able to match our model’s performance (100% correct) on these seven estates is not known. More generally, it remains to be seen how a GC-based classifier would perform compared to humans on estate, region, or varietal recognition across a wide range of wines. Given our strong performance with estate recognition, artificial and GC-based systems might be able to complement human tasters on wine recognition. We note that other groups have obtained promising results using chemical analysis to predict Rate-All-That-Apply sensory attributes, using techniques that would complement the GC approach presented here<sup>##UREF##13##26##,##REF##36705733##27##</sup>.</p>", "<p id=\"Par33\">To conclude, this study demonstrates that the wine chemical identity of the seven estates considered in this study can be revealed directly from raw chromatograms, without any need for manual extraction of peaks or optimization of the choice of chromatography and ionic scanning. It is quite likely that even better results could be achieved by allowing further tuning of these experimental variables.</p>" ]	[]	[ "<p id=\"Par1\">Connecting chemical properties to various wine characteristics is of great interest to the science of olfaction as well as the wine industry. We explored whether Bordeaux wine chemical identities and vintages (harvest year) can be inferred from a common and affordable chemical analysis, namely, a combination of gas chromatography (GC) and electron ionization mass spectrometry. Using 12 vintages (within the 1990–2007 range) from 7 estates of the Bordeaux region, we report that, remarkably, nonlinear dimensionality reduction techniques applied to raw gas chromatograms recover the geography of the Bordeaux region. Using machine learning, we found that we can not only recover the estate perfectly from gas chromatograms, but also the vintage with up to 50% accuracy. Interestingly, we observed that the entire chromatogram is informative with respect to geographic location and age, thus suggesting that the chemical identity of a wine is not defined by just a few molecules but is distributed over a large chemical spectrum. This study demonstrates the remarkable potential of GC analysis to explore fundamental questions about the origin and age of wine.</p>", "<p id=\"Par2\">Gas chromatography is a useful tool to identify and characterize wines, usually by selecting some compounds for a particular classification problem, yet, with limited success. Here, the authors decode the estates perfectly and age 50% correctly of twelve red Bordeaux wines from unrestricted, raw gas chromatograms using machine learning.</p>", "<title>Subject terms</title>" ]	[ "<title>Supplementary information</title>", "<p>\n\n\n</p>" ]	[ "<title>Supplementary information</title>", "<p>The online version contains supplementary material available at 10.1038/s42004-023-01051-9.</p>", "<title>Author contributions</title>", "<p>A.P., S.M., J.M.B., and M.S. devised the analysis ideas. A.P., S.M., and M.S. wrote the manuscript. M.S. and A.P. performed the analyses. M.S. created figures. J.L., L.R., and S.M. obtained the data and devised the data type.</p>", "<title>Peer review</title>", "<title>Peer review information</title>", "<p id=\"Par48\"><italic>Communications Chemistry</italic> thanks the anonymous reviewers for their contribution to the peer review of this work. A peer review file is available.</p>", "<title>Data availability</title>", "<p>The data for this study are available at <ext-link ext-link-type=\"uri\" xlink:href=\"https://github.com/mschart/wine_decoding\">https://github.com/mschart/wine_decoding</ext-link>.</p>", "<title>Code availability</title>", "<p>All the code for the analysis presented here is open source and publicly available at: <ext-link ext-link-type=\"uri\" xlink:href=\"https://github.com/mschart/wine_decoding\">https://github.com/mschart/wine_decoding</ext-link> All figures can be readily generated from the raw data contained in the same GitHub repository.</p>", "<title>Competing interests</title>", "<p id=\"Par49\">The authors declare no competing interests.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><title>Dimensionality reduction of chromatograms reflects the geography of the Bordeaux region.</title><p><bold>a</bold> t-SNE plot of the 80 concatenated chromatograms with the first two embedding dimensions. Colors correspond to different estates while vintages appear next to each data point. The resulting map recapitulates the geography of the Bordeaux region up to a rotation, but note that the overall orientation of the t-SNE projection is arbitrary. Wines from the same estate but different vintages tend to cluster together, with little overlap between clusters. Right bank estates (A, C and B from Pomerol and St-Emilion) and left bank estates (F, G, D, and E from Medoc) also tend to cluster together. Moreover, the left bank estates are organized along a north-south axis, E and D being the furthest north, while G and F are closer to Bordeaux. <bold>b</bold> Same as (<bold>a</bold>) but with the UMAP algorithm. <bold>c</bold> The 7 estates in our data set are shown in the same colors as in (<bold>a</bold>), coming from the two regions in South-West France (inset), highlighted by the ellipses on the right (Pomerol and St-Emilion) and left (Medoc) bank of the Garonne river. The clusters follow the same general organization as for t-SNE. <bold>d</bold> t-SNE applied to varietal percentages. <bold>e</bold> same as (<bold>d</bold>) but with UMAP. In (<bold>e</bold>), the distinction between right and left bank estates is less clear, and in both (<bold>d</bold>) and (<bold>e</bold>), there is no north-south axis on the left bank and some estates (A and B, E and D) are no longer distinguishable. This suggests that the blend is not the sole contributor to the map obtained with GC.</p></caption></fig>", "<fig id=\"Fig2\"><label>Fig. 2</label><caption><title>Supervised vintage and estate decoding.</title><p><bold>a</bold> Performance histograms for decoding estate identity using two classifiers - linear discriminant analysis (LDA) and logistic regression (LR). The horizontal black line in each histogram indicates mean performance across data splits. Chance performance (14%) is shown by the dashed line. Note that the histograms are smoothed, which is why they can go beyond 100. Each peak corresponds to one of the possible accuracies per run. The best average decoding accuracy was 99% correct for LDA and concat (all three types of chromatograms concatenated together), though comparable results were observed for the oak and ester chromatograms. Performance was markedly weaker for the offFla chromatogram (87% for both, LDA and LR). <bold>b</bold> Same as in (<bold>a</bold>) but for decoding vintages. Decoding performance was smaller overall than for estate identity, however performance for LDA and LR applied to the oak chromatogram was significantly above chance (<italic>p</italic> < 0.001, 27% correct versus 8% for chance) and, to a lesser extent, for offFla chromatogram (<italic>p</italic> = 0.0012). Concatenating chromatograms did not lead to stronger performance.</p></caption></fig>", "<fig id=\"Fig3\"><label>Fig. 3</label><caption><title>Identifying most estate-informative sections of the chromatograms.</title><p><bold>a</bold> A “survival of the fittest” algorithm was applied, removing the 2% bins of the ester chromatogram that had the least effect on estate decoding accuracy, before removing the next bin one by one, until the last bin was left. Importantly, the same decoding accuracy was achieved with the best 10% of the total data than with the complete chromatogram, showing that these sections have all the estate information. The top panel shows the decoding accuracy as a function of the fraction of the data with the best decoding accuracy. The lower panel shows the five most important sections (red) on top of an example ester chromatogram (blue). The red color darkness indicates their rank in the survival algorithm, darker bins being more informative. <bold>b</bold> Estate decoding accuracy per data bin (red bars) with an overlaid example chromatogram (blue), for each chromatogram type. After dividing the chromatogram into 50 equal bins, estate decoding was performed using only single bins with LDA as in Fig. ##FIG##1##2##. Test decoding accuracy is shown in red for each bin, fluctuating fairly continuously across section locations in the chromatogram with most having above-chance (0.14) decoding accuracy. This indicates that estate chemical identity is not defined by just a few bins of the chromatogram but is distributed throughout. The fact that the decoding performance only requires 5 bins (<bold>a</bold>) suggests that the information across bins is highly redundant. Similar results were obtained for oak and offFla (Figs. ##SUPPL##1##S8##, ##SUPPL##1##S9##). <bold>c</bold>, <bold>d</bold> show the results of the same analyses performed for vintage decoding. Note that the reduction of the oak chromatogram led to a 20% increase in performance, indicating that our decoder was subject to overfitting when applied to the whole chromatogram. Decoding performance from individual bins is lower than for estate decoding yet still clearly above chance for most segments, again suggesting that vintage information is distributed throughout the chromatogram and that there is a high level of redundancy across bins.</p></caption></fig>", "<fig id=\"Fig4\"><label>Fig. 4</label><caption><title>Estate and vintage decoding from compounds.</title><p><bold>a</bold>, <bold>b</bold> Dimensionality reduction of 32 compounds via tSNE and UMAP. The estate clusters are not as well marked as with the raw chromatograms, and the right bank wines (A, B, C) are not clearly separated from the left bank ones (D, E, F, G), particularly in the tSNE case (Fig. ##FIG##0##1##). <bold>c</bold> Performance histograms for decoding estate identity from subsets of compounds, using two classifiers: Linear discriminant analysis (LDA) and logistic regression (LR), as in Fig. ##FIG##1##2##. The horizontal black line in each histogram indicates mean performance across data splits. Chance performance (14%) is shown by the dashed line. The best average decoding accuracy was 91% correct for LR and m_concat (all three types of compounds concatenated together, 32 dimensions), though comparable results were observed for the oak and ester compounds. Performance was markedly weaker for the off-Flavor (offFla) compounds (41% for LDA). Overall performance is worse than with the raw chromatograms (Fig. ##FIG##1##2##). <bold>d</bold> Same as in (<bold>c</bold>) but for decoding vintages. Decoding performance was smaller overall than for estate identity, however performance for LDA and LR was significantly above chance (<italic>p</italic> < 0.001, 8% for chance) for all but offFla. Concatenating the three compound types into m_concat leads to slightly stronger performance.</p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[ "<supplementary-material content-type=\"local-data\" id=\"MOESM1\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM2\"></supplementary-material>" ]	[ "<fn-group><fn><p><bold>Publisher’s note</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn><fn><p><bold>Change history</bold></p><p>1/11/2024</p><p>A Correction to this paper has been published: 10.1038/s42004-024-01097-3</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"42004_2023_1051_Fig1_HTML\" id=\"d32e364\"/>", "<graphic xlink:href=\"42004_2023_1051_Fig2_HTML\" id=\"d32e431\"/>", "<graphic xlink:href=\"42004_2023_1051_Fig3_HTML\" id=\"d32e484\"/>", "<graphic xlink:href=\"42004_2023_1051_Fig4_HTML\" id=\"d32e561\"/>" ]	[ "<media xlink:href=\"42004_2023_1051_MOESM1_ESM.pdf\"><caption><p>Peer Review File</p></caption></media>", "<media xlink:href=\"42004_2023_1051_MOESM2_ESM.pdf\"><caption><p>Supplementary Material</p></caption></media>" ]	[{"label": ["1."], "surname": ["van Leeuwen", "Darriet"], "given-names": ["C", "P"], "article-title": ["The impact of climate change on viticulture and wine quality"], "source": ["J. Wine Econ."], "year": ["2016"], "volume": ["11"], "fpage": ["150"], "lpage": ["167"], "pub-id": ["10.1017/jwe.2015.21"]}, {"label": ["2."], "surname": ["van Leeuwen"], "given-names": ["C"], "article-title": ["Recent advancements in understanding the terroir effect on aromas in grapes and wines"], "source": ["Oeno. One"], "year": ["2020"], "volume": ["54"], "fpage": ["985"], "lpage": ["1006"]}, {"label": ["4."], "mixed-citation": ["Cosme, F., et al. Authentication of Douro DO monovarietal red wines based on anthocyanin profile: comparison of partial least squares\u2014discriminant analysis, decision trees, and artificial neural networks. "], "italic": ["Food Control"], "bold": ["125"]}, {"label": ["5."], "surname": ["Da Costa", "Valentin", "Castro", "Barbosa"], "given-names": ["NL", "LA", "IA", "RM"], "article-title": ["Predictive modeling for wine authenticity using a machine learning approach"], "source": ["Artif. Intell. Agric."], "year": ["2021"], "volume": ["5"], "fpage": ["157"], "lpage": ["162"]}, {"label": ["6."], "mixed-citation": ["Valls Fonayet, J., Loupit, G., & Richard, T. MS- and NMR-metabolomic tools for the discrimination of wines: Applications for authenticity. In "], "italic": ["Advances in Botanical Research"]}, {"label": ["10."], "surname": ["Koundouras"], "given-names": ["S"], "article-title": ["Environmental and viticultural effects on grape composition and wine sensory properties"], "source": ["Elements"], "year": ["2018"], "volume": ["14"], "fpage": ["173"], "lpage": ["178"], "pub-id": ["10.2138/gselements.14.3.173"]}, {"label": ["14."], "surname": ["Ferreira", "L\u00f3pez", "Escudero", "Cacho"], "given-names": ["V", "R", "A", "JF"], "article-title": ["Quantitative determination of trace and ultratrace flavor active compounds in red wines through gas chromatographic\u2013ion trap mass spectrometric analysis of microextracts"], "source": ["J. Chromatogr. A"], "year": ["1998"], "volume": ["806"], "fpage": ["349"], "lpage": ["354"], "pub-id": ["10.1016/S0021-9673(98)00070-3"]}, {"label": ["18."], "surname": ["Li", "Blackman", "Schmidtke"], "given-names": ["S", "JW", "LM"], "article-title": ["Exploring the regional typicality of Australian Shiraz wines using untargeted metabolomics"], "source": ["Aust. J. Grape Wine Res."], "year": ["2021"], "volume": ["27"], "fpage": ["378"], "lpage": ["391"], "pub-id": ["10.1111/ajgw.12493"]}, {"label": ["20."], "surname": ["Bramley", "Ouzman"], "given-names": ["RGV", "J"], "article-title": ["Underpinning terroir with data: on what grounds might subregionalization of the Barossa Zone geographical indication be justified?"], "source": ["Aust. J. Grape Wine Res."], "year": ["2022"], "volume": ["28"], "fpage": ["196"], "lpage": ["207"], "pub-id": ["10.1111/ajgw.12513"]}, {"label": ["21."], "surname": ["Pearson"], "given-names": ["W"], "article-title": ["Regionality in Australian Shiraz: compositional and climate measures that relate to key sensory attributes"], "source": ["Aust. J. Grape Wine Res."], "year": ["2021"], "volume": ["27"], "fpage": ["458"], "lpage": ["471"], "pub-id": ["10.1111/ajgw.12499"]}, {"label": ["22."], "mixed-citation": ["Koranga, M. Pandey, R., Joshi, M. & Kumar, M. Analysis of white wine using machine learning algorithms. "], "italic": ["Materials Today: Proceedings"]}, {"label": ["24."], "mixed-citation": ["Laboyrie, J. (2020). Composition et origine du bouquet de vieillissement des vins rouges de Bordeaux. "], "italic": ["Influences du terroir dans l\u2019expression aromatique des vins vieux"]}, {"label": ["25."], "surname": ["Ranaweera", "Bastian", "Gilmore", "Capone", "Jeffery"], "given-names": ["RKR", "SEP", "AM", "DL", "DW"], "article-title": ["Absorbance-transmission and fluorescence excitation-emission matrix (A-TEEM) with multi-block data analysis and machine learning for accurate intraregional classification of Barossa Shiraz wine"], "source": ["Food Control"], "year": ["2023"], "volume": ["144"], "fpage": ["109335"], "pub-id": ["10.1016/j.foodcont.2022.109335"]}, {"label": ["26."], "surname": ["Souza Gonzaga", "Bastian", "Capone", "Ranaweera", "Jeffery"], "given-names": ["L", "SEP", "DL", "RKR", "DW"], "article-title": ["Modelling Cabernet-Sauvignon wine sensory traits from spectrofluorometric data"], "source": ["OENO One"], "year": ["2021"], "volume": ["55"], "fpage": ["19"], "lpage": ["33"], "pub-id": ["10.20870/oeno-one.2021.55.4.4805"]}, {"label": ["28."], "surname": ["Antalick", "Perello", "de Revel"], "given-names": ["G", "M-C", "G"], "article-title": ["Development, validation, and application of a specific method for the quantitative determination of wine esters by headspace-solid-phase microextraction-gas chromatography\u2013mass spectrometry"], "source": ["Food Chem."], "year": ["2010"], "volume": ["121"], "fpage": ["1236"], "lpage": ["1245"], "pub-id": ["10.1016/j.foodchem.2010.01.011"]}, {"label": ["31."], "surname": ["van der Maaten", "Hinton"], "given-names": ["L", "G"], "article-title": ["Visualizing Data using t-SNE"], "source": ["J. Mach. Learn. Res."], "year": ["2008"], "volume": ["9"], "fpage": ["2579"], "lpage": ["2605"]}, {"label": ["32."], "mixed-citation": ["McInnes, L., Healy, J. & Melville, J. UMAP: Uniform manifold approximation and projection for dimension reduction. arXiv:1802.03426 [cs, stat] (2020)."]}, {"label": ["33."], "surname": ["Pedregosa"], "given-names": ["F"], "article-title": ["Scikit-learn: Machine Learning in Python"], "source": ["J. Mach. Learn. Res."], "year": ["2011"], "volume": ["12"], "fpage": ["2825"], "lpage": ["2830"]}]	{ "acronym": [], "definition": [] }	34	CC BY	no	2024-01-13 23:36:43	Commun Chem. 2023 Dec 5; 6:247	oa_package/5d/9e/PMC10698164.tar.gz
PMC10699810	0	[]	[]	[]	[]	[]	[ "<p>\n<bold>Note:</bold> This Comment is being published simultaneously in multiple journals. For the full list of journals see: https://www.bmj.com/content/full-list-authors-and-signatories-climate-nature-emergency-editorial-october-2023</p>", "<p>\n<bold>Citation:</bold> Abbasi K, Ali P, Barbour V, et al. Time to treat the climate and nature crisis as one indivisible global health emergency. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8307. doi:10.34172/ijhpm.2023.8307</p>" ]	[ "<p> Over 200 health journals call on the United Nations (UN), political leaders, and health professionals to recognise that climate change and biodiversity loss are one indivisible crisis and must be tackled together to preserve health and avoid catastrophe. This overall environmental crisis is now so severe as to be a global health emergency.</p>", "<p> The world is currently responding to the climate crisis and the nature crisis as if they were separate challenges. This is a dangerous mistake. The 28th Conference of the Parties (COP) on climate change is about to be held in Dubai while the 16th COP on biodiversity is due to be held in Turkey in 2024. The research communities that provide the evidence for the two COPs are unfortunately largely separate, but they were brought together for a workshop in 2020 when they concluded that: “Only by considering climate and biodiversity as parts of the same complex problem…can solutions be developed that avoid maladaptation and maximize the beneficial outcomes.”<sup>##UREF##0##1##</sup></p>", "<p> As the health world has recognised with the development of the concept of planetary health, the natural world is made up of one overall interdependent system. Damage to one subsystem can create feedback that damages another—for example, drought, wildfires, floods and the other effects of rising global temperatures destroy plant life, and lead to soil erosion and so inhibit carbon storage, which means more global warming.<sup>##UREF##1##2##</sup> Climate change is set to overtake deforestation and other land-use change as the primary driver of nature loss.<sup>##UREF##2##3##</sup></p>", "<p> Nature has a remarkable power to restore. For example, deforested land can revert to forest through natural regeneration, and marine phytoplankton, which act as natural carbon stores, turn over one billion tonnes of photosynthesising biomass every eight days.<sup>##REF##22378122##4##</sup> Indigenous land and sea management has a particularly important role to play in regeneration and continuing care.<sup>##UREF##3##5##</sup></p>", "<p> Restoring one subsystem can help another—for example, replenishing soil could help remove greenhouse gases from the atmosphere on a vast scale.<sup>##UREF##4##6##</sup> But actions that may benefit one subsystem can harm another—for example, planting forests with one type of tree can remove carbon dioxide from the air but can damage the biodiversity that is fundamental to healthy ecosystems.<sup>##UREF##5##7##</sup></p>", "<title>The Impacts on Health</title>", "<p> Human health is damaged directly by both the climate crisis, as the journals have described in previous editorials,<sup>##REF##34483099##8##,##REF##36257789##9##</sup> and by the nature crisis.<sup>##UREF##6##10##</sup> This indivisible planetary crisis will have major effects on health as a result of the disruption of social and economic systems — shortages of land, shelter, food, and water, exacerbating poverty, which in turn will lead to mass migration and conflict. Rising temperatures, extreme weather events, air pollution, and the spread of infectious diseases are some of the major health threats exacerbated by climate change.<sup>##UREF##7##11##</sup> “Without nature, we have nothing,” was UN Secretary-General António Guterres’s blunt summary at the biodiversity COP in Montreal last year.<sup>##UREF##8##12##</sup> Even if we could keep global warming below an increase of 1.5 °C over pre-industrial levels, we could still cause catastrophic harm to health by destroying nature.</p>", "<p> Access to clean water is fundamental to human health, and yet pollution has damaged water quality, causing a rise in water-borne diseases.<sup>##UREF##9##13##</sup> Contamination of water on land can also have far-reaching effects on distant ecosystems when that water runs off into the ocean.<sup>##REF##34087665##14##</sup> Good nutrition is underpinned by diversity in the variety of foods, but there has been a striking loss of genetic diversity in the food system. Globally, about a fifth of people rely on wild species for food and their livelihoods.<sup>##UREF##10##15##</sup> Declines in wildlife are a major challenge for these populations, particularly in low- and middle-income countries. Fish provide more than half of dietary protein in many African, South Asian and small island nations, but ocean acidification has reduced the quality and quantity of seafood.<sup>##REF##32599924##16##</sup></p>", "<p> Changes in land use have forced tens of thousands of species into closer contact, increasing the exchange of pathogens and the emergence of new diseases and pandemics.<sup>##UREF##11##17##</sup> People losing contact with the natural environment and the declining loss in biodiversity have both been linked to increases in noncommunicable, autoimmune, and inflammatory diseases and metabolic, allergic and neuropsychiatric disorders.<sup>##UREF##6##10##,##REF##32328397##18##</sup> For Indigenous people, caring for and connecting with nature is especially important for their health.<sup>##REF##28659102##19##</sup> Nature has also been an important source of medicines, and thus reduced diversity also constrains the discovery of new medicines.</p>", "<p> Communities are healthier if they have access to high-quality green spaces that help filter air pollution, reduce air and ground temperatures, and provide opportunities for physical activity.<sup>##UREF##12##20##</sup> Connection with nature reduces stress, loneliness and depression while promoting social interaction.<sup>##REF##30208869##21##</sup> These benefits are threatened by the continuing rise in urbanisation.<sup>##REF##35286193##22##</sup></p>", "<p> Finally, the health impacts of climate change and biodiversity loss will be experienced unequally between and within countries, with the most vulnerable communities often bearing the highest burden.<sup>##UREF##6##10##</sup> Linked to this, inequality is also arguably fuelling these environmental crises. Environmental challenges and social/health inequities are challenges that share drivers and there are potential co-benefits of addressing them.<sup>##UREF##6##10##</sup></p>", "<title>A Global Health Emergency</title>", "<p> In December 2022 the biodiversity COP agreed on the effective conservation and management of at least 30% percent of the world’s land, coastal areas, and oceans by 2030.<sup>##UREF##13##23##</sup> Industrialised countries agreed to mobilise $30 billion per year to support developing nations to do so.<sup>##UREF##13##23##</sup> These agreements echo promises made at climate COPs.</p>", "<p> Yet many commitments made at COPs have not been met. This has allowed ecosystems to be pushed further to the brink, greatly increasing the risk of arriving at ‘tipping points,’ abrupt breakdowns in the functioning of nature.<sup>##UREF##1##2##,##REF##36074831##24##</sup> If these events were to occur, the impacts on health would be globally catastrophic.</p>", "<p> This risk, combined with the severe impacts on health already occurring, means that the World Health Organization (WHO) should declare the indivisible climate and nature crisis as a global health emergency. The three pre-conditions for the WHO to declare a situation to be a Public Health Emergency of International Concern<sup>##UREF##14##25##</sup> are that it: (1) is serious, sudden, unusual or unexpected; (2) carries implications for public health beyond the affected State’s national border; and (3) may require immediate international action. Climate change would appear to fulfil all of those conditions. While the accelerating climate change and loss of biodiversity are not sudden or unexpected, they are certainly serious and unusual. Hence we call for WHO to make this declaration before or at the Seventy-seventh World Health Assembly in May 2024.</p>", "<p> Tackling this emergency requires the COP processes to be harmonised. As a first step, the respective conventions must push for better integration of national climate plans with biodiversity equivalents.<sup>##UREF##2##3##</sup> As the 2020 workshop that brought climate and nature scientists together concluded, “Critical leverage points include exploring alternative visions of good quality of life, rethinking consumption and waste, shifting values related to the human-nature relationship, reducing inequalities, and promoting education and learning.”<sup>##UREF##0##1##</sup> All of these would benefit health.</p>", "<p> Health professionals must be powerful advocates for both restoring biodiversity and tackling climate change for the good of health. Political leaders must recognise both the severe threats to health from the planetary crisis as well as the benefits that can flow to health from tackling the crisis.<sup>##UREF##15##26##</sup> But first, we must recognise this crisis for what it is: a global health emergency.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["1"], "mixed-citation": [" P\u00f6rtner HO, Scholes RJ, Agard J, et al. Scientific Outcome of the IPBES-IPCC Co-Sponsored Workshop on Biodiversity and Climate Change. Bonn: IPBES; 2021. "], "pub-id": ["10.5281/zenodo.4659159"]}, {"label": ["2"], "person-group": ["\n"], "surname": ["Ripple", "Wolf", "Lenton"], "given-names": ["WJ", "C", "TM"], "article-title": ["Many risky feedback loops amplify the need for climate action"], "source": ["One Earth"], "year": ["2023"], "volume": ["6"], "issue": ["2"], "fpage": ["86"], "lpage": ["91"], "pub-id": ["10.1016/j.oneear.2023.01.004"]}, {"label": ["3"], "mixed-citation": [" European Academies\u2019 Science Advisory Council (EASAC). Key Messages from European Science Academies for UNFCCC COP26 and CBD COP15. EASAC; 2021. "], "uri": ["https://easac.eu/publications/details/key-messages-from-european-science-academies-for-unfccc-cop26-and-cbd-cop15"]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Dawson", "Coolsaet", "Sterling"], "given-names": ["NM", "B", "EJ"], "article-title": ["The role of Indigenous peoples and local communities in effective and equitable conservation"], "source": ["Ecol Soc"], "year": ["2021"], "volume": ["26"], "issue": ["3"], "fpage": ["19"], "pub-id": ["10.5751/es-12625-260319"]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Bossio", "Cook-Patton", "Ellis"], "given-names": ["DA", "SC", "PW"], "article-title": ["The role of soil carbon in natural climate solutions"], "source": ["Nat Sustain"], "year": ["2020"], "volume": ["3"], "issue": ["5"], "fpage": ["391"], "lpage": ["398"], "pub-id": ["10.1038/s41893-020-0491-z"]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Levia", "Creed", "Hannah"], "given-names": ["DF", "IF", "DM"], "article-title": ["Homogenization of the terrestrial water cycle"], "source": ["Nat Geosci"], "year": ["2020"], "volume": ["13"], "issue": ["10"], "fpage": ["656"], "lpage": ["658"], "pub-id": ["10.1038/s41561-020-0641-y"]}, {"label": ["10"], "mixed-citation": [" WHO, UNEP, Convention on Biological Diversity. Connecting Global Priorities: Biodiversity and Human Health: A State of Knowledge Review. 2015. "], "uri": ["https://www.cbd.int/health/SOK-biodiversity-en.pdf"]}, {"label": ["11"], "mixed-citation": [" Magnano San Lio R, Favara G, Maugeri A, Barchitta M, Agodi A. How antimicrobial resistance is linked to climate change: an overview of two intertwined global challenges. Int J Environ Res Public Health 2023;20(3). "], "pub-id": ["10.3390/ijerph20031681"]}, {"label": ["12"], "mixed-citation": [" Jelskov U. \u201cWithout Nature, We Have Nothing\u201d: UN Chief Sounds Alarm at Key UN Biodiversity Event. UN News; 2022. "], "uri": ["https://news.un.org/en/story/2022/12/1131422"]}, {"label": ["13"], "mixed-citation": [" World Health Organization (WHO). State of the World\u2019s Drinking Water: An Urgent Call to Action to Accelerate Progress on Ensuring Safe Drinking Water for All. WHO; 2022. "], "uri": ["https://www.who.int/publications/i/item/9789240060807"]}, {"label": ["15"], "mixed-citation": [" Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES). Assessment Report on the Sustainable Use of Wild Species. IPBES; 2022. "], "uri": ["https://www.ipbes.net/sustainable-use-assessment"]}, {"label": ["17"], "mixed-citation": [" Dunne D. Climate Change \u201cAlready\u201d Raising Risk of Virus Spread Between Mammals. Carbon Brief; 2022. "], "uri": ["https://www.carbonbrief.org/climate-change-already-raising-risk-of-virus-spread-between-mammals/"]}, {"label": ["20"], "mixed-citation": [" Macguire F, Mulcahy E, Rossington B. The Lancet Countdown on Health and Climate Change: Policy Brief for the UK. 2022. "], "uri": ["https://s41874.pcdn.co/wp-content/uploads/Lancet-Countdown-2022-UK-Policy-Brief_EN.pdf"]}, {"label": ["23"], "mixed-citation": [" Secretariat of the Convention on Biological Diversity. COP15: Nations Adopt Four Goals, 23 Targets for 2030 In Landmark UN Biodiversity Agreement. Convention on Biological Diversity; 2022. "], "uri": ["https://www.cbd.int/article/cop15-cbd-press-release-final-19dec2022"]}, {"label": ["25"], "mixed-citation": [" World Health Organization (WHO). WHO Guidance for the Use of Annex 2 of the International Health Regulations (2005). WHO; 2010. "], "uri": ["https://www.who.int/publications/m/item/who-guidance-for-the-use-of-annex-2-of-the-international-health-regulations-(2005)"]}, {"label": ["26"], "mixed-citation": [" Australian Government Department of Health and Aged Care. Consultation on Australia\u2019s first National Health and Climate Strategy. Australian Government Department of Health and Aged Care; 2023. "], "uri": ["https://www.health.gov.au/news/consultation-on-australias-first-national-health-and-climate-strategy"]}]	{ "acronym": [], "definition": [] }	26	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 25; 12:8307	oa_package/2c/66/PMC10699810.tar.gz
PMC10699811	0	[ "<title>Background</title>", "<p> Ensuring universal and equitable access to essential medicines is an important contributor towards universal health coverage in low- and middle-income countries (LMICs). Successful implementation of effective health policies is a critical mechanism by which national governments can address their population’s health needs, especially the poorest and most vulnerable.<sup>##UREF##0##1##,##REF##29702846##2##</sup></p>", "<p> Medicine pricing policies are priorities of most governments in LMICs,<sup>##UREF##1##3##, ####UREF##2##4##, ##REF##36457058##5####36457058##5##</sup> and can target various stages of the supply chain, from manufacturing to retailing.<sup>##UREF##0##1##,##REF##28063134##6##,##REF##35209945##7##</sup> The use of a regulatory framework is a major approach to managing medicines prices.<sup>##UREF##3##8##, ####REF##31357098##9##, ##REF##23057369##10##, ##UREF##4##11##, ##UREF##5##12####5##12##</sup> For example, at the manufacturing end, pharmaceutical companies can be incentivized by the government through policies such as value-added tax (VAT) exemptions or bulk purchases to reduce their ex-factory prices.<sup>##UREF##0##1##,##UREF##1##3##</sup> At the retail level, prices can be regulated through standardized markup regimes and the promotion of substitution of high-priced branded medicines with quality-assured generic and biosimilar medicines.<sup>##UREF##1##3##,##UREF##3##8##</sup> Additionally, governments can regulate the entry of high-priced medicines through cost or risk sharing.<sup>##REF##25461860##13##</sup></p>", "<p> Implementations of medicines pricing policies typically involve diverse policy actors including government,<sup>##UREF##6##14##, ####REF##31365534##15##, ##UREF##7##16####7##16##</sup> wholesalers,<sup>##REF##23057369##10##,##UREF##8##17##</sup> manufacturers,<sup>##REF##31365534##15##, ####UREF##7##16##, ##UREF##8##17##, ##REF##28903757##18####28903757##18##</sup> professional bodies<sup>##UREF##4##11##,##UREF##7##16##,##REF##30478491##19##</sup> public and private health facilities.<sup>##UREF##4##11##,##REF##30891247##20##</sup> Actors’ engagements in policy implementation are influenced by multiple contextual enablers or barriers such as the presence (or absence) of robust implementation and impact monitoring systems<sup>##REF##25073407##21##,##REF##26239041##22##</sup> and the related (in)adequate policy-makers’ understanding of expected outcomes.<sup>##REF##23057369##10##,##REF##17546309##23##</sup> Understanding the context can therefore help answer important questions related to how and why the implementation of health policies occurs and what understanding it can shed on the observed versus the desired policy outcomes.</p>", "<p> Policy implementation is complex and the processes, actors, context, and content of policy interact to influence achievement of policy outcomes.<sup>##REF##10139469##24##</sup> An in-depth understanding of medicines pricing policies, including their implementation processes, actors involved, and contextual influences can therefore inform interventions to improve effectiveness of these policies in improving access to medicines. While research exists on the implementation of medicine pricing policies covering processes,<sup>##UREF##3##8##,##REF##23057369##10##,##UREF##4##11##</sup> actors’ involvement,<sup>##UREF##5##12##,##UREF##7##16##,##REF##30478491##19##</sup> and contextual barriers and enablers,<sup>##REF##30891247##20##,##REF##15098277##25##,##UREF##9##26##</sup> this body of knowledge remains rather fragmented and comprehensive analyses are particularly limited from LMICs.</p>", "<p> Since 2017, the Government of Ghana has tried to improve medicine pricing and access to essential medicines (ie, medicines that satisfy healthcare needs of Ghanaians)<sup>##UREF##10##27##</sup> by implementing policies related to VAT exemptions for selected imported pharmaceutical products and a framework contracting (FC).<sup>##UREF##11##28##,##UREF##12##29##</sup> The expected outcome of the VAT exemption policy is a 30% reduction in the National Health Insurance Scheme (NHIS) medicines tariffs,<sup>##UREF##13##30##, ####UREF##14##31##, ##UREF##15##32####15##32##</sup> whereas the intended outcome of the FC policy is a centralized procurement process for bulk purchase and negotiated reduced prices of high-demand essential medicines.<sup>##UREF##16##33##</sup></p>", "<p> The VAT exemption policy involved the review of the 2015 VAT Exemption Regulations (L.I 2218),<sup>##UREF##17##34##</sup> amendment of the VAT law,<sup>##UREF##18##35##</sup> and promulgation of the VAT Exemption Regulations 2017 (L.I 2255).<sup>##UREF##11##28##</sup> A total of 552 Active Pharmaceutical Ingredients (APIs,) manufacturing inputs and packaging materials, and 483 imported finished pharmaceutical products were exempted from VAT.<sup>##UREF##11##28##</sup> Under the FC policy, an agreement was made with selected vendors to supply essential medicines at negotiated prices.<sup>##UREF##16##33##</sup> The FC policy was a recommendation of the 2012 Health Commodity Supply Chain Master Plan.<sup>##UREF##19##36##</sup> Both VAT exemptions and FC policies have been implemented since 2018, and therefore represent relevant case studies to understand the implementation of medicines pricing policies in Ghana.</p>", "<p> This paper seeks to contribute to bridging the aforementioned knowledge gaps by reporting our analysis of the implementation of VAT exemptions for selected imported pharmaceutical products and the FC in Ghana. Our research questions were: In what way did the policy contents for VAT exemptions and FC policies shaped the implementation (specifically, duration and degree of formality) of these policies? How has involvement of policy actors shaped the implementation of medicines pricing policies? Which contextual enablers and barriers affected the implementation of these policies? In what way has the interplay between contents, context and actors affected the implementation of medicines pricing policies and the achievement of intended policy outcomes?</p>", "<p> We hope this paper will be of interest, and relevance, to different stakeholders including designers and implementers of medicines pricing policies, private sector stakeholders interested in engaging with the implementation of national or sub-national policies, and scholars interested in advancing their understanding of policy analysis in LMICs.</p>" ]	[ "<title>Methods</title>", "<p> This paper builds on and consolidates, results of our systematic review<sup>##REF##36457058##5##</sup> and stakeholder analyses<sup>##UREF##7##16##</sup> from an AMIPS (Access to Medicines through Improved Pricing Strategies) study which examined implementation of four medicines pricing policies in order to inform improved policy implementation and contribute to improved access to essential medicines in Ghana. A cross-sectional qualitative study design was used.</p>", "<title> Data Collection</title>", "<p> Data were collected through document reviews, in-depth interviews (IDIs), focus group discussions (FGDs), and consultative meetings with purposefully identified informants.</p>", "<p> Using policy document reviews, we mapped the contents of each policy, their implementation processes, policy actors involved and revealed documented barriers and enablers. The documents were sourced from the Ministry of Health (MoH) website, MoH Pharmacy Directorate, and Google Scholar. We reviewed legislative instruments, Parliament reports, NHIS Medicines List, and technical working group (TWG) meeting reports (n = 18). Our main inclusion criterion was relevance to FC and VAT exemptions for pharmaceutical products. Documents with core focus on other medicines’ pricing policies were excluded. Examples of specific documents included the report of the Committee on Subsidiary Legislation on the VAT Exemptions Regulations (L.I 2255) (October 2017), the Local Pharmaceutical Production Committee on the review of restricted list report (December 2016), and procurement of essential medicines through FC report (November 2019).</p>", "<p> A total of 30 IDIs were conducted from August 2020 to March 2021, to understand FC and VAT exemptions policy implementation processes, actors involved, and contextual influences. The anonymized respondents’ profiles are shown in ##TAB##0##Table 1##.<sup>##UREF##7##16##</sup> Respondents were purposefully identified from the documents and using snowballing from the previous IDIs and consultative meetings. A question guide was utilised for the IDIs (See ##SUPPL##0##Supplementary file 1##), which was semi-structured by implementation processes, timelines, actors involved, and contextual barriers and enablers to policy implementation. The IDIs were conducted via telephone, zoom, or in person as feasible, and each preceded by obtaining verbal or written informed consent. All IDIs were in English, lasted on average 45 minutes, were digitally recorded, transcribed verbatim, and anonymised for analysis.</p>", "<p> Two urban health facilities were purposively selected because we were able to obtain the requisite numbers of participants for an FGD and the required space to observe all COVID-19 safety protocols as prescribed by the Ghana Health Service (GHS). The FGDs were conducted in February 2021 with public healthcare professionals to understand their views on the policy implementation processes, barriers, and enablers. The FGDs were held in Accra, and in each facility, ten individuals with professional backgrounds in procurement and supplies, purchasing, administration, and pharmacy participated. They were conducted in person, lasted on average 1 hour and 20 minutes, and consent was obtained for participation and to record proceedings. The discussion notes were transcribed verbatim and anonymised for analysis.</p>", "<p> Six consultative meetings were held throughout the study to communicate and validate emerging findings with relevant stakeholders. The meetings were held between October 2020 and May 2021 and involved the National Medicines Pricing Committee (NMPC) (October 2020, April 2021), pharmaceutical sector stakeholders (December 2020), medicine price mark-up working group (December 2020), Society of Private Medical and Dental Practitioners (February 2021) and NMPC and pharmaceutical sector stakeholders (May 25, 2021). These meetings were organised in collaboration with the MoH Pharmacy Directorate. The MoH invited attendees and meetings lasted four hours on average. During meetings, the MoH representatives and members of the study team led discussions on medicines pricing implementation processes, barriers and enablers, potential solutions, and the uptake of study findings for policy and practice. The researchers took notes at all meetings to reduce recall bias, which were subsequently analysed alongside formal minutes. To further address potential recall bias and improve quality, data sourced from interviews, document reviews, and consultative meetings were triangulated.</p>", "<title> Data Analysis</title>", "<p> Thematic content analysis was used, which followed a framework method for analyzing qualitative data.<sup>##REF##24047204##37##</sup> Framework method involves seven steps: (1) transcription, (2) familiarization with the data, (3) coding, (4) developing a working analytical framework, (5) applying the analytical framework, (6) charting data into the framework matrix, and (7) interpreting the data.</p>", "<p> Following transcription, the anonymized interview transcripts, documents reviews, and researchers’ notes from the consultative meetings were initially examined by AK and LB to familiarize with the whole dataset. The data was then coded for analysis using the four components of the Walt and Gilson’s health policy triangle: actors, contents, contexts, and processes.<sup>##REF##10139469##38##</sup></p>", "<p> The policy triangle constituted our working analytical framework, to help explain how and why the policies were implemented, and key influences on policy processes from actors, contents, and contexts. Actors denote individuals, organizations, groups and governments and their actions and inactions that affect the policy. Content refers to the substance of the policy which details its constituent part. Context includes systemic factors such as political, economic, social or cultural, national, and international which may have influenced the policy implementation. Processes refer to ways in which a policy is initiated, developed, and implemented.<sup>##REF##10139469##38##</sup> The four parameters of the policy triangle are interrelated, for example, actors’ (in)actions are influenced by the context in which policies are implemented. Policy actors can exercise their power to influence policy decisions as they engage in the policy process<sup>##UREF##7##16##</sup> and can sometimes form alliances through negotiation, consultation, and consensus building. <sup>##UREF##20##39##</sup> The policy content can shape implementation modalities, for example through building mechanisms for rapport and trust with communities. Contextual environment influences implementation processes, contents, and actors.<sup>##REF##10139469##38##</sup> To better understand the context, we relied on the three-tier framework comprising macro (national and international political and economic influences), meso (organizational practices and structures), and micro (individual interests and preferences) levels.<sup>##UREF##21##40##</sup></p>", "<p> The analytical framework was then applied to the coded interview transcripts, insights from documents reviews, and researchers’ notes from the consultative meetings, to identify common patterns of meaning based on the research questions. The emerging results were further grouped and reviewed to generate a thematic map of the findings, corresponding to the four themes and reflecting our research questions ie, (1) policy content influence on VAT exemption and FC policy implementation processes, (2) actors roles/influence on VAT exemption and FC policies implementation processes, (3) contextual factors influence on VAT exemption and FC policies implementation processes, and (4) interplay between policy content, actors’ roles and context on policy implementation outcomes.</p>", "<p> The findings were further interpreted, specifically examining potential linkages between the four themes to identify the interplay between policy contents, actors and contexts in relation to the policy implementation and achievement of policy outcomes.</p>" ]	[ "<title>Results</title>", "<p> The four analytical themes relate to our research questions and provide a structure for our results. Following reporting influences of contents, actors and then contexts on policy implementation, we reflect on the complex interplay between these in shaping the implementation processes.</p>", "<p>\n##TAB##1##Table 2## summarizes the influences of policy contents, actors, and context on the implementation processes and resulting policy outcome for the FC and VAT exemption policies. Each of these is further explained in the next sections.</p>", "<title> Influences of Policy Contents on Implementation Processes</title>", "<p> Our analysis revealed two main implications of how policy contents (ie, nature and complexity) affected policy implementations: effects on implementation duration and degree of formality of implementation processes. The FC policy — which sought to create a centralized procurement process for the bulk purchase of selected essential medicines and negotiate medicine prices with vendors and by so doing standardize the tendering processes for the framework agreement — had a long implementation duration. The complex nature of the FC policy shaped the implementation structures and demanded a long process of selection, quantification, tendering evaluation, and negotiation of pricing model with several vendors per each implementation cycle (##FIG##0##Figures 1## and ##FIG##1##2##). The FC implementation has gone through three phases with high volume, high value and high supply risk essential medicines selected and quantified by key policy actors (See ##SUPPL##1##Supplementary file 2## for FC selected essential medicines). On the other hand, VAT exemption policy implementation required a much simpler process, involving an application for VAT exemptions with the required documentation as shown in ##FIG##2##Figure 3##. Data from interviews showed that responsible agencies in a sequential manner reviewed and approved applications and if all required documents were accurate and uploaded, approval was obtained within an average of 14 days.</p>", "<p> The policy content also influenced the degree of formality of the implementation processes. The VAT exemption policy is Legislative Instrument 2255, a revised version of the Legislative Instrument 2218 approved by the Parliament of Ghana for implementation. Because LI 2255 is a revised version, there were already existing implementation structures to support the process, as noted by one respondent,</p>", "<p> “<italic toggle=\"yes\">There were existing structures put in place for Ghana Revenue Authority to provide VAT exemptions to qualified applicants</italic>” [Public Sector].</p>", "<p> During FC policy implementation there were formal engagements with stakeholders as mandated by the Public Procurement Authority standard tender documents, however, the required meetings with vendors rather lengthened the implementation.</p>", "<title> Influences of Policy Actors on the Implementation Processes</title>", "<p> The main influence of policy actors over policy implementation is degree of actors’ participation and resultant implications on efficiency of decision-making. There was a high degree of participation of varied stakeholders for FC and VAT exemption policies, creating avenues for decision-making and promoting inclusiveness. TWGs with multiple stakeholders were created for both policy implementation processes (see ##TAB##1##Table 2##) and these TWGs made decisions on selected medicines for implementation, tendering processes, exemptions applications, price negotiations, and coordination of the implementation processes.</p>", "<p> “<italic toggle=\"yes\">We tried to involve all relevant stakeholders from the beginning, and this was very important for the Ministry of Health to have engaging and participatory processes with all hands-on deck”</italic> [Public Sector].</p>", "<p> As national policies, there was inherent multi and cross-sectoral collaboration, however, the VAT exemption policy implementation was more cross-sectoral because of its nature and therefore involved a wider range of actors such as the Parliament which provided high political support. On the other hand, the FC policy was more ‘technical’ with several steps and decisions around tendering, procurement, and price negotiations requiring actors with technical expertise in tendering, procurement, and price negotiations.</p>", "<p> Although implementation processes were generally dominated by government agencies, as some of these agencies are mandated to ensure access to health and/or facilitate the implementation, notably non-state actors such as pharmaceutical industry were involved in the implementation decisions. The local pharmaceutical industry actors participated in the national competitive tendering process and importation of APIs, manufacturing inputs, and finished products. Further details of the policy actors’ powers, engagement, and resultant influences over FC and VAT exemptions are reported elsewhere.<sup>##UREF##7##16##</sup></p>", "<title> Contextual Influences on the Implementation Process</title>", "<p> Three contextual enablers were identified from our analysis. First, high political support and will. For instance, the minister of health signed the memorandum of understanding (MOU) with the vendors as his commitment to the FC implementation. Also, the intent to abolish the 17.5% VAT on selected finished imported medicines not produced in Ghana was stated in the 2016 manifesto of the government in power.<sup>##UREF##22##41##</sup> This intention was further captured in the national 2017 Budget Statement and Financial policy with the Ministries of Finance and Health tasked to implement.<sup>##UREF##13##30##</sup></p>", "<p> “<italic toggle=\"yes\">There was high political will and increased leadership commitment for VAT exemption policy implementation and the Parliament was supportive” </italic>[Professional Association].</p>", "<p> Second, the implementation of already existing policies. The existence of VAT Regulations 2015 (L.I 2218)<sup>##UREF##17##34##</sup> allowed for timely promulgation of the VAT (Amendment) Regulation 2017 (L.I 2255)<sup>##UREF##11##28##</sup> which spelled out the selected pharmaceutical products, raw materials, and packaging materials to be exempted. Additionally, existing national structures, for example, the Public Procurement Laws (Act 663 and Act 914)<sup>##UREF##23##42##,##UREF##24##43##</sup> and national medicines policy<sup>##UREF##2##4##</sup> augmented the FC policy implementation in terms of promoting access to quality affordable medicines through a national competitive tendering process.</p>", "<p> Third, institutional capacities. The sufficient capacity of the MoH together with its agencies such as the National Health Insurance Authority (NHIA) to negotiate with pharmaceutical industry players and agree on prices and essential medicines to be exempted was an enabler of policy implementation. Also, the institutional capacity of the Ghana Revenue Authority (GRA) to host the Integrated Customs Management Systems (ICUMS) portal for ease of application is an enabler for VAT exemption implementation.</p>", "<p> We also found three main contextual constraints to implementation of VAT exemption and FC policies. First, economic factors such as the depreciation of the local currency, increasing inflation rate, high bank interest rate, and increasing utility cost negatively affected the vendor’s ability to fulfill their orders under the FC policy and maintain lower prices for VAT exempted finished products. For example, the Bank of Ghana, Inter-Bank exchange rate (GH₵/US$) increased from 4.9506 in January 2019, to 5.4672 in January 2020, to 5.7604 in 2021, and 6.0236 in January 2022. (<uri xlink:href=\"https://www.bog.gov.gh/economic-data/exchange-rate/\">https://www.bog.gov.gh/economic-data/exchange-rate/</uri>).</p>", "<p> “<italic toggle=\"yes\">Economic factors such as bank interest rate, inflation and depreciating Ghana cedi are variables that negatively influence pharmaceutical prices and affect already agreed prices”</italic> [Industry Association].</p>", "<p> The second constrain was the limited administrative capacities of (<italic toggle=\"yes\">a</italic>) health facilities to pay debts and agreed prices on time and (<italic toggle=\"yes\">b</italic>) vendors to quote competitive prices during the tendering processes.</p>", "<p> “<italic toggle=\"yes\">The challenge of indebtedness of facilities to suppliers is serious and they used this as a reason to not supply essentials medicines causing shortages”</italic> [Public Sector].</p>", "<p> During the tendering processes, some vendors quoted unrealistic prices, which subsequently proved a challenge because they were unable to supply medicines at that price under the contract.</p>", "<p> “<italic toggle=\"yes\">The MoH must ensure that the prices quoted are competitive enough such that suppliers will not later say that they cannot supply because the contract prices are too low”</italic> [Service Provider].</p>", "<p> Last, the impact of the COVID-19 pandemic. The pharmaceutical industry was not spared the brunt of COVID-19-related global supply chain disruption and shortage with increased shipping costs and delays. As noted by an importer during an interview, COVID-19 changed the supply chain cycle, importation timing and costs of finished products, active ingredients, and packaging materials became unpredictable, and these negatively affected the supply of medicines on time and at the agreed prices.</p>", "<title> Interplay Between Policy Contents, Actors, and Contexts in Achieving Policy Outcomes </title>", "<p> The interplay of policy content (nature and complexity), policy actors (participation and efficiency), and contextual feasibility (enablers and constraints) shaped the achievement of policy outcomes. In the implementation of the ‘at least’ 30% price reduction in 2018, data from documents reviewed and interviews show that expert TWG members initially decided to apply a 30% price reduction to the NHIS medicines list because the government is the largest buyer, and the pharmaceutical market is highly uncontrolled in terms of prices.<sup>##UREF##14##31##</sup> However, not all NHIS medicines prices were reduced by 30%, during the process, and this appears to reflect the interrelatedness of policy content, actors’ actions, and context. The Ghana National Chamber of Pharmacy representatives argued that some medicine prices had been reduced since the passage and implementation of the VAT Regulations, (L.I) 2218 in 2015, and also price reductions will have to depend on medicines brand type and foreign exchange rate as economic context had bearings on how medicines were to be priced. Therefore, when the 30% reduction was applied to the NHIS’ 600 medicines, prices of 77 medicines were considered outliers. Prices of 11 out of the 77 medicines were further reduced and these included glimepiride 1mg tablet which was reduced by 50% from GH₵ 0.80 (2016 price) to GH₵ 0.40 (2018 price). The remaining 66 had higher prices than expected, for example, omeprazole 20mg tablet price was increased by 3%.<sup>##UREF##14##31##</sup></p>", "<p> The interrelatedness of policy content, actors, and context on the implementation process was also evident during FC implementation. With unfavourable economic indicators affecting vendors’ ability to supply medicines at the agreed prices, vendors requested upward adjustments of the contract prices. The request was made to the MoH and approval was sought from the Ministry of Finance (MoF). Although there were no standardized price adjustment formulae for the FC implementation, the MoH managed to negotiate upward adjustments with the vendors. As noted by respondents, there were 8% and 20% upward price adjustments for phases 1 (2018) and 2 (2019) respectively and there is an ongoing discussion for an upward price adjustment for phase 3 (2020-2021).</p>", "<p> The interrelatedness of policy content, actors, and context influencing implementation outcomes give rise to five identified attributes of medicines pricing policy implementation: (1) policy nature and complexity, (2) inclusiveness, (3) organizational feasibility, (4) economic feasibility, and (5) political will and leadership. The descriptions are summarized in ##TAB##2##Table 3##.</p>" ]	[ "<title>Discussion</title>", "<p> We analysed implementation of VAT exemptions and FC for essential medicines in Ghana, including influences over implementation from policy contents, actors and context.</p>", "<p> The use of FC and VAT exemptions to regulate medicines prices and promote availability and affordability is not unique to Ghana.<sup>##REF##35690779##44##,##REF##32708060##45##</sup> However, implementation approaches vary as implementation structures and formalities, modalities, processes, and actors’ involvement are usually context-specific. Implementation of the VAT exemptions and FC policies in Ghana comprise a blend of ‘top-down’ and ‘bottom-up’ approaches to implementation. For both policies, decisions were mainly taken at the national level largely through legislative and administrative processes, reflecting ‘top-down’ policy-making.<sup>##UREF##25##46##,##UREF##26##47##</sup> However, a ‘bottom-up’ approach, which focuses on negotiations, consensus building, and local discretion over implementation<sup>##UREF##25##46##,##UREF##26##47##</sup> has also featured. Vendors, after signing contracts, withheld supplies from highly indebted facilities and renegotiated for upward price adjustments, reflecting their power to shape local implementation as ‘street level bureaucrats.’<sup>##UREF##27##48##</sup></p>", "<p> Our results show that the nature and level of complexity of policy content shaped the implementation modalities such as the number of state implementing agencies. The broad nature of VAT exemption policy required involvement of multiple non-health state agencies, whereas implementation of a more technical framework agreement was mainly centered within the health sector. Policy clarity in terms of ensuring easy-to-understand language, clear roles and interactions among policy actors is critical for effective policy implementation.<sup>##UREF##26##47##,##UREF##28##49##</sup> Our results also highlight the importance of having clear policy aims and expected outcomes aligned with supporting national laws and guidelines. While the former is well-recognized, the latter ie, consistency with other laws and guidelines is often implicit but is arguably critical for successful policy implementation.</p>", "<p> Our results illustrate the importance of participatory policy implementation, which can enable engagements of policy actors across multiple sectors for example through TWGs. Participatory approaches are critical and for designing and implementing policies,<sup>##UREF##29##50##</sup> and can further augment the knowledge base of the policy processes<sup>##UREF##30##51##</sup> for example through expert committees constituted for evidence sharing.<sup>##UREF##7##16##,##REF##31723963##52##</sup> In our study, the MoH actively engaged other state agencies and pharmaceutical industry throughout the implementation. The value of involvement of different stakeholders — such as pharmaceutical wholesalers, manufacturers, retailers, government agencies, health facilities and professional bodies — is also documented in other medicines pricing studies.<sup>##REF##23057369##10##,##UREF##8##17##,##REF##28903757##18##,##REF##30891247##20##</sup> There are claims that multi-stakeholder involvement contributes towards universal health coverage<sup>##REF##22388502##53##</sup> national health insurance system<sup>##REF##30505863##54##</sup> and research priority-setting.<sup>##REF##30460042##55##</sup></p>", "<p> In the case of the two examined policies, the implementation processes were however dominated by government agencies and pharmaceutical industry. Although the actors’ roles, powers, and resultant influences on the policy implementation are discussed elsewhere,<sup>##UREF##7##16##</sup> personal commitments of some health facility managers and the Minister of Health are worth mentioning. Such policy champions are often critical to spearhead, shape and support policy initiatives,<sup>##REF##17933652##56##</sup> though of course a more balanced engagement of different stakeholders is important for shared ownership and effective implementation.</p>", "<p> Different contextual barriers and enablers shaped implementation of the two medicines pricing policies in Ghana. The main enablers included political support, multistakeholder engagement, and existing institutional structures and other laws augmenting VAT exemption and FC. As noted in other works, political support,<sup>##REF##18245803##57##</sup> engagement of different policy actors<sup>##REF##31390295##58##</sup> and the use of existing structures<sup>##REF##31438977##59##</sup> are important determinants of effective policy implementation. The contextual enablers can create different opportunities for policy actors,<sup>##UREF##31##60##</sup> for example to act and work towards improving access to medicines. The main contextual barrier to policy implementation from our study was unfavourable economic environment comprising increasing inflation rate and depreciating local currency, echoing similar findings from South Africa.<sup>##REF##29587777##61##</sup></p>", "<p> Our results reinforce the argument that the interplay between policy context, processes, content, and actors can shape the achievement of policy outcomes.<sup>##REF##10139469##38##</sup> The policy outcomes in this study, which included price reduction and improved access, were mixed. For example, currency depreciation, disrupted supply chain due to COVID-19, and high indebtedness of some health facilities adversely affected the ability of vendors to supply medicines under the framework agreement. Furthermore, due to the influence from the powerful Ghana National Chamber of Pharmacy the 30% price reduction was not fully realized for all NHIS-listed medicines. On the other hand, existence of national procurement laws, VAT exemptions laws, and NHIS medicines list, all facilitated the timely implementation of the VAT exemptions that resulted in price reduction. As noted in an earlier study, contextual factors in an interrelating manner can serve as a constraint or an opportunity for timely and effective policy implementation.<sup>##REF##26022699##62##</sup></p>", "<p> The interrelatedness of policy content, actors, and context influencing implementation outcomes suggested five attributes of effective implementation of medicines pricing policies, shown in ##TAB##2##Table 3##. These attributes are not specific to medicines pricing policies and thus can contribute to wider scholarship on health policy analysis through further advancing conceptualization of determinants of effective policy implementation.</p>", "<p> A recent systematic review of medicines pricing policies in sub-Saharan Africa revealed four domains of potential policy options: targeted public subsidies, regulatory frameworks and direct price control, generic medicine policies and purchasing policies.<sup>##REF##36457058##5##</sup> Ghanaian FC policy falls within the regulatory framework, whereas VAT exemptions policy mostly is an example of Government’s subsidy to reduce medicines pricing. While the focus of this study was on examining implementation of these two policies, the policy designers should also be aware of further policy options to reduce medicines pricing. It is equally important, however, to be cognizant of the context-specificity of different policy options with regard to the country’s policy, political, structural, and health systems context.</p>", "<p> Our analysis suggests four policy lessons and implications. First, having clearly defined policy objectives is equally important as having measures in place to mitigate effects of constraining contextual factors on policy implementation and outcomes. Second, a clear legitimacy and mandate to regulate medicines pricing is important, but there is also a need to balance the multiple agendas of different policy actors toward the expected policy outcomes. Third, appropriate sequencing of tasks to be performed by independent agencies and stakeholders during policy implementation is salient and demands attention, especially during participatory decision-making. Fourth, a clear and structured process can be a useful facilitator of effective policy implementation, but it needs to be simple enough for the policy actors to easily navigate the prescribed processes.</p>", "<p> We acknowledge two study limitations. First, we focused on VAT exemptions and FC only, and while we believe some broader lessons emerge from the study, some findings may not be generalizable to further medicines pricing policy options. Second, the implementation of these policies is ongoing, so the processes, structures, and contextual influences may further evolve. Despite these limitations, our analysis provides relevant and timely lessons to inform improvements to on-going implementation and facilitate achievement of policy outcomes.</p>" ]	[ "<title>Conclusion</title>", "<p> Varied enabling and constraining contextual factors, role and active participation of stakeholders, nature of policy content, and structures influenced the implementation of VAT exemption and FC for selected essential medicines in Ghana. Understanding how and why context, policy content, stakeholders, and processes interact, and influence medicines pricing policy implementation outcome is therefore important in the design and implementation of interventions aimed at reducing medicines prices and improving access to medicines.</p>" ]	[ "<p>\n<bold>Background:</bold> Implementing medicines pricing policy effectively is important for ensuring equitable access to essential medicines and ultimately achieving universal health coverage. However, published analyses of policy implementations are scarce from low- and middleincome countries. This paper contributes to bridging this knowledge gap by reporting analysis of implementation of two medicines pricing policies in Ghana: value-added tax (VAT) exemptions and framework contracting (FC) for selected medicines. We analysed implications of actor involvements, contexts, and contents on the implementation of these policies, and the interplay between these. This paper should be of interest, and relevance, to policy designers, implementers, the private sector and policy analysts.\n</p>", "<p><bold>Methods:</bold> Data were collected through document reviews (n=18), in-depth interviews (n=30), focus groups (n=2) and consultative meetings (n=6) with purposefully identified policy actors. Data were analysed thematically, guided by the four components of the health policy triangle framework.\n</p>", "<p><bold>Results:</bold> The nature and complexity of policy contents determined duration and degree of formality of implementation processes. For instance, in the FC policy, negotiating medicines prices and standardizing the tendering processes lengthened implementation. Highly varied stakeholder participation created avenues for decision-making and promoted inclusiveness, but also raised the need to manage different agendas and interests. Key contextual enablers and constraints to implementation included high political support and currency depreciation, respectively. The interrelatedness of policy content, actors, and context influenced the timeliness of policy implementations and achievement of intended outcomes, and suggest five attributes of effective policy implementation: (1) policy nature and complexity, (2) inclusiveness, (3) organizational feasibility, (4) economic feasibility, and (5) political will and leadership.\n</p>", "<p><bold>Conclusion:</bold> Varied contextual factors, active participation of stakeholders, nature, and complexity of policy content, and structures have all influenced the implementation of medicines pricing policies in Ghana.</p>", "<p>\n<bold>Citation:</bold> Koduah A, Baatiema L, Kretchy IA, et al. Implementation of medicines pricing policies in Ghana: the interplay of policy content, actors’ participation, and context.<italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7994. doi:10.34172/ijhpm.2023.7994</p>" ]	[ "<title>Acknowledgements</title>", "<p> We acknowledge the NMPC members, MoH and our respondents.</p>", "<title>Ethical issues</title>", "<p> This study involves human participants. Ethical approval received from the ethics committees of the Ghana Health Service (GHS-ERC006/02/20) and the University of Leeds School of Medicine (MREC 19-060). Participants gave informed consent to participate in the study before taking part.</p>", "<title>Competing interests</title>", "<p> Authors are members of the NIHR-funded AMIPS (Access to Medicines through Improved Pricing Strategies) project a collaboration between the Universities of Ghana and Leeds, and the GHS, which sought to examine implementation of four medicine pricing policies in Ghana to inform improved policy implementation and contribute to improved access to essential medicines.</p>", "<title>Disclaimers</title>", "<p> Augustina Koduah is a member of the NMPC. The views expressed in this paper are solely the responsibilities of the named authors and do not necessarily reflect the decisions of the committee.</p>", "<title>Funding</title>", "<p> This research was commissioned by the National Institute for Health Research (NIHR) NIHR Global Health Policy and Systems Research Development Award using UK aid from the UK Government (grant number: 130219).</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nSchematic Outline of Framework Contracting Implementation Process. Abbreviations: MoF, Ministry of Finance; TWG, Technical Working Group.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nFramework Contracting Implementation Pricing Model.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nSchematic Outline of Value-Added Tax Exemptions Application Process. Abbreviations: FDA, Food and Drugs Authority; GRA, Ghana Revenue Authority; ICUMS, Integrated Customs Management Systems; MoH, Ministry of Health; VAT, value-added tax; DTRD, Domestic Tax Revenue Division; IDF, Import Declaration Form; SSNIT, Social Security and National Insurance Trust.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>List of Sectors and Agencies of Respondents<sup>##UREF##7##16##</sup>\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Sector </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Institution </bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Respondents </bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"7\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" colspan=\"1\">Government agencies</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">GRA</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">MoH</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">MoF</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">NHIA</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GHS-RHD</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GHS-RMS</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GHS-HQ</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"6\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Service providers</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Teaching hospital </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Regional health facility </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public hospital </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Public polyclinic </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private hospital </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Christian Health Association of Ghana </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Development partner </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">WHO</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Professional association </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">PSGH</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Society of Private Medical and Dental Practitioners </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Pharmaceutical industry </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pharmaceutical Manufacturers Association of Ghana </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">CPPA</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pharmaceutical wholesaler/importer/retailer </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">NGO</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Coalition of Non-Governmental Organizations in Health </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Ghana NCDs Alliance</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Summary of Influence of Policy Content, Policy Actors and Context on Implementation Process and the Resulting Policy Outcomes\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr style=\"background-color:#eeeeee\"><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Policy and</bold>\n<break/>\n<bold>Expected Outcome</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Implementation Year</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Content Influence on Implementation Processes</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Actors Influences on Implementation processes</bold>\n</th><th colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Contextual Influences on Implementation Processes</bold>\n</th><th rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Resulting Outcomes</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Enablers</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Constraints</bold>\n</th></tr><tr><td rowspan=\"3\" style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">FC/Centralised procurement process for high demand essential medicines and negotiated lower prices</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2018</td><td rowspan=\"3\" style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">The nature and complexity of policy content ie, to create centralised procurement for selected and negotiate lower prices for high medicines influenced the length and duration of the implementation process as shown in ##FIG##0##Figure 1##. This lasts on average a year</td><td rowspan=\"3\" style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Involvement of several actors influenced the degree of participation and efficiency. For example, <break/>1. RHAs, RMSs, THs, NHIA, FDA, GHSC-PSM, MoH, P&SC, MoH-Pharmacy, and GHS-SSDM (ie, TWG)<break/>– selected the high volume, high value, and high supply risk essential medicines for centralised procurement and price negotiation<break/>– determined required quantities<break/>– prepared tender documents<break/>– publically received tenders <break/>– determined the capacity of vendors to supply selected medicines <break/>– negotiated lower prices. See ##FIG##2##Figure 3## for pricing models<break/><break/>2. Minister of Health, THs Chief Executive Officers and GHS Director General and selected vendors<break/>– signed MOU<break/><break/>3. RHAs and THs <break/>– signed contracts with the selected vendors to supply the selected essential medicines<break/><break/>4. Vibrant local pharma industry <break/>– participated in national competitive tendering processes</td><td rowspan=\"3\" style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">1. Political support<break/>– the Minister of Health facilitated the implementation process by signing an MOU <break/><break/>2. Institutional capacity of the MoH and agencies to negotiate prices<break/>– the collaborative approach toward FC implementation was a facilitator<break/><break/>3. Administrative capacity of health facilities<break/>– some facilities ring-fenced drug revolving fund for FC payment<break/><break/>4. Other policies <break/>– eg, public procurement laws</td><td rowspan=\"3\" style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">1.Economic factors<break/>– depreciation of local currency<break/>– increasing inflation rate<break/>– high bank interest rate<break/><break/>2. High degree of outlier prices quoted by the pharmaceutical industry during the tendering process<break/>– organizational interest to make more profits<break/>– some vendors did not supply medicines at the agreed prices<break/><break/>3. Administrative (in)capacity of health facilities<break/>– high indebtedness of some facilities <break/>– unable to call-off all the quantities agreed on<break/><break/>4. COVID-19 pandemic<break/>– delayed global supply chain </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">54 Essential medicines lower prices negotiated and centrally procured under framework with 8% upward price adjustment </td></tr><tr><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2019</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">65 Essential medicines lower prices negotiated and centrally procured under framework with 20% upward price adjustment</td></tr><tr><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2020-2021</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">65 Essential medicines lower prices negotiated and centrally procured under framework</td></tr><tr><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">VAT exemption/At least 30% reduction in NHIS listed medicines prices</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2018</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The degree of formality and straight- forwardness of the Parliament approved policy content and aim ie, remove VAT from 552 APIs, manufacturing inputs and packaging materials and 483 imported finished pharmaceutical products shaped the length and duration of the implementation process as shown in ##FIG##1##Figure 2##. This lasts on average two weeks</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Multisectoral organizational involvement beyond the health sector influences the degree of participation and efficiency. For example, <break/>1. MoH, GNCOP, PSGH, MOTI, NHIA, PMAG, FDA, WHO, GRA, CPPA, GHS (ie, TWG)<break/>– selected pharmaceutical products for VAT exemption<break/>– coordinated implementation processes<break/><break/>2. Parliament of Ghana<break/>– approved the Legislative Instrument L.I 2255 for implementation <break/><break/>3. GRA an agency of the MoF <break/>– hosts the ICUMS online portal (<uri xlink:href=\"https://gra.gov.gh/customs/icums/\">https://gra.gov.gh/customs/icums/</uri>)<break/>– approves VAT exemption application<break/><break/>4. Vibrant local pharmaceutical industry<break/>– importation of API, manufacturing inputs and finished products </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1. High political support <break/>– VAT exemption for selected pharmaceutical stated in the 2016 Manifesto of the government in power, 2017 national budget statement<break/>– the Minister of Health facilitated implementation process<break/><break/>2. Other policies facilitated timely implementation<break/>– VAT regulations 2015 (L.I. 2218)<break/>– Public Procurement Laws<break/><break/>3. Institutional capacity of GRA<break/>– VAT exemption applied for on the ICUMS online portal<break/><break/>4. Collaborative approach to policy implementation<break/>– multi-sectoral </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1. Economic factors<break/>– depreciation of local currency<break/>– increasing inflation rate<break/>– high bank interest rate<break/><break/>2. Institutional process<break/>– Pharmaceutical companies apply individually for exempted products on the ICUMS portal and this time-consuming especially if one imports several products<break/></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">533 NHIS 2018 listed medicines prices reduced by at least 30%.<break/>11 NHIS 2018 listed medicines prices reduced by more than 30%.<break/>66 NHIS 2018 listed medicines had higher prices than expected</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Attributes of Medicines Pricing Policy Implementation\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Attributes </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Description </bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Policy nature and complexity </td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Clear and straightforwardness of policy aims and expected outcomes. <break/>Embeddedness in existing national policies</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Inclusiveness </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Active participation and effective management of stakeholders to ensure expected outcomes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Organizational feasibility </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Organizational structures and technical experts to support the process</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Economic feasibility </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Economic drivers intended and unintended influences on the policy and how these are mitigated</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Political will and leadership </td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Strong political support at all levels to lead and coordinate the process</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Having clearly defined medicines pricing policy objectives is equally important for effective implementation, as having legal and organizational structures to implement these objectives. </p></list-item><list-item><p>A clear legitimacy and mandate to regulate medicines pricing are critical for implementation, but there is also a need to balance multiple agendas and priorities of different policy actors. </p></list-item><list-item><p>Appropriate sequencing of tasks to be performed by stakeholders during medicines pricing policy implementation can be salient and demands attention, especially in participatory decision-making. </p></list-item><list-item><p>A clear and structured process can be a useful facilitator of policy implementation but needs to be simple enough for the policy actors to easily navigate the processes. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> Availability of quality, safe and affordable medicines is vital for achievement of universal health coverage. National policies are often designed and implemented by governments to reduce medicines prices and make quality and safe medicines available to all. The government of Ghana introduced two such policies: value-added tax (VAT) exemptions for selected medicines and framework contracting (FC) for high-demand medicines. Initially, some medicine prices were reduced as planned, but numerous challenges such as the depreciation of the Ghanaian currency, unpredictable pharmaceutical supply chain system due to the COVID-19 pandemic, and indebtedness of some health facilities, have resulted in delays in medicines supply. Detailed analyses of implementation processes, such as the one reported in this article, can help improve implementation processes, and ultimately contribute to improved access to essential medicines.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Interview Guide.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 2. List of Essential Medicines for FC Phase 1.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: GRA, Ghana Revenue Authority; MoH, Ministry of Health; MoF, Ministry of Finance; NHIA, National Health Insurance Authority; GHS-RHD, Ghana Health Service Regional Health Directorate; GHS-RMS, Ghana Health Service Regional Medical Store; GHS-HQ, Ghana Health Service Headquarters; WHO, World Health Organization; PSGH, Pharmaceutical Society of Ghana; CPPA, Community Pharmacy Practice Association; NCDs, Noncommunicable diseases; NGO, non-governmental organization.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: API, active pharmaceutical ingredients; CPPA, Community Pharmacy Practice Association; FDA, Food and Drugs Authority; FC, framework contracting; GHS, Ghana Health Service; GHS-SSDM, Ghana Health Service Supplies Stores and Drug Management; GNCOP, Ghana National Chamber of Pharmacy; GRA, Ghana Revenue Authority; GHSC-PSM, Global Health Supply Chain-Procurement and Supply Management; ICUMS, Integrated Customs Management Systems; MoF, Ministry of Finance; MoH, Ministry of Health; NHIA, National Health Insurance Authority; NHIS, National Health Insurance Scheme; PMAG, Pharmaceutical Manufacturers Association of Ghana; PSGH, Pharmaceutical society of Ghana; MOTI, Ministry of Trade and Industrial; TWG, Technical Working Group; P&SC, Procurement and Supply Chain; RHAs, Regional Health Administrations; RMSs, Regional Medical Stores; THs, teaching hospitals; VAT, value-added tax; WHO, World Health Organization; MOU, memorandum of understanding.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7994-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7994-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7994-g003\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7994-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7994-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "person-group": ["\n"], "surname": ["Bashaar", "Hassali", "Saleem", "Alrasheedy", "Thawani"], "given-names": ["M", "MA", "F", "A", "V"], "article-title": ["Efficacy of international approaches to medicine price regulation and control: a scoping review"], "source": ["J Appl Pharm Sci"], "year": ["2017"], "volume": ["7"], "issue": ["4"], "fpage": ["227"], "lpage": ["241"], "pub-id": ["10.7324/japs.2017.70434"]}, {"label": ["3"], "person-group": ["\n"], "surname": ["World Health Organization"], "given-names": ["(WHO)"], "source": ["WHO Guideline on Country Pharmaceutical Pricing Policies"], "edition": ["2nd ed"], "year": ["2020"], "publisher-loc": ["Geneva"], "publisher-name": ["WHO"], "size": ["1"]}, {"label": ["4"], "mixed-citation": [" Ministry of Health. Ghana National Medicines Policy. 3rd ed. Accra: Ministry of Health; 2017. "]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Bangalee", "Suleman"], "given-names": ["V", "F"], "article-title": ["Has the increase in the availability of generic drugs lowered the price of cardiovascular drugs in South Africa?"], "source": ["Health SA"], "year": ["2016"], "volume": ["21"], "fpage": ["60"], "lpage": ["66"], "pub-id": ["10.1016/j.hsag.2015.10.004"]}, {"label": ["11"], "mixed-citation": [" Ma\u00efga D, Ma\u00efga S, Ma\u00efga MD. [Mechanism and implication of regulation of the pricing of essential medicines in the private pharmaceutical sector in Mali]. Med Trop (Mars) 2010;70(2):184-188. [French]. "]}, {"label": ["12"], "mixed-citation": [" Guimier JM, Candau D, Garenne M, Teuli\u00e8res L. [Why drug prices are high in sub-Saharan Africa. Analysis of price structure: the case of Senegal]. Sante 2005;15(1):41-52. [French]. "]}, {"label": ["14"], "person-group": ["\n"], "surname": ["d\u2019Almeida", "Essi", "Camara", "Coriat"], "given-names": ["C", "MJ", "M", "B"], "article-title": ["Access to second-line antiretroviral therapeutic regimens in low-resource settings: experiences from Cameroon"], "source": ["J Acquir Immune DeficSyndr"], "year": ["2011"], "volume": ["57 Suppl 1"], "fpage": ["S55"], "lpage": ["58"], "pub-id": ["10.1097/QAI.0b013e318220787d"]}, {"label": ["16"], "person-group": ["\n"], "surname": ["Koduah", "Baatiema", "Kretchy"], "given-names": ["A", "L", "IA"], "article-title": ["Powers, engagements and resultant influences over the design and implementation of medicine pricing policies in Ghana"], "source": ["BMJ Glob Health"], "year": ["2022"], "volume": ["7"], "issue": ["5"], "fpage": ["e008225"], "pub-id": ["10.1136/bmjgh-2021-008225"]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Steyn", "Burger", "Serfontein", "Lubbe"], "given-names": ["R", "JR", "JH", "MS"], "article-title": ["Influence of a new reference-based pricing system in South Africa on the prevalence and cost of antidiabetic medicine: a pilot study"], "source": ["Int J Pharm Pract"], "year": ["2007"], "volume": ["15"], "issue": ["4"], "fpage": ["307"], "lpage": ["311"], "pub-id": ["10.1211/ijpp.15.4.0009"]}, {"label": ["26"], "person-group": ["\n"], "surname": ["Tran", "Manji", "Njuguna"], "given-names": ["DN", "I", "B"], "article-title": ["Solving the problem of access to cardiovascular medicines: revolving fund pharmacy models in rural western Kenya"], "source": ["BMJ Glob Health"], "year": ["2020"], "volume": ["5"], "issue": ["11"], "fpage": ["e003116"], "pub-id": ["10.1136/bmjgh-2020-003116"]}, {"label": ["27"], "mixed-citation": [" Ministry of Health. Ghana Essential Medicines List. 7th ed. Accra: Ghana National Drugs Programme; 2017. "]}, {"label": ["28"], "mixed-citation": [" Government of Ghana. Legislative Instrument (L.I) 2255 Value Added Tax (Exemption of Active Ingredients, Selected Inputs and Selected Drugs for Pharmaceuticals) (Amendments) Regulations, 2017. Accra: Ghana Publishing Company Ltd; 2017. "]}, {"label": ["29"], "mixed-citation": [" Ministry of Health. Justification for Number of Medicines to Be Selected for Procurement Under Costed Framework Contracting Agreement Project for Ghana. Accra: Ministry of Health; 2017. "]}, {"label": ["30"], "mixed-citation": [" Government of Ghana. Report of the Committee on Subsidiary Legislation on the Value Added Tax Regulations, 2017 (L.I.2255). Accra: Parliament of Ghana Library; 2017. "]}, {"label": ["31"], "mixed-citation": [" Ministry of Health. Report of the VAT Exemption Implementation Committee to the Minister for Health. Accra: Ministry of Health; 2018. "]}, {"label": ["32"], "mixed-citation": [" Addo C. Health Minister Announces a 30 Per Cent Drop in NHIS Medicine Prices. Ghana News Agency; 2018. "]}, {"label": ["33"], "mixed-citation": [" Ministry of Health. Framework Contracting Evaluation Report. Accra: Ministry of Health; 2019. "]}, {"label": ["34"], "mixed-citation": [" Government of Ghana. Value Added Tax (Exemption of Active Ingredients, Selected Inputs and Selected Drugs or Pharmaceuticals) Regulations, 2015 (L.I. 2218). Accra: Assembly Press; 2015. "]}, {"label": ["35"], "mixed-citation": [" Government of Ghana. Value Added Tax (Amendment) Act 2017 (Act 948). Accra: Assembly Press; 2017. "]}, {"label": ["36"], "mixed-citation": [" Ministry of Health. Health Commodity Supply Chain Master Plan. Accra: Ministry of Health; 2012. "]}, {"label": ["39"], "mixed-citation": [" Hill M, Hupe P. Implementing Public Policy: Governance in Theory and Practice. SAGE Publications; 2002. "]}, {"label": ["40"], "person-group": ["\n"], "surname": ["Mirzoev", "Das", "Ebenso"], "given-names": ["T", "M", "B"], "article-title": ["Contextual influences on the role of evidence in health policy development: what can we learn from six policies in India and Nigeria?"], "source": ["Evid Policy"], "year": ["2017"], "volume": ["13"], "issue": ["1"], "fpage": ["59"], "lpage": ["79"], "pub-id": ["10.1332/174426415x14454407579925"]}, {"label": ["41"], "mixed-citation": [" New Patriotic Party (NPP). Manifesto for Election: Creating Prosperity and Equal Opportunity for All. Ghana: NPP; 2016. "]}, {"label": ["42"], "mixed-citation": [" Government of Ghana. Public Procurement Act (Act 663). Accra: Assembly Press; 2003. "]}, {"label": ["43"], "mixed-citation": [" Government of Ghana. Public Procurement Act (Amendment) Act 914. Accra: Assembly Press; 2016. "]}, {"label": ["46"], "mixed-citation": [" Parsons W. Public Policy: An Introduction to the Theory and Practice of Policy Analysis. Edward Elgar Publishing; 1995. "]}, {"label": ["47"], "mixed-citation": [" Buse K, Mays N, Walt G. Making Health Policy. McGraw-Hill Education (UK); 2012. "]}, {"label": ["48"], "mixed-citation": [" Lipsky M. Street-Level Bureaucracy: Dilemmas of the Individual in Public Service. New York: Russell Sage Foundation; 1980. "]}, {"label": ["49"], "person-group": ["\n"], "surname": ["Hudson", "Hunter", "Peckham"], "given-names": ["B", "D", "S"], "article-title": ["Policy failure and the policy-implementation gap: can policy support programs help?"], "source": ["Policy Des Pract"], "year": ["2019"], "volume": ["2"], "issue": ["1"], "fpage": ["1"], "lpage": ["14"], "pub-id": ["10.1080/25741292.2018.1540378"]}, {"label": ["50"], "person-group": ["\n"], "surname": ["Bobbio"], "given-names": ["L"], "article-title": ["Designing effective public participation"], "source": ["Policy Soc"], "year": ["2019"], "volume": ["38"], "issue": ["1"], "fpage": ["41"], "lpage": ["57"], "pub-id": ["10.1080/14494035.2018.1511193"]}, {"label": ["51"], "person-group": ["\n"], "surname": ["Bijlsma", "Bots", "Wolters", "Hoekstra"], "given-names": ["RM", "PW", "HA", "AY"], "article-title": ["An empirical analysis of stakeholders\u2019 influence on policy development: the role of uncertainty handling"], "source": ["Ecol Soc"], "year": ["2011"], "volume": ["16"], "issue": ["1"], "fpage": ["51"]}, {"label": ["60"], "mixed-citation": [" Grindle MS, Thomas JW. Public Choices and Policy Change: The Political Economy of Reform in Developing Countries. Baltimore, MD: Johns Hopkins University Press; 1991. "]}]	{ "acronym": [], "definition": [] }	62	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 11; 12:7994	oa_package/7a/34/PMC10699811.tar.gz
PMC10699812	0	[ "<title>Introduction</title>", "<p> The paper by Holmström et al<sup>##REF##35247937##1##</sup> benefits a methodological enhancement in response to the challenges in implementing new policies in healthcare. In this research design, one central method (ie, action research [AR]) was used and enriched by selectively importing another method (ie, system dynamics [SD]). Accordingly, the authors integrated SD into AR in five case studies related to the health sector. In this regard, frameworks for consultancy assignments/client and socio-analytical questions were used to identify the project stages and bridge the two approaches. Finally, the authors identified and described general work principles and patterns whereby the synthesis of AR and SD can support the identification and implementation of workable solutions to the concerned challenges. As such, this complementarity was expected to exploit the benefits of both approaches holistically.</p>", "<p> In this commentary, we add to the perspective of Holmström et al and reflect more deeply upon the methodological approach of the paper. In particular, we aim to extend the methodological aspects of this paper using the ongoing mixed research and multi-methodology debates and inform the readers of the challenges raised in adopting such integrations.</p>" ]	[ "<title>Towards a New Multi-methodology Framework</title>", "<p> In the multi-methodology debates, different frameworks have been suggested to guide method(s) selection in problematic situations. Two key frameworks can be identified in this regard<sup>##UREF##3##5##,##UREF##13##15##</sup>: (1) deductive or theory-led frameworks that derive from specific hypotheses or existing theories; and (2) inductive or practice-led frameworks that are generally built on the synthesis of method(s) selections in practices. The first type of framework was dominant in early debates on multi-methodology theory and practice. Yet, after the accumulation of interventions over the years, most recent frameworks are designed on the basis of synthesizing available evidence on combining methods.<sup>##UREF##13##15##</sup></p>", "<p> The paper by Holmström et al<sup>##REF##35247937##1##</sup> described a method selection in practice deriving, particularly on reflexivity, group development, feedback-oriented explanation of the problems, and testing improvement actions <italic toggle=\"yes\">in silico</italic>. Later on, this experience can be synthesized and complemented with other related methodological and practical evidences, likely leading to the construction of an inductive or practice-led framework. We hope considering the above issues, among others, helps pave the way towards improving health problems using the proposed research design as well as perhaps developing a more workable and effective multi-methodology framework.</p>" ]	[]	[]	[]	[ "<p>This commentary discusses the paper by Holmström et al that explored how system dynamics (SD) may contribute effectively to an action research (AR) process to improve five health case studies. Accordingly, we reviewed some of the methodological aspects of the proposed integration of SD into AR using ongoing debates on multi-methodology and mixed methods research. In a systemic evaluation of the proposed design, we concentrated on some of the common distinct features of SD and AR, and the challenges as well as the expected outcomes of this integration. Finally, we tried to position the suggested framework within the multi-methodology efforts and to pave the way for developing it in future research and practice.</p>", "<p>\n<bold>Citation:</bold> Zolfagharian M. Integrating system dynamics into action research: drivers and challenges in a synergetic complementarity: Comment on \"Insights gained from a re-analysis of five improvement cases in healthcare integrating system dynamics into action research.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7585. doi:10.34172/ijhpm.2023.7585</p>" ]	[ "<title>Drivers in Combining System Dynamics and Action Research</title>", "<p> Increasing critical awareness about the challenges and strengths of various approaches in dealing with different (dimensions and phases of) complex problematic situations has made the use of diverse methods and models more essential.<sup>##UREF##0##2##,##UREF##1##3##</sup> Systemic evaluation of mixed research designs involves an investigation of the combined methods, the quality and the peculiarities of the integration, and the assessment of the achieved results (ie, emergent collective insights).<sup>##UREF##2##4##</sup></p>", "<p> With regard to the latter, Holmström et al demonstrated that the proposed mixed-method approach derives, among others, the benefits of applying either approach in isolation. The authors reported more coherent, holistic, and robust outcomes with a higher likelihood of sustained actualization achieved through a deep engagement among the participants while gaining ownership and commitment to decisions (see also ##BOX##0##Box 1##). However, critically evaluating and promoting the quality and impact<sup>##UREF##2##4##,##UREF##3##5##</sup> of this integration might be considered as a promising direction for future applications. Interested readers can apply the related debates and frameworks in mixed methods research and multi-methodology interventions.<sup>##UREF##2##4##, ####UREF##3##5##, ##UREF##4##6####4##6##</sup></p>", "<p> To investigate the combined methods (ie, SD and AR), I want to emphasize on some striking similarities between these approaches that make their integration promising. Hence, the advantages of combining SD and AR can be considered mutual, whether SD integrates into AR as Holmström et al did or some of SD’s inputs can be taken from AR’s results. These common features are expected to be reinforced and synergetic, and provide emerging properties (cf. the outcomes) in case of their integration with each other.</p>", "<p> First, both approaches, with multiple paradigmatic underpinnings, can individually serve as a fertile ground for combining various quantitative, qualitative, and mixed methods.<sup>##UREF##6##8##, ####UREF##7##9##, ##UREF##8##10####8##10##</sup></p>", "<p> Furthermore, systemic thinking is acknowledged as a grounding for AR that may broaden action and deepen research. That is, AR conducted with a systemic perspective in mind or built upon a formal systemic model, such as SD model, promises to construct meaning and action that resonates strongly with people’s experiences within a systemic world. As such, the cooperation of the stakeholders in the implementation phases would be more involved.<sup>##UREF##5##7##</sup></p>", "<p> Finally, SD approach is almost conducive to eliciting, capturing, and changing stakeholders’ mental models through the modelling process.<sup>##UREF##9##11##</sup> Similarly, AR also aims to transform the social reality through intervening in a problematic situation and changing the mindset of stakeholders.<sup>##UREF##6##8##</sup></p>", "<p> In continue, I will point out to the quality and the peculiarities of the integration, by addressing the related challenges.</p>", "<title>Challenges of Integrating System Dynamics Into Action Research</title>", "<p> The proposed mixed research design by Holmström et al held off the most challenges of the mixed research design that might affect the feasibility and efficiency of multi-methodology interventions.<sup>##UREF##0##2##</sup> Most importantly, philosophical challenges of integrating SD and AR can be mounted by adopting critical and transformative or pragmatist paradigms as the compatible philosophical underpinning of both approaches.<sup>##UREF##5##7##,##UREF##8##10##, ####UREF##9##11##, ##UREF##10##12####10##12##</sup></p>", "<p> The similarities between SD and AR as well as work principles suggested in Holmström et al likely moderate the challenge on theoretical fitness of these approaches in terms of the coherence of integration across SD and AR as well as providing an added value for improving the concerned problematic situation and learning about it.</p>", "<p> However, practical challenges still exist in applying the proposed work principles in the health sector. Hence, Holmström et al<sup>##REF##35247937##1##</sup> demonstrated that “in none of the cases did the participants have to learn the basics of model building or SD terminology. However, they understood sufficiently [the basics of SD modelling] to see the simulation results as credible and useful.” Yet, the facilitator should express willingness and equip with SD and AR skills to engage efficiently with stakeholders over long periods.</p>", "<p> Acting in the framework of paradigms and methodologies requires knowing the (underpinnings of) research process along with bodily involvement, experience, and practice. As such, the cognition process preferences of the concerned researchers and stakeholders play a significant role in working across SD and AR and adopting the proposed design. This psychological challenge is quite significant in this design as AR and SD are both value-oriented but originate from different research traditions with distinct assumptions. As such, there might be cognitive barriers that lead to the resistance of researchers and practitioners to adopt the integration of SD into AR.</p>", "<p> Add to these challenges additional time and cost required in mixed research due to the need, among others, to collect and analyze two different types of data. This workload delays delivering an urgent solution to a complex problematic situation. You should also note the time-consuming nature of SD projects, as it can take weeks or even months for an expert modeler to create a robust and well-calibrated simulator.<sup>##UREF##9##11##</sup> However, as Holmström et al<sup>##REF##35247937##1##</sup> claimed, virtual testing of the solutions via SD modelling process increases the overall time efficiency of this approach, and can outweigh a stand-alone AR approach.</p>", "<p> Furthermore, adopting this integration while engaging with stakeholders does not necessarily guarantee successful contributions to practical knowledge. On the one hand, not all interventions deliver helpful knowledge and solutions because the intervention might be poorly designed and conducted. On the other hand, there might be epistemological challenge raised by the participatory approaches that rely only on the co-production of knowledge between the participants.<sup>##UREF##8##10##,##UREF##11##13##</sup> To moderate this challenge, the projects should always incorporate an understanding of the relevant extant literature/theories, as a profound foundation, with the lay knowledge of the participants in a coherent design. In this regard, using Brailsford’s three levels of implementation of simulations by Holmström et al<sup>##REF##35247937##1##</sup> seems to be instrumental. Of course, academic researchers, who aim to plan an AR design, should also avoid the trap of developing abstract theories with a cursory engagement with the practitioners without deeply involving them in the knowledge production process.</p>", "<p> Finally, the interactive nature of mixed methods research implies a reiterative cycle within the workflow.<sup>##UREF##4##6##</sup> The authors indicated elsewhere this cyclical process; however, what we see in Figure 2, as the chronological workflows by case, is a sequential process that treats all cases, somehow, with the same beginning and end but includes different sequences of intermediate steps. Hence, both AR and SD involve dynamic, emergent, and continuous feedback processes that develop as those engaged, individually or collectively, deepen their understanding of the issues to be addressed.<sup>##UREF##6##8##,##UREF##9##11##</sup> Accordingly, it is suggested to consider the whole process (rather than just individual steps) as an iterative and reciprocal cycle that guides the researchers and practitioners to engage in a reflective process.</p>", "<p> Overall, considering the above challenges and drivers, the choice to adopt various degrees of a mix between the SD and AR (as illustrated in Figure 1) largely depends on the initial research question, which in turn is likely to be influenced by the background, skills, and expertise of the facilitator/researcher in either/both approaches, interests of the stakeholders, and available time, data and other resources.<sup>##UREF##7##9##</sup> Accordingly, problem owners might enjoy the consistency and the efficiency of a stand-alone approach due to the incompatibility of either one to the concerned situation. For example, if there is difficulty in the identification of the causal loop diagrams for the concerned problem, a pure AR or AR in combination with other approaches will be more rewarding.</p>", "<title>Challenges of the Participatory Approaches in Coercive Situations</title>", "<p> AR is an evident candidate approach when the objective is to explore theory related to practice and improve the concerned problem with the cooperation of related participants. However, it is necessary to consider the type of involved participants before adopting the proposed AR enhanced by SD.<sup>##UREF##12##14##</sup> Holmström et al<sup>##REF##35247937##1##</sup> claimed that the groups in all case studies, except case 1, include Coalesced Authority, Power, and Influence required for decision-making and implementation of a solution. This group composition seems to be aligned with the participants in a pluralistic (rather than in a unitary or coercive) relationship. As such, the proposed mixed research design can converge the divergences in the opinions of the participants about the problems as well as their resolutions.</p>", "<p> Hence, those in a pluralist relationship differ in that, although their basic interests are compatible, they do not share the same values and beliefs. Space needs to be made available within which debate, disagreement, and even conflict, can take place. If this is done, and all feel they have been involved in decision‐making, then accommodations and compromises are accessible, at least temporarily. As such, the benefits of the mixed research will be somehow accessible.</p>", "<p> However, participants in coercive relationships with few shared interests would hold irreconcilable values and beliefs. In these situations, compromise is impossible, so no agreed objectives and subsequently no convergence can be obtained to direct action. Decisions are taken based on who has the most power, which is common in cases of tension between hierarchical power and the power of the professions rather than in cases of decentralized or democratic situations. In these problematic situations, divergence or creative phase might also be limited as the minorities with less power do not even feel safe to express their ideas in the meetings (absolutely if invited to). As such, alternative approaches should be adopted in order to comply with the peculiarities of these types of participants in the problematic situation.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that he has no competing interests.</p>" ]	[]	[]	[]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>\n<bold>Box 1.</bold> The Added Value of Integrating System Dynamics Into Action Research<sup>##REF##35247937##1##,##UREF##5##7##</sup>\n</title><list list-type=\"bullet\"><list-item><p>More coherent, holistic, and robust outcomes </p></list-item><list-item><p>Higher likelihood of sustained actualization </p></list-item><list-item><p>More (objective) reflexivity about the concerned problem </p></list-item><list-item><p>Feedback-oriented explanation of the problems </p></list-item><list-item><p>Testing the impacts of improvement actions/scenarios <italic toggle=\"yes\">in silico</italic></p></list-item></list></sec></boxed-text>" ]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "person-group": ["\n"], "surname": ["Mingers", "Brocklesby"], "given-names": ["J", "J"], "article-title": ["Multimethodology: towards a framework for mixing methodologies"], "source": ["Omega"], "year": ["1997"], "volume": ["25"], "issue": ["5"], "fpage": ["489"], "lpage": ["509"], "pub-id": ["10.1016/s0305-0483(97)00018-2"]}, {"label": ["3"], "mixed-citation": [" Page SE. The Model Thinker: What You Need to Know to Make Data Work for You. London, UK: Hachette; 2018. "]}, {"label": ["4"], "person-group": ["\n"], "surname": ["Nastasi", "Hitchcock", "Gutierrez", "Oshrin"], "given-names": ["BK", "JH", "R", "S"], "article-title": ["Promoting quality of mixed methods consultation research: a synergistic participatory framework"], "source": ["J Educ Psychol Consult"], "year": ["2022"], "volume": ["32"], "issue": ["1"], "fpage": ["22"], "lpage": ["45"], "pub-id": ["10.1080/10474412.2021.1887743"]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Franco", "Lord"], "given-names": ["LA", "E"], "article-title": ["Understanding multi-methodology: Evaluating the perceived impact of mixing methods for group budgetary decisions"], "source": ["Omega"], "year": ["2011"], "volume": ["39"], "issue": ["3"], "fpage": ["362"], "lpage": ["372"], "pub-id": ["10.1016/j.omega.2010.06.008"]}, {"label": ["6"], "mixed-citation": [" Nastasi BK, Hitchcock JH, Brown LM. An inclusive framework for conceptualizing mixed methods design typologies: moving toward fully integrated synergistic research models. In: Tashakkori A, Teddlie C, eds. SAGE Handbook of Mixed Methods in Social & Behavioral Research. 2nd ed. Thousand Oaks, CA: SAGE Publications; 2010:305-338. "]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Flood"], "given-names": ["RL"], "article-title": ["The relationship of \u2018systems thinking\u2019 to action research"], "source": ["Syst Pract Action Res"], "year": ["2010"], "volume": ["23"], "issue": ["4"], "fpage": ["269"], "lpage": ["284"], "pub-id": ["10.1007/s11213-010-9169-1"]}, {"label": ["8"], "mixed-citation": [" Bradbury-Huang H. The SAGE Handbook of Action Research. 3rd ed. SAGE Publications Ltd; 2015. "]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Zolfagharian", "Romme", "Walrave"], "given-names": ["M", "AGL", "B"], "article-title": ["Why, when, and how to combine system dynamics with other methods: towards an evidence-based framework"], "source": ["J Simul"], "year": ["2018"], "volume": ["12"], "issue": ["2"], "fpage": ["98"], "lpage": ["114"], "pub-id": ["10.1080/17477778.2017.1418639"]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Zolfagharian", "Akbari", "Fartookzadeh"], "given-names": ["M", "R", "H"], "article-title": ["Theory of knowledge in system dynamics models"], "source": ["Found Sci"], "year": ["2014"], "volume": ["19"], "issue": ["2"], "fpage": ["189"], "lpage": ["207"], "pub-id": ["10.1007/s10699-013-9328-9"]}, {"label": ["11"], "mixed-citation": [" Morecroft JD. Strategic Modelling and Business Dynamics: A Feedback Systems Approach. John Wiley & Sons; 2015. "]}, {"label": ["12"], "mixed-citation": [" Christ TW. Teaching mixed methods and action research: pedagogical, practical, and evaluative considerations. In: Tashakkori A, Teddlie C, eds. SAGE Handbook of Mixed Methods in Social & Behavioral Research. 2nd ed. Thousand Oaks, CA: SAGE Publications; 2010:643-676. "]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Eden", "Ackermann"], "given-names": ["C", "F"], "article-title": ["Theory into practice, practice to theory: action research in method development"], "source": ["Eur J Oper Res"], "year": ["2018"], "volume": ["271"], "issue": ["3"], "fpage": ["1145"], "lpage": ["1155"], "pub-id": ["10.1016/j.ejor.2018.05.061"]}, {"label": ["14"], "mixed-citation": [" Jackson MC. Critical Systems Thinking and the Management of Complexity. John Wiley & Sons; 2019. "]}, {"label": ["15"], "mixed-citation": [" Zolfagharian M. How To Study Transition Problems? Theories, Methods and Models. Netherlands: Eindhoven University of Technology; 2019. "]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 31; 12:7585	oa_package/ff/da/PMC10699812.tar.gz
PMC10699813	0	[ "<title>Background</title>", "<p> The COVID-19 crisis posed an extreme threat to human health. An infection with the SARS-CoV-2 virus could not only come with a variety of disabling symptoms (eg, coughing, difficulty breathing, headache, and fatigue) but could also result in hospitalization in case of severe symptoms. To illustrate, in Belgium, where the present long-term study took place, more than 146 000 people were hospitalized throughout the pandemic, with 1465 new people requiring daily intensive care at the peak of the second wave.<sup>##UREF##0##2##</sup> To prevent a collapse of the healthcare system and to save lives, governments around the world took a range of restrictive measures that varied in severity and duration. In some cases, authorities enforced a lockdown, travel bans and a restricted mobility perimeter, allowing citizens only to move around within a narrow radius of their homes. These measures proved effective in reducing the spread of the virus.<sup>##REF##32330703##3##,##REF##34789505##4##</sup></p>", "<title> The Interplay Between the Stringency of the Measures and the Hospitalization Numbers </title>", "<p> Across countries and time, hospitalization numbers, a reliable index of the actual epidemiological situation, and the stringency of the implemented measures did not always go hand in hand.<sup>##REF##34242239##5##</sup> With comparable hospitalization numbers on average, some countries (eg, China) imposed more severe restrictions than others (eg, Sweden). Similarly, countries also differed in how quickly the measures were adapted to changes in the epidemiological situation.<sup>##REF##35999620##6##</sup> In addition, some governments relied on economic indicators (eg, economic growth<sup>##UREF##1##7##</sup>), while others had predetermined epidemiological markers to adapt the stringency of the measures.<sup>##UREF##2##8##</sup> Overall, countries that lacked a coherent policy proved less efficient in facing the pandemic, whereas countries that monitored infections closely and implemented clear and consistent measures using transparent and efficient communication strategies, were far more effective in combatting the crisis.<sup>##UREF##3##9##</sup></p>", "<p> Most countries were not adequately prepared to face the pandemic and needed to learn along the road to find a balance between the stringency of the measures that was needed to control the epidemiological situation and the collateral damage at the economic, social, and psychological levels.<sup>##UREF##4##10##</sup> Indeed, imposed behavioral restrictions were often fiercely criticized for producing economic loss,<sup>##REF##34511220##11##</sup> and stimulated conspiracy thinking,<sup>##REF##34456450##12##</sup> street protests<sup>##UREF##5##13##</sup> and societal debate questioning their necessity.<sup>##REF##32562476##14##</sup> Often people seemed to lose their motivation to adhere to the measures,<sup>##UREF##6##15##</sup> even defying the measures altogether, thereby endangering the health of others. Apparently, psychological costs emerged because strict measures violated people’s basic needs for autonomy, competence, and relatedness,<sup>##UREF##7##16##,##UREF##8##17##</sup> thereby undermining people’s mental health as evidenced through enhanced feelings of insecurity,<sup>##REF##32744841##18##</sup> decreased vitality,<sup>##REF##33643114##19##</sup> and reduced life satisfaction.<sup>##REF##34501473##20##</sup></p>", "<p> However, lenient measures were not necessarily better. Indeed, the slow introduction of strict measures in times of rising hospitalizations was criticized because governments came across as too passive, insufficiently reliable or incompetent to protect the populations’ safety and mental health.<sup>##REF##34456450##12##</sup> Lenient measures may also be an external signal to people that the situation is not quite serious, which would contradict their internal signal of higher risk perception. Interestingly, too lenient measures stimulated a sizeable proportion of the population to spontaneously engage in health-protective behavior such as avoiding social contacts<sup>##REF##33118180##21##</sup> and public transportation.<sup>##REF##34312455##22##</sup> These spontaneous self-restrictions apparently reduced feelings of uncertainty and ambiguity that were provoked by inadequate governmental interventions to contain the (perceived) health threat.<sup>##REF##14769087##23##</sup></p>", "<title> Present Study</title>", "<p> Although prior studies have mainly focused on relating psychological variables to either the epidemiological situation<sup>##REF##35621438##1##</sup> or to stringency of the measures,<sup>##REF##35193043##24##</sup> the above description suggests that their impact is not one-sidedly positive or negative. What may be especially critical is the interaction between both, with the impact of the stringency of behavioral measures varying as a function of the epidemiological threat. In a nutshell, the proportionality between the measures and the actual health situation is of paramount importance with higher fit translating into a better psychological response of the population. Collecting data across the entire pandemic in Belgium, the current study seeks, as far as we know for the first time, to examine the interplay between the actual epidemiological situation (in terms of the hospitalization load) and the stringency of the measures (in terms of the stringency index<sup>##REF##34242239##5##</sup>) in predicting a wide range of behavioral, motivational, and mental health outcomes.</p>", "<p> Specifically, we focus on people’s self-reported adherence to the measures and their motivation for doing so within the framework of the Self-Determination Theory.<sup>##UREF##7##16##</sup> In addition to amotivation (ie, denoting a low level of motivation), two qualitatively different types of motivation are discerned. Autonomous or high-quality motivation reflects the full endorsement of measures out of personal value and conviction, whereas controlled or poor-quality motivation represents pressured form of motivation (eg, to avoid sanctions). Higher mental health is evidenced when the basic psychological needs for autonomy (perceived authenticity and psychological freedom), competence (perceived mastery and efficacy in the things one do) and relatedness (feeling warm relationships with others) are fulfilled and was assessed through of the presence of vitality and life satisfaction and absence of symptoms of depression and anxiety.<sup>##REF##35621438##1##</sup></p>", "<p> The herein proposed <italic toggle=\"yes\">proportionality hypothesis</italic> specifically aimed to shed light on the interplay between these stringency and epidemiological threat.<sup>##REF##16318600##25##,##UREF##9##26##</sup> Specifically, we hypothesized that the level of behavioral adherence, motivation, risk perception, and mental health of the population depends on the proportionality (or fit) between the stringency of the measures and the actual epidemiological threat. We tested our proportionality hypothesis from two angles. First, we reasoned that a higher daily hospitalization load would predict a less adaptive pattern of motivation and well-being outcomes (eg, vitality, depression symptoms) when a more lenient, instead of a stricter, set of measures prevails. For instance, stricter measures would buffer against the higher anxiety experienced on days with a high number of hospitalizations. Also, stricter measures would not necessarily be experienced as autonomy-constraining because, if they come across as appropriate in the given circumstances, they may foster endorsement of and commitment to the measures. Conversely, the absence of strict measures on days with high hospitalization load would erode people’s motivation to adhere to the measures, possibly because it may elicit a sense of helplessness and lack of control. A second way to examine the interplay between hospitalization load and stringency of the measures is to zoom in on those days with low hospitalizations rates. If the measures in place are still strict on these days, they may be experienced as frustrating basic needs for autonomy, competence, and relatedness and undermining people’s mental health. Conversely, lenient measures in such situation will afford greater opportunities for basic need satisfaction and improved mental health.<sup>##UREF##9##26##</sup></p>" ]	[ "<title>Methods</title>", "<title> Participants and Procedure</title>", "<p> From the first day of the Belgian lockdown, we launched an online questionnaire through social media platforms and newspapers. We advertised the study as dealing with people’s experiences during lockdown. Prior to completing the questionnaire, participants signed an informed consent in which the voluntary nature of the study was emphasized. People could quit anytime without negative consequences and the collected data would be handled confidentially. Initially, we distributed the questionnaire on a daily basis but the pace of collecting data went down after 60 days.</p>", "<p> We collected data from March 19, 2020 until May 16, 2022 (ie, 788 days), with at least 30 participants completing the questionnaire on any given day for 421 days (ie, 53.4%). This periods contains 211 days (50%) before March 2021, the month in which the vaccination campaign for the total population started. In total, 273 722 participants (<italic toggle=\"yes\">M</italic><sub>age</sub> = 49.47; 63.9% female; 33% single) completed the questionnaire, with an average of 644 participants per day (range: 32–6363). Participants who already had completed the questionnaire before were excluded (ie, based on their email address and an item assessing previous completions of the questionnaire). Further, 32.4% reported to have no or secondary graduation, 36.8% had a Bachelor’s degree and 30.8% had a Master’s degree. In total, 80.6% reported to have no comorbidities with 16.2% reported to have one.</p>", "<title> Measures</title>", "<title> Adherence</title>", "<p> We assessed self-reported adherence to the four most important corona measures in Belgium (ie, washing hands, wearing a mouth mask, avoiding contact with others, and maintaining physical distance) with one item each. Participants indicated on a scale ranging from 1 (“I do not adhere to it at all”) to 5 (“I totally adhere to it”) the extent to which they followed each of the four measures. Internal consistency was acceptable, with a Cronbach’s alpha of 0.84 on the between-day level and a Cronbach’s alpha of 0.81 on the between-person level.</p>", "<title> Motivation</title>", "<p> We assessed people’s motivation to adhere to the corona safety measures with an adapted version of the Behavioral Regulation in Sport Questionnaire.<sup>##REF##18648109##27##</sup> After the stem “Over the past week, I adhered to these measures…,” people answered four items for autonomous motivation (eg, “…because I find it personally relevant”; α<sub>between-days</sub> = 0.89, α<sub>between-person</sub> = 0.81) and 4 items for controlled motivation (eg, “…because I feel compelled to do so”; α<sub>between-days</sub> = 0.86, α<sub>between-person</sub> = 0.82). Additionally, we conducted 4 items for amotivation assessing reasons for not adhering the measures (eg, “…because I do not believe that the current approach to the corona crisis helps solve the problem cause”; α<sub>between-days</sub> = 0.86, α<sub>between-person</sub> = 0.74). Respondents rated items on a 5-point scale ranging from 1 (“not at all true”) to 5 (“totally true”). Internal consistencies were acceptable on both levels.</p>", "<title> Risk Perception</title>", "<p> We measured risk perception with four items,<sup>##UREF##10##28##</sup> two of which asked participants to estimate the probability to be infected by the coronavirus in the near future (1 = “Very small” to 5 = “Very big”; α<sub>between-days</sub> = 0.83, α<sub>between-person</sub> = 0.79) and two items the severity of the symptoms when infected (1 = “Not at all serious” to 5 = “Very serious”; α<sub>between-days</sub> = 0.81, α<sub>between-person</sub> = 0.80). Participants answered both questions twice, once with respect to themselves and once with respect to the Belgian population.</p>", "<title> Psychological Need Satisfaction</title>", "<p> Participants completed a brief version of the Basic Psychological Need Satisfaction and Need Frustration Scale (12 items).<sup>##UREF##11##29##</sup> They rated items in reference to the preceding week on a 5-point scale ranging from 1 (“not at all true”) to 5 (“totally true”). Six items assessed participants’ experience of satisfaction and six others the frustration of the psychological needs for autonomy, relatedness, and competence. To reduce the number of variables, a composite score was created by subtracting the averaged need frustration score from the averaged need satisfaction. As a result, the relative index ranged from -4 to +4 with 0 denoting the tipping point between frustration (ie, negative score) and satisfaction (ie, positive score). Example items are: “I felt that my decisions reflected what I really wanted” (ie, autonomy), “I had the impression that people I spent time with disliked me” (ie, relatedness), and “I felt confident that I could do things well” (ie, competence). Internal consistencies were acceptable for autonomy (α<sub>between</sub>= 0.84; α<sub>within</sub>= 0.65), competence (α<sub>between</sub>= 0.78; α<sub>within</sub>= 0.67) and relatedness (α<sub>between</sub>= 0.78; α<sub>within</sub>= 0.64).</p>", "<title> Well-Being</title>", "<title> Life Satisfaction and Vitality</title>", "<p> To measure life satisfaction, we selected the item “In the previous week, I was satisfied with my life.” of the Satisfaction with Life Scale<sup>##UREF##12##30##</sup> in line with the study of Brenning et al.<sup>##REF##36252954##31##</sup> We did the same for vitality based on the Subjective Vitality Scale scale (“In the previous week, I felt energized”<sup>##REF##9327588##32##</sup>) and asked participants to report on a scale ranging from 1 (“seldom or never, less than 1 day”) to 4 (“mostly or all the time, 5 to 7 days”). We chose this single item method for the sake of practicality<sup>##UREF##13##33##</sup> while losing little validity of these measures.<sup>##REF##24890827##34##</sup></p>", "<title> Depressive and Anxiety symptoms</title>", "<p> We assessed depressive symptoms by means of a 6-item version of the Center for Epidemiological Studies—Depression scale (CES-D<sup>##REF##19348103##35##,##UREF##14##36##</sup>). We measured anxiety symptoms with a 4-item version of the State Trait Anxiety Inventory (STAI<sup>##REF##1393159##37##</sup>). We added one item from the full version of the STAI to tap into anxiety in a more direct way (ie, “I felt anxious”). The stem (ie, “During the past week”) preceded all items and participants provided their answers on a scale ranging from 1 (“seldom or never, less than 1 day”) to 4 (“mostly or all the time, 5 to 7 days”). Internal consistencies were acceptable for both depressive symptoms (α<sub>between</sub>= 0.76; α<sub>within</sub>= 0.61) and anxiety symptoms (α<sub>between</sub>= 0.73; α<sub>within</sub>= 0.59).</p>", "<title> Hospitalizations</title>", "<p> We secured data on hospitalizations from Sciensano, the national public health institute.<sup>##UREF##0##2##</sup> As this parameter comes in exponentials, we log-transformed this variable to include it in linear analyses. The hospitalization numbers relied on the same data collection protocol throughout the period covered in our study (See Figure S1, ##SUPPL##0##Supplementary file 1##).</p>", "<title> Stringency of the Measures</title>", "<p> To operationalize the strictness of the implemented measures, we used the Stringency index.<sup>##REF##34242239##5##</sup> These authors tracked the strictness of measures across the world and generated the Oxford COVID-19 Government Response Tracker (OxCGRT). OxCGRT provides a percentage representing the level of stringency of restrictions across time and relies on nine indicators: school closures, workplace closures, cancellation of public events, restrictions on public gatherings, closures of public transport, stay-at-home requirements, public information campaigns, restrictions on domestic movements, and international travel controls. The index on a given day corresponds to the mean score of the nine metrics, each ranging from 0 (the most lenient restrictions) to 100 (the most severe restrictions; See Figure S2).</p>", "<title> Plan of Analysis</title>", "<p> All analyses were done in Rstudio.<sup>##UREF##15##38##</sup> Before inspecting the associations between variables at the between-day level, we calculated the intra-class correlation (ICC). The ICC reflects how strongly observations within days are associated and thus represents the proportion of between-day variance relative to the within-day (or between-person) variance. Because our predictors (ie, hospitalizations and stringency) are at the between-day level, a sufficient amount of variance in the outcomes needs to be at the between-day level to justify the use of a multilevel approach.<sup>##REF##21687445##39##</sup> Next, we calculated Pearson correlations to check for the associations between variables at the between-day and within-day level.</p>", "<p> In the main analyses, we examined the unique and interactive contribution of hospitalization load and stringency index. As both predictors varied only between days, we used linear mixed regression with ‘days’ as the random effect, thereby allowing the model to calculate the parameters and statistics accounting for the level of dependent variance in the dataset within days (ie, between-persons). In addition, we controlled the current associations for differences between two phases of the crisis, with phase 1 (19/03/2020–28/02/2021) as the first year of the crisis with no vaccinated people and phase 2 (01/03/2021–19/03/2022) including other variants (like omicron) and a particular number of vaccinated people in the population. Both continuous predictors were centered to keep the standard deviation (SD) of the variables original for the sake of interpretability.<sup>##UREF##16##40##</sup> Also, we calculated variance-inflation-factors (VIFs) to check for the level of multicollinearity, which is indicated by VIF-values higher than 4. In their output, we rely on standardized coefficients. Also, we added effect sizes by calculating the partial eta-square, because <italic toggle=\"yes\">P </italic>values are affected by the size of the current sample. An eta-squared of 0.01 indicates a small effect, while a value between 0.02 and 0.06 indicates a moderate effect and everything higher than 0.08 indicates a large effect.<sup>##UREF##17##41##</sup></p>", "<p> To gain a clear understanding of significant interaction effects, we show the effect of hospitalization numbers on a given outcome by the level of the stringency index. In the output, we therefore report the Johnson-Neyman interval,<sup>##REF##14797902##42##</sup> showing for which values of the stringency index the simple slopes are significant (See example Figure S3). For the sake of visibility, we calculated the predicted values of the model for low (-1 SD) and high (+1 SD) levels, corresponding to, respectively, 39% and 72% for the stringency of the measures and 1130 (7.03) and 4230 (8.35) (logged) daily hospitalizations.</p>", "<p> For these levels, we also added standardized simple slope coefficients to the figure. Finally, to obtain a clear and summarizing overview of the various findings, involving 11 outcomes, we created a bar plot with the centered predicted values of the linear mixed regression models across four situations. These four situations are identical to the four points in the interaction figures and, hence, reflect different combinations of low vs. high hospitalizations and lenient vs. strict measures. The syntax and anonymized data can be found on <uri xlink:href=\"https://osf.io/sa498/\">https://osf.io/sa498/</uri>.</p>" ]	[ "<title>Results</title>", "<title> Preliminary Analyses</title>", "<p> First, the ICC’s justified the use of a multilevel approach, with 3%-14% of the variance in the outcomes showing at the between-day level. Second, Pearson correlations can be found in ##TAB##0##Table 1##, with correlations on the between-person level in the upper diagonal and those on the between-day level in the lower diagonal. The number of daily hospitalizations was positively, yet modestly, correlated with the stringency index. As ##FIG##0##Figure 1## shows, there were days during the crisis with a high number of hospitalizations and a non-stringent set of measures and vice versa, even within both crisis phases.</p>", "<p> Further, when compared to the stringency of the measures, the number of daily hospitalizations yielded a less strong and pronounced pattern of correlates with the various outcomes. Number of daily hospitalizations related positively to behavioral adherence, autonomous motivation, and perceived infection. Rather surprisingly, number of daily hospitalizations was unrelated to perceived severity of infection. Finally, daily hospitalizations correlated with one of the three basic needs (ie, lower competence) and three of the four well-being outcomes, that is, people reported somewhat higher symptoms of anxiety and lower vitality and life satisfaction on days when more hospitalizations were recorded. The stringency index yielded a stronger pattern of correlates, with stringency being positively correlated with adherence, autonomous motivation, perceived severity, and symptoms of anxiety and depression and being negatively correlated with amotivation, need satisfaction, vitality, and life satisfaction.</p>", "<title> Primary Analyses</title>", "<p> The output of the linear mixed regression models with standardized coefficients and model information can be found in ##TAB##1##Tables 2## and ##TAB##2##3##. In general, no models showed indication for multicollinearity. As a main effect, the stringency of the measures was positively related to adherence, autonomous motivation, perceived severity as well as symptoms of depression and anxiety, while being negatively related to perceived infection, satisfaction of all three psychological needs, vitality, and life satisfaction. A similar pattern of findings emerged for hospitalization load, although no unique effect was found for controlled motivation and amotivation. First, these main effects of both predictors are distinct from the effect of the crisis phase, which showed that the second phase included lower adherence, autonomous motivation, risk perception and need satisfaction, and higher controlled motivation and amotivation. Second, these effects should be interpreted with caution given that an interaction effect emerged systematically in the prediction of all thirteen outcomes. Partial eta squares indicate that these interaction effects were moderate to large (ranging between 0.02 and 0.26).</p>", "<p> The pattern of interactions was similar for all outcomes, with the effect of high versus low hospitalization load being reduced to non-significance or even reversed as a function of the stringency of the measures. Whereas under conditions of high stringency, high versus low hospitalization load contributed positively to adherence, autonomous motivation (##FIG##1##Figure 2##), perceived severity (##FIG##2##Figure 3##), all three need satisfactions (##FIG##3##Figure 4##), life satisfaction, and symptoms of anxiety and depression (##FIG##4##Figure 5##), a negative association emerged under conditions of low stringency. When observing the Johnson-Neyman intervals, perceived infection is the only variable with only significant slopes for low values, indicating that higher hospitalizations never significantly resulted in lower perceived infection.</p>", "<p> Although the interaction analyses allow one to examine whether the contribution of hospitalization load differed as a function of stringency, ##FIG##5##Figure 6## provides a more detailed insight through direct mean-level comparison of the four critical cells in the interaction figures. For the sake of interpretability, the proportional situations (strict-high, lenient-low) are visualized as the two sets of bars in the middle of each panel. Congruent with our reasoning, we were especially interested in contrasting (<italic toggle=\"yes\">a</italic>) high versus low hospitalization load in case of strict measures (ie, first two columns for each outcome; grey zone in ##FIG##5##Figure 6##) and (<italic toggle=\"yes\">b</italic>) high versus low hospitalization load in case of lenient measures (ie, last two columns for each outcome, white zone in ##FIG##5##Figure 6##).</p>", "<p> When hospitalizations were high compared to low, strict measures came with more adherence and autonomous motivation, less controlled motivation and amotivation, a higher perceived risk for infection and severity, less psychological need frustration, more vitality and life satisfaction, and less anxiety and depressive symptoms. In case of lenient measures, the opposite pattern emerged: high relative to low hospitalizations resulted in less adherence, less autonomous motivation, more controlled motivation and amotivation, more perceived infection and less perceived severity, more need frustration, less vitality and life satisfaction, and more symptoms of anxiety and depression.</p>" ]	[ "<title>Discussion</title>", "<p> During the COVID-19 pandemic, governments had to navigate between on the one hand controlling the epidemiological situation by imposing behavioral restrictions and on the other hand maintaining people’s motivation to adhere to the measures, enforcing the mental health of the population and avoid societal rebelliousness.<sup>##REF##32682159##43##,##REF##34299896##44##</sup> Duringpost-pandemic times, different countries took the initiative to install committees to reflect on and evaluate the management of the COVID-19 crisis and what could be learned for future crises. The present study, that is based on a large dataset collected throughout the entire pandemic, is of direct added value to such evaluations as we examined the interplay between the epidemiological situation (based on the actual daily hospitalizations) and the stringency of the measures (based on the stringency index) in the prediction of people’s psychological and behavioral functioning. Assessing a wide range of critical outcomes throughout the pandemic, including people’s adherence, motivation, risk perception and mental health, we predicted and indeed found an intriguing pattern of findings.</p>", "<title> The Role of Proportional Stringency of Health-Protective Measures</title>", "<p> Day-to-day variation in hospitalization load and stringency predicted uniquely day-to-day variation in all outcomes. Yet, the most striking and consistent pattern of findings concerns the hypothesized two-way interaction effects. The effect sizes of these interactions were in many cases the highest and their interplay <italic toggle=\"yes\">qualified </italic>the observed main effects for hospitalization load and stringency. Our findings highlight the importance of approaching the psychological effects of the pandemic through the perspective of proportionality (or fit), rather than solely through the main effects of both. A comparison of the mean level differences of the four extreme cells (ie, high-low, strict-lenient) in ##FIG##5##Figure 6## provides a more detailed insight. Overall, the best outcomes are obtained when the stringency of the measures were proportional to the urgency of the epidemiological situation, as indexed by hospitalization load. In line with the proportionality hypothesis, strict measures come with more favorable outcomes in case of high hospitalization load, while lenient measures come with more favorable outcomes in case of low hospitalization load.</p>", "<p> On days when measures were disproportionally strict (ie, low-strict; cell 1 in ##FIG##5##Figure 6##), people’s well-being was compromised, with citizens reporting more symptoms of anxiety and depression and lower life satisfaction and vitality. A variety of factors could potentially play a role herein. First, on such days, the basic psychological needs for autonomy, competence, and relatedness may be under threat, thus entailing experiences of need frustration which is a robust predictor of madadjustement.<sup>##UREF##18##45##</sup> While people may accept the restriction of freedom, this is no longer the case when the stringency of the measures is disproportional to the hospitalization load. Second, the elevated anxiety may reflect citizens’ concerns regarding how long these strict measures would last and whether they would ever get removed, raising worries regarding the predictability of the situation. Third, people may begin to look back at the time when no strict measures were imposed on them. Such a comparison may elicit feelings of resentment, if not anger and even rebelliousness, which explains why their controlled motivation and amotivation to adhere to measures is highest under these circumstances.<sup>##UREF##19##46##</sup> Hence, to preserve people’s motivation, need satisfaction and mental health, strict measures can better be withdrawn as soon the epidemiological situation allows.</p>", "<p> In contrast, when strict measures were proportional (ie, high-strict; cell 2 in ##FIG##5##Figure 6##), a more adaptive pattern appears. In spite of the presence of strict measures, citizens report higher adherence and display a more adaptive motivational pattern characterized by high autonomous and low controlled motivation and low amotivation. Presumably the risk to become severely ill makes strict measures perceived as a proportional and, therefore, internalized.<sup>##UREF##20##47##,##REF##33047037##48##</sup> Internalized measures are considered adequate responses to handle the health threat and result in more autonomously motivated compliance.<sup>##UREF##19##46##,##REF##20980707##49##</sup> Also in terms of need satisfaction, strict measures do not come by definition with a loss of need-satisfying opportunities. After all, strict measures were often taken on moments when the situation was highly uncertain and, hence, strict measures would potentially bring back a sense of control and safety in life. In other words, strict measures may contribute to preserving people’s well-being and serving as a buffer against a potential rise in anxiety. Prior work in other contexts such as schooling<sup>##UREF##21##50##</sup> and procedural justice<sup>##UREF##9##26##</sup> similarly suggests that measures and rules are less likely to thwart people’s basic psychological needs and well-being when they are perceived to be proportional.<sup>##REF##16318600##25##</sup></p>", "<p> Much as strict measures are not inherently ‘bad’ or ‘good,’ this is also the case for lenient measures: also lenient measures can be disproportional in relation to the epidemiological situation (ie, lenient-high; cell 4 in ##FIG##5##Figure 6##). On such days, people report more maladjustment compared to a situation characterized by a proportional lenient policy (ie, lenient-low). When a government fails to take action when the hospitalization load is high, people report higher anxiety and depressive complaints, lower need satisfaction, and they display a maladaptive motivational pattern. The anxiety arising under these circumstance may now be due to people’s health concerns, induced by the absence of a swift and coordinated action to prevent a further escalation of the situation. In light of governments’ failure or courage to introduce strict measures, people seem to become demotivated. They question the overall strategy of the government and may no longer believe that their actions result in desirable outcomes.</p>", "<p> Three additional findings deserve being mentioned. First, across the four situations, the most optimal situation is when lenient measures are proportional. ie, lenient-low; cell 3 in ##FIG##5##Figure 6##. Such days are marked by the lowest levels of controlled motivation and amotivation, low perceived infection, the highest levels of need satisfaction, the highest well-being (ie, vitality and life satisfaction) and the lowest ill-being (ie, anxiety and depressive symptoms). One could approach such period as a crisis-absent situation, as neither measures nor hospitalizations are high on such days.</p>", "<p> Second, both types of risk perception — the probability and severity component — show a different pattern. The highest levels of perceived infection rate are reported on days with disproportional lenient measures, while perceived severity is the lowest on such days. Although people perceived a high risk to be infected, the low stringency of the measures apparently results in a low perceived severity of symptoms. Apparently, this suggests that the stringency of the measures qualifies the meaning of the epidemiological situation. In line with this reasoning, we note that the perceived severity only follows the hospitalization numbers on days with proportionally strict measures.</p>", "<p> Third, we found significant differences for the phase of the crisis. Our dataset includes data collected across two years of the COVID-19 crisis in Belgium, but obviously, across time several fundamental parameters changed. For instance, the vaccination campaign starting from March 2021 for the general population and the rising of COVID-19 variants with different features (eg, Omicron) should be considered, as they affected people’s perception to be infected and to have severe symptoms, and their motivation to adhere health-protective measures.<sup>##REF##34961635##51##</sup> As another example, some authors addressed the concept of ‘pandemic fatigue’ as the perceived inability to keep up with the restrictions.<sup>##REF##34345009##52##</sup> The current findings support this idea, with the second part of the crisis having significantly lower levels of behavioral adherence and autonomous motivation, higher controlled motivation and amotivation, lower risk perception, more need frustration and lower vitality. However, effect sizes differed. Although it could be expected the pandemic impacted people’s mental health significantly, it was especially for these variables that the lowest effect sizes were found.</p>", "<title> Implications for Policy and Future Crises</title>", "<p> The current findings are of utmost importance for policy-makers as they provide a unique and informative insight in the effects of the conducted policy on diverse aspects of people’s psychological functioning. A critical question is how disproportional situations could have been avoided by policy-makers. In our view, the introduction of a “corona barometer” is critical.<sup>##UREF##22##53##</sup> A corona barometer is a color-coded schema in which each color represents a set of measures that become operational in accordance with predefined epidemiological thresholds (eg, hospitalization numbers, for examples, see Ireland and New-Zealand). This entails a number of psychological advantages, including a greater sense of control and predictability for both policy-makers and citizens and may help to install a balanced or proportional set of measures in accordance with the epidemiological situation. A corona barometer would also allow the population to better anticipate upcoming political decisions in view of the changing epidemiological situation and support policy-makers to communicate clearly.<sup>##UREF##23##54##</sup> This may help people not only to prepare better for new restrictions but also to take greater responsibility for their behavior in the actual epidemiological context and to induce a sense of “ownership” of the measures. Due to the lack of a colour-coded schema in Belgium, people were often surprised by unexpected (in time) and disproportional (in stringency) political interventions, which were perceived to be based on unclear and undefined criteria.</p>", "<p> Our findings may also relate to the role of perceived legitimacy and procedural justice.<sup>##REF##16318600##25##</sup> Procedural justice refers to the public perception that authorities’ decisions are fair and justifiable, resulting in more positive feelings,<sup>##UREF##24##55##</sup> higher trust,<sup>##UREF##25##56##</sup> and more autonomous motivation.<sup>##UREF##9##26##</sup> Even when politicians have to take tough decisions, the principles of procedural justice may work as an important moderator for their psychological effects. That is, even when measures are intrusive and demanding on the part of the citizens, communication that is open, transparent, timely, and informed should buffer for its negative impact. By cultivating this notion of proportionality, politicians might not only enhance the legitimacy of their actions, but also the perception of them as taking care of the concerns of the population with both competence and benevolence.<sup>##REF##35344775##57##</sup></p>", "<title> Limitations</title>", "<p> The current study involved the collection of multiple cross-sectional waves as independent groups of participants took part in the study across time. Due to the lack of longitudinal data across time, we are only able to compare mean-level differences between days to shed light on the direction of effects. For instance, although the slow introduction of strict measures in times of increasing hospitalization numbers may have caused growing levels of anxiety, anxiety may also have prevented policy-makers from introducing stringent measures which they feared would deteriorate individuals’ well-being.</p>", "<p> The sample itself was rather self-selective as only individuals with internet access and both the understanding and willingness to complete a questionnaire participated in the study. Also in terms of sociodemographical variables, we had a higher prevalence of women having a partner and a higher education. As previous research already demonstrated the significant role of these factors in the current study variables, with especially male, being single and having a lower education resulting in lower autonomous motivation, lower well-being and lower adherence, the absolute means in terms of the population might be underrepresented in the current findings. This is the reason why we especially focused on the structural associations within the current dataset.</p>", "<p> The present proportionality hypothesis draws upon the idea that measures vary in their level of perceived legitimacy.<sup>##REF##16318600##58##</sup> Yet, this underlying mechanism was not tested as such, as has been the case in earlier research.<sup>##REF##20980707##49##</sup> Future research may more directly test the mediational role of this psychological mechanism to account for the interplay between stringency and hospitalization load on people’s motivation, risk perception, and well-being. It is important to consider the actual meaning of a (dis)proportional situation. For the sake of interpretation, we currently displayed the predicted values for ‘Low’ and ‘High’ values, corresponding one SD from the mean of the stringency index and (logged) hospitalization numbers. Of course, whether the numbers absolutely represent lenient or strict measures or low or high hospitalizations remains open to debate. These labels were currently determined based on a data-driven approach. Admittedly, and although the literature lacks well-established recommendations about these issues, a epidemiological perspective on these results might provide a different interpretation of these results.</p>" ]	[ "<title>Conclusion</title>", "<p> Given the uncertain character of the COVID-19 pandemic, national authorities faced the challenge to react appropriately as the epidemiological situation evolved. In the current study, we examined on a daily level how the interplay between the actual epidemiological situation and the objectively reported stringency of the measures affected people’s self-reported adherence, motivation, risk perception, need satisfaction, and well-being. Results showed that when the governmental interventions were not proportionate to the epidemiological situation, lower levels of adherence, autonomous motivation, need satisfaction, and well-being ensued. Specifically, when lenient measures were disproportional, respondents reported even more controlled motivation, amotivation and risk of infection. These results are striking, as they provide a hitherto unsuspected view on how health-protective measures may shape the effects of the pandemic on people’s behavioral and psychological functioning.</p>" ]	[ "<p>\n<bold>Background:</bold> The stringency of the measures taken by governments to combat the COVID-19 pandemic varied considerably across countries and time. In the present study, we examined how the proportionality to the epidemiological situation is related to citizens’behavior, motivation and mental health.\n</p>", "<p><bold>Methods:</bold> Across 421 days between March 2020 and March 2022, 273,722 Belgian participants (<italic toggle=\"yes\">M<sub>age</sub></italic> = 49.47; 63.9% female; 33% single) completed an online questionnaire. Multiple linear mixed regression modeling was used to examine the interaction between the epidemiological situation, as indicated by the actual hospitalization numbers, and the stringency index to predict day-to-day variation in the variables of interest.\n</p>", "<p><bold>Results:</bold> Systematic evidence emerged showing that disproportional situations, as opposed to proportional situations, were associated with a clear pattern of maladaptive outcomes. Specifically, when either strict or lenient measures were disproportional in relation to the epidemiological situation, people reported lower autonomous motivation, more controlled motivation and amotivation, less adherence to sanitary rules, higher perceived risk of infection, lower need satisfaction, and higher anxiety and depressive symptoms. Perceived risk severity especially covaried with the stringency of the measures. At the absolute level, citizens reported the highest need satisfaction and mental health during days with proportional lenient measures.\n</p>", "<p><bold>Conclusion:</bold> Stringent measures are not per se demotivating or compromising of people’s well-being, nor are lenient measures as such motivating or enhancing well-being. Only proportional measures, that is, measures with a level of stringency that is aligned with the actual epidemiological situation, are associated with the greatest motivational, behavioral, and mental health benefits.</p>", "<p>\n<bold>Citation:</bold> Waterschoot J, Morbée S, Van den Bergh O, et al. How the stringency of the COVID-19 restrictions influences motivation for adherence and well-being: the critical role of proportionality. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8021. doi:10.34172/ijhpm.2023.8021</p>" ]	[ "<title>Acknowledgements</title>", "<p> The Motivation Barometer is an initiative launched by the University of Ghent, and it eventually brought together researchers from the University of Leuven, the Université catholique de Louvain, and the Université libre de Bruxelles. The Motivation Barometer was continued throughout the pandemic thanks to funding provided by the University of Ghent and the Belgian Ministry of Public Health.</p>", "<title>Ethical issues</title>", "<p> The project was approved by the ethical committee of Ghent University, Belgium (N° 2020/37). Informed consent was obtained from all the participants. All methods/protocols were performed in accordance with the relevant guidelines and regulations.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Data Availability Statement</title>", "<p> All analysis code, and research materials are available at Open Science Framework (<uri xlink:href=\"https://osf.io/sa498/\">https://osf.io/sa498/</uri>). Correspondence concerning this article should be addressed to Joachim Waterschoot, Faculty of Psychology, Department of Developmental, Personality, and Social Psychology, Ghent, Belgium. Email: <email>[email protected]</email>, Tel. + 09 264 62 70.</p>", "<title>Funding</title>", "<p> This work was supported by the Belgian Federal Ministry of Health through RIZIV (Rijksinstituut voor ziekte- en invaliditeitsverzekering)/INAMI (institut national de maladie-invalidité). They had no role in any part of the work.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nScatterplot With Distributions Between the Stringency Index and the (Logged) Number of Hospitalizations by Phase of The Crisis. <italic toggle=\"yes\">Note. </italic>A dot represents one day. We jittered the positions of the dots with value 1 to provide a overview of all dots without overlap.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nVisualizations of Interaction Effects for Adherence and Types of Motivation With Standardized Simple Slope Coefficients. <italic toggle=\"yes\">Note</italic>: * <italic toggle=\"yes\">P</italic> <.05, <italic toggle=\"yes\">P</italic> <.01, * <italic toggle=\"yes\">P</italic> <.001; ‘Low’ and ‘High’ refer to the standard deviations, respectively, under and above the mean of the variable. n.s. refers to the values of the stringency index (as moderator) for which the association between hospitalization and the outcome is not significant, from left to right: [-0.94, -0.14], [-0.29, -0.00], [-0.08, 0.15], and [-0.07, 0.13].</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nVisualizations of Interaction Effects for Risk Perception With Standardized Simple Slope Coefficients. <italic toggle=\"yes\">Note</italic>: * <italic toggle=\"yes\">P</italic> <.05, <italic toggle=\"yes\">P</italic> <.01, * <italic toggle=\"yes\">P</italic> <.001; ‘Low’ and ‘High’ refer to the standard deviations, respectively, under and above the mean of the variable. n.s. refers to the values of the stringency index (as moderator) for which the association between hospitalization and the outcome is not significant, from left to right: [0.53, 1.25] and [-0.01, 0.28].</p></statement></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4</label><statement><p>\nVisualizations of Interaction Effects for Basic Psychological Needs With Standardized Simple Slope Coefficients. <italic toggle=\"yes\">Note</italic>: * <italic toggle=\"yes\">P</italic> <.05, <italic toggle=\"yes\">P</italic> <.01, * <italic toggle=\"yes\">P</italic> <.001. We only showed the y-axis from -1.5 to 2.5, instead of the full -4 to +4 range, for the sake of interpretability; ‘Low’ and ‘High’ refer to the standard deviations, respectively, under and above the mean of the variable. n.s. refers to the values of the stringency index (as moderator) for which the association between hospitalization and the outcome is not significant, from left to right: [0.03, 0.22], [-0.05, 0.76], and [0.06, 0.34].</p></statement></fig>", "<fig position=\"float\" id=\"F5\"><label>Figure 5</label><statement><p>\nVisualizations of Interaction Effects for Well-Being With Standardized Simple Slope Coefficients. <italic toggle=\"yes\">Note</italic>: * <italic toggle=\"yes\">P</italic> <.05, <italic toggle=\"yes\">P</italic> <.01, * <italic toggle=\"yes\">P</italic> <.001; ‘Low’and ‘High’ refer to the standard deviations, respectively, under and above the mean of the variable. n.s. refers to the values of the stringency index (as moderator) for which the association between hospitalization and the outcome is not significant, from left to right: [0.17, 0.87], [0.29, 0.64], [0.41, 0.78], and [0.21, 0.54].</p></statement></fig>", "<fig position=\"float\" id=\"F6\"><label>Figure 6</label><statement><p>\nSummarized Figure of Interactions for the <italic toggle=\"yes\">High</italic> and <italic toggle=\"yes\">Low</italic> Levels of Hospitalizations and Stringency Index. Note. The bars in this figure refers to the values of low and high hospitalization numbers and stringent measures, based on the interaction effect visualized in ##FIG##2##Figures 3##-##FIG##4##5##.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Multilevel Pearson Correlations on the Between-Day (Lower Diagonal) and Between-Person (Upper Diagonal) Level\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Mean</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>SD</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>ICC</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>1.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>2.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>3.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>4.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>5.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>6.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>7.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>8.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>9.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>10.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>11.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>12.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>13.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>14.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>15.</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Crisis-related factors</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1. Hospitalisations</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7.69</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.66</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2. Stringency index</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">55.37</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">16.5</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.23<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Motivation</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3. Adherence</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.91</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.00</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.13</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.11<sup>b</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.72<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.63<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.26<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.49<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.27<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.50<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.24<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.04<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.06<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.04<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.06<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.04<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4. Autonomous</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.45</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.17</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.13</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.12<sup>b</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.39<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.84<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.43<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.63<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.36<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.61<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.47<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.11<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.20<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.11<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.16<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.08<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.14<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5. Controlled</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.61</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.05</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.06</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.01</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.14<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.31<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.70<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.45<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.14<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.30<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.49<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.21<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.25<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.16<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.20<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.20<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.23<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6. Amotivation</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.37</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.90</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.11</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.26<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.75<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.90<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.70<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.26<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.46<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.46<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.22<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.25<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.16<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.20<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.17<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.23<sup>a</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Risk perception</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7. Perceived infection</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.98</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.82</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.07</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.31<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.02</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.04</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.46<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.13<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.05<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.03<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.05<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.01<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.11<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.03<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8. Perceived severity</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.91</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.92</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.14</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.09</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.57<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.85<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.73<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.11<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.69<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.09</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.29<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.08<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.03<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.04<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.01</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Psychological needs</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9. Autonomy</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.20</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.70</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.08</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.43<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.03</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.45<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.88<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.46<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.07</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.11<sup>c</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.45<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.46<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.37<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.43<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.44<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.46<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10. Competence</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.48</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.54</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.10<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.59<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.51<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.28<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.26<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.14<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.16<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.46<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.50<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.53<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.48<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.50<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.57<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.60<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11. Relatedness</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.72</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.46</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.07</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.46<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.26<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.15<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.67<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.14<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.37<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.86<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.67<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.41<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.44<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.43<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.52<sup>a</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Well-being</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12. Vitality</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.72</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.03</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.05</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.15<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.32<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.30<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.09</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.33<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.41<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.44<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.49<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.49<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.65<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.64<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.60<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13. Life satisfaction</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.86</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.04</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.05</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.14<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.27<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.15<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.14<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.55<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.16<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.05</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.22<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.63<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.47<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.61<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.63<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.66<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.63<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14. Anxiety symptoms</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.13</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.80</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.09</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.19<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.21<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.15<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.09</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.47<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.22<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.11<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.21<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.56<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.48<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.52<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.53<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">-0.64<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.76<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">15. Depressive symptoms</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1.7</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.68</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.05</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.10</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.32<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.13<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-0.11<sup>c</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.45<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.18<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.24<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-0.53<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-0.60<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-0.53<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-0.28<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">-0.46<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.50<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Linear Mixed Regression Models With Standardized Coefficients and Effect Sizes (Part A)\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n</td><td rowspan=\"2\" colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\">\n<bold>Adherence</bold>\n</td><td colspan=\"6\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Motivation</bold>\n</td><td colspan=\"4\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Risk Perception</bold>\n</td></tr><tr><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Autonomous </bold>\n<break/>\n<bold>Motivation</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Controlled </bold>\n<break/>\n<bold>Motivation</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Amotivation</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Perceived </bold>\n<break/>\n<bold>Infection</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Perceived </bold>\n<break/>\n<bold>Severity</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Between-subject level</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Age</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.18<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.21<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.21<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.23<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.25<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.05</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Gender [female]</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.19<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.14<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.11<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.14<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education level</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.05</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Comorbidity</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.07</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.07</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.17<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Between-days level</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Phase [second]</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.66<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.50</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.55<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.29</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.36<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.10</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.69<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.44</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.36<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.12<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.56<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.41<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Hospitalizations</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.17<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.07</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.12<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.06</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.47<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.21</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Stringency index</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.22<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.19<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.30<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.42<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.28</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Interaction<sup>b</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.14<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.23<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.39<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.14</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.31<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.16</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.20<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.05</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.15<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.05</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"13\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">Random effects</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">σ<sub>Crisis days</sub></td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.02</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.08</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.04</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.03</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.03</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.04</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">σ<sub>Residuals</sub></td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.71</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.23</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.03</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.74</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.62</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.71</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"13\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">Model information</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Maximum VIF</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.47</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.47</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.32</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.31</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.17</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.04</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">R<sup>2</sup> marginal</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.07</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.07</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.05</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.07</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.02</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.14</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">R<sup>2</sup> conditional</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.72</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.49</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.25</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.56</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.36</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.66</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Linear Mixed Regression Models With Standardized Coefficients and Effect Sizes (Part B)\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n</td><td colspan=\"6\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Basic Psychological Needs</bold>\n</td><td colspan=\"8\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Mental Health</bold>\n</td></tr><tr><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Autonomy</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Competence</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Relatedness</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Vitality</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Life </bold>\n<break/>\n<bold>Satisfaction</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Anxiety </bold>\n<break/>\n<bold>Symptoms</bold>\n</td><td colspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Depression </bold>\n<break/>\n<bold>Symptoms</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>β</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>η</bold><sup>2</sup><sub>p</sub>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Between-subject level</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Age</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.21<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.23<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.16<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.20<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.16<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.25<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.05 </td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.24<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.05</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Gender [female]</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.06</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.05</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.13<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Education level</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.06</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Comorbidity</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.05</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.06</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.06</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Between-days level</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Phase [second]</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.30<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.33<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.31<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.12</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.10</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Hospitalizations</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.08<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.05</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.11<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.20<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.06</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.32<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.46<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.15</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.27<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.06</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Stringency index</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.35<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.38<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.11</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.20<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.45<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.21</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.13<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.09</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.35<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Interaction<sup>b</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.45<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.20</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.08<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.32<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.11</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.39<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.14</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.32<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.10</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">-0.30<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"15\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">Random effects</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">σ<sub>Crisis days</sub></td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.14</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.05</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.04</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.02</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.03</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.02</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.01</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">σ<sub>Residuals</sub></td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">2.64</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">2.32</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">2.09</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.03</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.04</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.62</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.44</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"15\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">Model information</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Maximum VIF</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.46</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.47</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.47</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.24</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.48</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.47</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">1.49</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">R<sup>2</sup> marginal</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.04</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.05</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.02</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.04</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.03</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.07</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.06</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">R<sup>2</sup> conditional</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.28</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.36</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.3</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.53</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.22</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.25</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">0.26</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>The current findings provide a unique and informative insight into how the role of (dis)proportional measures affects different aspects of psychological functioning in the population. </p></list-item><list-item><p>The implementation of stricter measures is not per se demotivating or psychologically damaging if it is proportional and legitimate to what is required. </p></list-item><list-item><p>Milder measures are not per se motivating because they may be perceived as lax and insufficient when a threat requires a political response. </p></list-item><list-item><p>The monitoring of psychological aspects of the population over time is critical in order to closely observe how the population’s perception is affected by even objective parameters and implementations. </p></list-item><list-item><p>During uncertain times such as the COVID-19 crisis, instruments such as a Corona Barometer should be implemented to provide a number of psychological advantages, such as a greater sense of control and predictability. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> During the COVID-19 crisis, people’s motivation and mental health were affected by the epidemiological situation (ie, the number of hospitalizations) and the political situation (ie, the implementation of measures). Although previous work has shown that stricter measures led to lower levels of well-being,<sup>##REF##35621438##1##</sup> we tested the proportionality hypothesis and showed that stricter measures led to lower levels of mental health and motivation only when they were not proportional to the epidemiological situation. Conversely, in times of high hospitalization rates, lenient policies led to higher perceived change in infection and more amotivation. The most ideal pattern was found when both political and epidemiological situations were proportional. These results show that although a proportional situation was required at the macro level, people were willing to control the pandemic without psychological costs. Therefore, as long as the situation requires clear and transparent rules, strict measures could be required.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1 contains Figures S1-S3.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: ICC, intra-class correlation; SD, standard deviation.</p><p>\n<sup>a</sup><italic toggle=\"yes\">P</italic> < .001; <sup>b</sup><italic toggle=\"yes\">P</italic> < .01; <sup>c</sup><italic toggle=\"yes\">P</italic> < .05.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviation: VIF, variance-inflation-factor.</p><p>\n<sup>a</sup><italic toggle=\"yes\">P</italic> < .001.</p><p>\n<sup>b</sup>Interaction refers to the interaction between hospitalizations and stringency index.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviation: VIF, variance-inflation-factor.</p><p>\n<sup>a</sup><italic toggle=\"yes\">P</italic> < .001.</p><p>\n<sup>b</sup>Interaction refers to the interaction between hospitalizations and stringency index.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-8021-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8021-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8021-g003\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8021-g004\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8021-g005\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8021-g006\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-8021-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["2"], "mixed-citation": [" Belgium COVID-19 Studies - Sciensano. Looker Studio. "], "uri": ["http://lookerstudio.google.com/reporting/7e11980c-3350-4ee3-8291-3065cc4e90c2/page/ykUGC?feature=opengraph"]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Bajra", "Aliu", "Aver", "\u010cade\u017e"], "given-names": ["UQ", "F", "B", "S"], "article-title": ["COVID-19 pandemic\u2013related policy stringency and economic decline: was it really inevitable?"], "source": ["Econ Res EkonIstraz"], "year": ["2023"], "volume": ["36"], "issue": ["1"], "fpage": ["499"], "lpage": ["515"], "pub-id": ["10.1080/1331677x.2022.2077792"]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Keeling", "Hill", "Gorsich"], "given-names": ["MJ", "EM", "EE"], "article-title": ["Predictions of COVID-19 dynamics in the UK: short-term forecasting and analysis of potential exit strategies"], "source": ["PLoSComput Biol"], "year": ["2021"], "volume": ["17"], "issue": ["1"], "fpage": ["e1008619"], "pub-id": ["10.1371/journal.pcbi.1008619"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Saeed", "Bader", "Al-Naffouri", "Alouini"], "given-names": ["N", "A", "TY", "MS"], "article-title": ["When wireless communication responds to COVID-19: combating the pandemic and saving the economy"], "source": ["Front Comms Net"], "year": ["2020"], "volume": ["1"], "fpage": ["566853"], "pub-id": ["10.3389/frcmn.2020.566853"]}, {"label": ["10"], "mixed-citation": [" Jalloh MF, Zeebari Z, Nur SA, et al. Drivers of COVID-19 policy stringency in 175 countries and territories: COVID-19 cases and deaths, gross domestic products per capita, and health expenditures. medRxiv [Preprint]. July 7, 2022. "], "uri": ["https://www.medrxiv.org/content/10.1101/2022.07.05.22277269v1"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Ismangil", "Lee"], "given-names": ["M", "M"], "article-title": ["Protests in Hong Kong during the COVID-19 pandemic"], "source": ["Crime Media Cult"], "year": ["2021"], "volume": ["17"], "issue": ["1"], "fpage": ["17"], "lpage": ["20"], "pub-id": ["10.1177/1741659020946229"]}, {"label": ["15"], "mixed-citation": [" Zhao J, Lee M, Ghader S, et al. Quarantine fatigue: first-ever decrease in social distancing measures after the COVID-19 pandemic outbreak before reopening United States. arXiv [Preprint]. June 5, 2020. "], "uri": ["https://arxiv.org/abs/2006.03716"]}, {"label": ["16"], "mixed-citation": [" Ryan RM, Deci EL. Self-Determination Theory: Basic Psychological Needs in Motivation, Development, and Wellness. Guilford Publications; 2017. "]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Vansteenkiste", "Ryan", "Soenens"], "given-names": ["M", "RM", "B"], "article-title": ["Basic psychological need theory: advancements, critical themes, and future directions"], "source": ["MotivEmot"], "year": ["2020"], "volume": ["44"], "issue": ["1"], "fpage": ["1"], "lpage": ["31"], "pub-id": ["10.1007/s11031-019-09818-1"]}, {"label": ["26"], "person-group": ["\n"], "surname": ["Van Petegem", "Trinkner", "van der Kaap-Deeder", "Antonietti", "Vansteenkiste"], "given-names": ["S", "R", "J", "JP", "M"], "article-title": ["Police procedural justice and adolescents\u2019 internalization of the law: integrating self-determination theory into legal socialization research"], "source": ["J Soc Issues"], "year": ["2021"], "volume": ["77"], "issue": ["2"], "fpage": ["336"], "lpage": ["366"], "pub-id": ["10.1111/josi.12425"]}, {"label": ["28"], "person-group": ["\n"], "surname": ["Wolff", "Larsen", "\u00d8gaard"], "given-names": ["K", "S", "T"], "article-title": ["How to define and measure risk perceptions"], "source": ["Ann Tour Res"], "year": ["2019"], "volume": ["79"], "fpage": ["102759"], "pub-id": ["10.1016/j.annals.2019.102759"]}, {"label": ["29"], "person-group": ["\n"], "surname": ["Chen", "Vansteenkiste", "Beyers"], "given-names": ["B", "M", "W"], "article-title": ["Basic psychological need satisfaction, need frustration, and need strength across four cultures"], "source": ["MotivEmot"], "year": ["2015"], "volume": ["39"], "issue": ["2"], "fpage": ["216"], "lpage": ["236"], "pub-id": ["10.1007/s11031-014-9450-1"]}, {"label": ["30"], "person-group": ["\n"], "surname": ["Pavot", "Diener"], "given-names": ["W", "E"], "article-title": ["Review of the satisfaction with life scale"], "source": ["Psychol Assess"], "year": ["1993"], "volume": ["5"], "issue": ["2"], "fpage": ["164"], "lpage": ["172"], "pub-id": ["10.1037/1040-3590.5.2.164"]}, {"label": ["33"], "person-group": ["\n"], "surname": ["Allen", "Iliescu", "Greiff"], "given-names": ["MS", "D", "S"], "article-title": ["Single item measures in psychological science"], "source": ["Eur J Psychol Assess"], "year": ["2022"], "volume": ["38"], "issue": ["1"], "fpage": ["1"], "lpage": ["5"], "pub-id": ["10.1027/1015-5759/a000699"]}, {"label": ["36"], "person-group": ["\n"], "surname": ["Radloff"], "given-names": ["LS"], "article-title": ["The CES-D scale: a self-report depression scale for research in the general population"], "source": ["Appl Psychol Meas"], "year": ["1977"], "volume": ["1"], "issue": ["3"], "fpage": ["385"], "lpage": ["401"], "pub-id": ["10.1177/014662167700100306"]}, {"label": ["38"], "mixed-citation": [" R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2022. "], "uri": ["https://www.R-project.org/"]}, {"label": ["40"], "person-group": ["\n"], "surname": ["Yzerbyt", "Muller", "Judd"], "given-names": ["VY", "D", "CM"], "article-title": ["Adjusting researchers\u2019 approach to adjustment: On the use of covariates when testing interactions"], "source": ["J Exp Soc Psychol"], "year": ["2004"], "volume": ["40"], "issue": ["3"], "fpage": ["424"], "lpage": ["431"], "pub-id": ["10.1016/j.jesp.2003.10.001"]}, {"label": ["41"], "person-group": ["\n"], "surname": ["Levine", "Hullett"], "given-names": ["TR", "CR"], "article-title": ["Eta squared, partial eta squared, and misreporting of effect size in communication research"], "source": ["Hum Commun Res"], "year": ["2002"], "volume": ["28"], "issue": ["4"], "fpage": ["612"], "lpage": ["625"], "pub-id": ["10.1111/j.1468-2958.2002.tb00828.x"]}, {"label": ["45"], "person-group": ["\n"], "surname": ["Vansteenkiste", "Ryan"], "given-names": ["M", "RM"], "article-title": ["On psychological growth and vulnerability: basic psychological need satisfaction and need frustration as a unifying principle"], "source": ["J PsychotherIntegr"], "year": ["2013"], "volume": ["23"], "issue": ["3"], "fpage": ["263"], "lpage": ["280"], "pub-id": ["10.1037/a0032359"]}, {"label": ["46"], "person-group": ["\n"], "surname": ["Morb\u00e9e", "Vermote", "Waterschoot"], "given-names": ["S", "B", "J"], "article-title": ["Adherence to COVID-19 measures: the critical role of autonomous motivation on a short-and long-term basis"], "source": ["Motiv Sci"], "year": ["2021"], "volume": ["7"], "issue": ["4"], "fpage": ["487"], "lpage": ["496"], "pub-id": ["10.1037/mot0000250"]}, {"label": ["47"], "mixed-citation": [" Gangire Y, Da Veiga A, Herselman M. A conceptual model of information security compliant behaviour based on the self-determination theory. In: 2019 Conference on Information Communications Technology and Society (ICTAS) 2019; Durban, South Africa. p. 1-6. "], "pub-id": ["10.1109/ictas.2019.8703629"]}, {"label": ["50"], "person-group": ["\n"], "surname": ["Aelterman", "Vansteenkiste", "Van Keer", "Haerens"], "given-names": ["N", "M", "H", "L"], "article-title": ["Changing teachers\u2019 beliefs regarding autonomy support and structure: the role of experienced psychological need satisfaction in teacher training"], "source": ["Psychol Sport Exerc"], "year": ["2016"], "volume": ["23"], "fpage": ["64"], "lpage": ["72"], "pub-id": ["10.1016/j.psychsport.2015.10.007"]}, {"label": ["53"], "mixed-citation": [" The Brussels Times. Belgium\u2019s Coronavirus Barometer: How Does it Work? "], "uri": ["https://www.brusselstimes.com/203129/belgiums-coronavirus-barometer-how-does-it-work"]}, {"label": ["54"], "person-group": ["\n"], "surname": ["Martela", "Hankonen", "Ryan", "Vansteenkiste"], "given-names": ["F", "N", "RM", "M"], "article-title": ["Motivating voluntary compliance to behavioural restrictions: self-determination theory-based checklist of principles for COVID-19 and other emergency communications"], "source": ["Eur Rev Soc Psychol"], "year": ["2021"], "volume": ["32"], "issue": ["2"], "fpage": ["305"], "lpage": ["347"], "pub-id": ["10.1080/10463283.2020.1857082"]}, {"label": ["55"], "person-group": ["\n"], "surname": ["Mazerolle", "Bennett", "Davis", "Sargeant", "Manning"], "given-names": ["L", "S", "J", "E", "M"], "article-title": ["Procedural justice and police legitimacy: a systematic review of the research evidence"], "source": ["J Exp Criminol"], "year": ["2013"], "volume": ["9"], "issue": ["3"], "fpage": ["245"], "lpage": ["274"], "pub-id": ["10.1007/s11292-013-9175-2"]}, {"label": ["56"], "person-group": ["\n"], "surname": ["Nix", "Wolfe", "Rojek", "Kaminski"], "given-names": ["J", "SE", "J", "RJ"], "article-title": ["Trust in the police: the influence of procedural justice and perceived collective efficacy"], "source": ["Crime Delinq"], "year": ["2015"], "volume": ["61"], "issue": ["4"], "fpage": ["610"], "lpage": ["640"], "pub-id": ["10.1177/0011128714530548"]}]	{ "acronym": [], "definition": [] }	58	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 10; 12:8021	oa_package/33/70/PMC10699813.tar.gz
PMC10699814	0	[ "<title>Background</title>", "<p> Patients with dementia often show complex patterns of multimorbidity, involving various healthcare organisations and professionals, which makes coordination difficult and hinders cost-effective care.<sup>##REF##32738937##1##</sup> Additionally, an increasing share of patients remains living at home, leading to additional challenges in care coordination and a potential increased risk of urgent admissions for people with advanced dementia in case such home-based care is not properly provided and coordinated.<sup>##REF##23510826##2##</sup> Ultimately, this results in higher mortality, reduced quality of life, and increased healthcare expenditures for this patient group.<sup>##REF##28267802##3##,##REF##24472217##4##</sup> Better integration of care is key to bending this cost curve and decreasing admission risks whilst increasing quality of care.<sup>##REF##23510826##2##,##UREF##0##5##,##REF##30429060##6##</sup></p>", "<p> Case management strategies with one dedicated care professional have been shown to be beneficial in this regard,<sup>##REF##25560977##7##</sup> but such strategies are likely to leave other healthcare providers unaware of each other’s care activities and of the health status of their shared patients. Also, case management strategies can be relatively expensive and are probably not sustainable given the growing staff shortages in healthcare.<sup>##REF##16684985##8##,##UREF##1##9##</sup> Alternatively, general practitioners (GPs) have been shown to deliver post-diagnosis dementia care that is of equal quality and cost-effectiveness compared to specialized memory clinics.<sup>##REF##24282511##10##,##REF##22589500##11##</sup> Primary care professionals could therefore potentially play a more prominent role in facilitating high-quality integrated care for patients with dementia; a strategy that has already been shown to be cost-effective for occupational therapy.<sup>##REF##18171718##12##</sup></p>", "<p> The DementiaNet programme is an integrated network-based approach that was implemented in 2015 in the Netherlands to enable this transition towards primary care-based integrated dementia care.<sup>##UREF##2##13##</sup> With the DementiaNet programme, local community care networks were formed to facilitate interprofessional collaboration between primary healthcare professionals from medical, care, and social domains who are caring for the same patients.<sup>##UREF##2##13##</sup> Four key elements apply to each network: (1) a transition towards network-based care; (2) appointment of one or two dedicated network leaders; (3) network goal-setting for quality improvement purposes; and (4) interprofessional training on relevant self-chosen topics.<sup>##UREF##2##13##</sup> In total, 40 networks have been formed so far. Results showed improvements in networks’ quality of care and interprofessional collaboration over a period up to six years.<sup>##REF##29949608##14##, ####UREF##3##15##, ##UREF##4##16####4##16##</sup></p>", "<p> A comparable community network programme targeted at patients with Parkinson’s disease was among the first to show that a such an approach can be beneficial for health outcomes and costs over a three-year period.<sup>##REF##29246470##17##</sup> However, thus far, it has not yet been studied if these improvements in quality of care within the DementiaNet programme have led to reduced admission risks and healthcare costs. Also, evidence on these outcomes for other dementia-specific programmes remains inconclusive as a result of varying study periods and small study samples.<sup>##UREF##5##18##, ####REF##32853159##19##, ##REF##26750619##20####26750619##20##</sup> Moreover, the available studies look at hospital-initiated network programmes instead of primary care-based community network approaches.<sup>##UREF##5##18##, ####REF##32853159##19##, ##REF##26750619##20####26750619##20##</sup> Therefore, the aim of this study is to determine the long-term impact on admission risks and healthcare costs of DementiaNet’s community care network approach.</p>" ]	[ "<title>Methods</title>", "<title> Study Design and Data</title>", "<p> We performed a retrospective longitudinal cohort analysis on routinely-collected claims data from a large cohort of Dutch inhabitants insured by cooperation ‘Volksgezondheidszorg’ (VGZ), one of the largest non-profit insurance companies in the Netherlands with a market share of 24.3%.<sup>##UREF##6##21##</sup> The majority of healthcare in the Netherlands is delivered through two coexisting schemes: curative care and long-term care (see ##BOX##1##Box 1##). Compulsory and automatic enrolment within both schemes ensures that our data contains most health claims of insured patients with dementia. Our data includes claims for curative care from January 1, 2015 to December 31, 2019, supplemented with claims for long-term care from January 1, 2016 to December 31, 2019 for patients who reside in regions where VGZ is also accountable for their long-term care (see ##BOX##1##Box 1##). Data in both datasets was combined on anonymised patient information. All research processes were determined to be in accordance with regulations regarding general data protection.</p>", "<title> Participants</title>", "<p> Patients with dementia were identified using specific pharmacy and care activity claims that a recent publication on dementia networks in the Netherlands found are strongly correlated with dementia<sup>##UREF##8##23##</sup> (see ##SUPPL##0##Supplementary file 1##). As dementia is a progressive condition, patients can be identified as having dementia from their first dementia care activity claim onwards. When identified, a patient’s claims data is included from the year prior to the first dementia care activity onwards. Patients below the age of 40 were excluded from the analytical cohort, in line with the aforementioned publication on dementia networks.<sup>##UREF##8##23##</sup></p>", "<p> The cohort was subsequently divided into two groups according to whether they received care from one of the community care networks that participated in the DementiaNet programme. A GP is present in all networks, so participants were included in the intervention group if their listed GP was delivering dementia care within a community care network set up under the DementiaNet programme. The control group consisted of the remaining dementia patients – those who were not treated by a GP participating in one of the networks. The intervention setup and methods are described in more detail elsewhere.<sup>##UREF##2##13##</sup></p>", "<title> Outcomes</title>", "<p> This study focused on two primary outcome measures: hospital admission and total healthcare costs. We also included supportive (secondary) outcome measures of the two respective primary outcomes.</p>", "<p> For admissions, the primary outcome was the effect of the DementiaNet programme on the risk of hospital admission. The secondary outcomes related to admissions measured risks of emergency department visits, intensive care admissions, primary care crisis admissions, and admission into nursing home settings. Besides admission risks, the effect on the number of in-hospital nursing days was also studied. The methods to derive these outcomes from the claims data can be found in ##SUPPL##0##Supplementary file 1##. Time-to-event analyses were considered relevant outcomes as well, but were excluded from our analyses due to possible inaccuracies arising from delays in submission of claims by providers<sup>##UREF##9##24##</sup> and the influence of waiting times for nursing home admission.<sup>##UREF##10##25##</sup></p>", "<p> For healthcare costs, the primary outcome studied was annual total healthcare costs across curative and long-term care per patient during the period of 2016-2019. Total annual costs were measured as the total monetary value of healthcare claims in both the curative and long-term care sector per year. Secondary outcome measures were the effects on sub-elements of total healthcare costs, being annual total care costs, primary care costs, hospital care costs, district nursing (ie, care at home outside of long-term care) costs, and pharmacy costs during the years 2015-2019 for curative care. For long-term care, annual per patient costs during the period of 2016-2019 were included.</p>", "<title> Procedures and Statistical Analysis</title>", "<p> All data processing and analysis procedures were performed using the statistical computing program R. Data was merged on patient level for every individual treatment year between 2015-2019 on an intention-to-treat basis, meaning all health claims between 2015-2019 were included from point of diagnosis regardless of possible changes in a patient’s curative care consumption pattern as a result of, for instance, nursing home admission.</p>", "<p> Baseline differences between the intervention and control group were determined based on <italic toggle=\"yes\">t</italic> tests or Wilcoxon rank sum test for continuous variables or χ<sup>2</sup> tests for categorical variables. Comparisons were made for both the curative care and smaller long-term care cohort originating from this larger cohort as enrolment in long-term care data is not completely random (see ##BOX##1##Box 1##). Also, temporary effects on healthcare use in the Dutch long-term care sector as a result of policy reforms in 2015<sup>##REF##37269863##26##</sup> could have introduced certain differences. Baseline differences between DementiaNet subgroups with different years of programme enrolment were also studied.</p>", "<p> Differences in outcomes between the DementiaNet group and the control group were assessed by mixed effects regression models, allowing us to control for unobserved bias arising from possible clustering of repeated measurements within patients over treatment years and practice variation between GP-practices.<sup>##REF##26029491##27##</sup> Only random intercepts were added since analysis of variance (ANOVA) test established that adding random slopes did not significantly improve model fits. Linearity, homogeneity of variance, and normal distribution of residuals were tested with residual plots and data was transformed accordingly if model assumptions were being violated. Being treated by a GP enrolled in a DementiaNet community care network was coded as a dichotomous variable that converted from the year of a GP’s enrolment onwards to let participants serve as their own control for healthcare use until the year of enrolment. The treatment year was included to utilise the longitudinal aspect of the data and to enable measurements of effects per treatment year within patients. We also controlled for several confounders: sex,<sup>##REF##31410066##28##,##REF##22713212##29##</sup> age,<sup>##REF##31410066##28##,##REF##22713212##29##</sup> cumulative multimorbidity-score,<sup>##REF##31410066##28##,##REF##25955163##30##</sup> year of diagnosis,<sup>##REF##31410066##28##,##REF##25955163##30##</sup> and socioeconomic status (SES). For models including long-term care data, an additional correction for region and average curative care expenses were added. The methods to derive these confounders from the claims data can be found in ##SUPPL##0##Supplementary file 1##. Separate models were fitted for all primary and secondary outcome measures to test model assumptions and distribution.</p>", "<p> For models determining differences in admission risks, mixed effects logistic regression models assuming binomial distributions were used. However, as a binomial distribution did not fit the data for the number of in-hospital nursing days, a Poisson distribution was used. Similarly, the relationship between DementiaNet community care networks and nursing home admissions was assessed by logistic regression models without any mixed effects due to a lack of repeated measures since patients, once admitted, often no longer leave a nursing home and are therefore only admitted once. All models used count data of events at patient level to calculate the risk of a specific event. In case a limited number of events per patient per year resulted in models unable to accurately cluster measurements per patient, only a random intercept for GP-practice number was added and data was no longer clustered per treatment year. Age and number of co-occurring chronic diseases were rescaled into an ordinal and dichotomous variable to better fit the binary predictors and outcomes used in the logistic models.</p>", "<p> For healthcare costs, differences were assessed by mixed effects linear regression models assuming Gaussian distributions. Both a random intercepts per patient and GP-practice were added.</p>", "<p> Community care networks participating in the DementiaNet programme are currently mostly concentrated within two regions in the east and south of the Netherlands. Large differences in prices for hospital care can exist as a result of price negotiations between healthcare insurers and providers.<sup>##UREF##11##31##</sup> As a sensitivity analysis for variations due to regional clustering and price negotiations, a linear mixed model containing standardised prices for hospital care activities from the Dutch healthcare authority was used. Additionally, to study the effect of DementiaNet on several types of curative care admissions at once, we performed a sensitivity analysis in which hospital admission, emergency department visit, intensive care unit admission, and primary care crisis admission were merged into a single variable “curative care admissions.”</p>" ]	[ "<title>Results</title>", "<p> Curative care claims data contained 38 799 patients with dementia, and after excluding patients below the age of 40, the dataset contained 38 525 patients. Of these, 485 patients were treated by community care networks participating in the DementiaNet programme (see Figure). Long-term care data was available for 9677 patients, including 252 patients treated by community care networks (see Figure). Seventy-five individual primary care physicians amongst 31 primary care practices participating in the DementiaNet programme were identified in the claims data.</p>", "<p>\n##TAB##0##Tables 1## and ##TAB##1##2## show the descriptive statistics of the intervention group and control group. Besides age and SES, groups were comparable for most patient characteristics at baseline, including 5-year mortality rates and year of dementia diagnosis (##TAB##0##Table 1##). With respect to the long-term care claims, there was a significantly higher percentage of women in the control group and patients in the control group were significantly older. In addition, the intervention group mainly consisted of people of high and low SES category, although this was evenly distributed in the control group (see ##TAB##1##Table 2##). Differences in 5-year mortality rates and year of dementia diagnosis between both groups remained non-significant. Table S2 in ##SUPPL##1##Supplementary file 2## shows differences in subgroups per year of DementiaNet enrolment. Groups were comparable with regards to number of comorbidities and gender, but showed differences in age, mortality during study period and SES.</p>", "<p>\n##TAB##2##Table 3## shows the relationship between inclusion in community care networks participating in the DementiaNet programme and admission risks, adjusted for comorbidity, SES, gender, and age. Patients in the DementiaNet group had lower risk of all types of admissions. Patients being treated within community care networks participating in the DementiaNet programme showed to have incurred 12% significantly less in-hospital nursing days (relative risk [RR] 0.88; 95% CI: 0.77–0.96). Hospital and intensive care admission risks showed trends for significance at the <italic toggle=\"yes\">P</italic> <.1 level (odds ratio [OR] 0.83; 95% CI: 0.67–1.03 and OR 0.59; 95% CI: 0.34–1.01). Additional analyses per year of DementiaNet enrolment (##SUPPL##1##Supplementary file 2##) showed comparable results for risk of hospital admission for all years. Patients within community care networks participating in the DementiaNet programme were significantly less often admitted into nursing homes at baseline, but these differences were not significant when controlling for confounders in the linear regression model (ie, region, comorbidity, SES, gender, and age).</p>", "<p>\n##TAB##3##Table 4## shows the results of the linear mixed-model comparisons of patients included in community care networks and the control group related to healthcare costs, adjusted for comorbidity, year of diagnosis, SES, gender, and age. DementiaNet community care network inclusion was associated with a non-significant decrease of 3.6% in annual total healthcare costs per patient (<italic toggle=\"yes\">P</italic> =.303; -10.4–3.2). Additional analyses per year of DementiaNet enrolment (##SUPPL##1##Supplementary file 2##) showed non-significant results across all years as well. For hospital care (over 35% of total costs for curative care between 2015-2019), a significant decrease of 19.7% (95% CI: -7.6–30.3) in annual costs was found. Primary care costs (4% of total costs for curative care between 2015-2019) showed a significant increase of 10.2% (95% CI: 2.3–18.6) when compared to controls. All other cost categories showed no significant differences between patients included in community care networks participating in the DementiaNet programme and the control group.</p>", "<p> Results for the sensitivity analyses are shown in ##SUPPL##2##Supplementary file 3##. The outcomes of the model with standardised prices for hospital care and the model with cost prices were found to be almost identical (see Table S4 in ##SUPPL##2##Supplementary file 3##). The effect of DementiaNet on all curative care admissions combined in one variable showed comparable results with regards to the protective trend of DementiaNet on admissions shown in ##TAB##2##Table 3## as well (OR 0.84; 95% CI: 0.70–1.02) (see Table S5 in ##SUPPL##2##Supplementary file 3##).</p>" ]	[ "<title>Discussion and Conclusion</title>", "<p> This study aimed to assess the long-term impact of DementiaNet’s community care network approach on admission risks and healthcare for patients with dementia and demonstrates its potential as a strategy to achieve more sustainable and integrated dementia care, resulting in beneficial effects for both admission risks and hospital care costs over a period of up to five years. Our results indicate that participation in the DementiaNet programme could result in fewer hospitalisations but could also prevent more serious intensive care admissions and admissions into nursing homes. This study also shows that, besides reducing admission risks and in-hospital nursing days, the DementiaNet programme does not seem to increase total healthcare costs and can reduce annual hospital care costs by as much as 19.7%, which, in absolute terms, far exceeds the 10.2% increase in primary care costs.</p>", "<p> A recent meta-analysis of the effects of psychosocial interventions concludes that care coordination strategies could decrease nursing home admission rates of patients with dementia.<sup>##REF##32223022##32##</sup> Although this seems in line with our results, both studies on which this pooled effect is based concern unidimensional, hospital-initiated case management-like programmes instead of community network approaches.<sup>##REF##32223022##32##</sup> All other strategies in this meta-analysis, both unidimensional and multidimensional, failed to show results.<sup>##REF##32223022##32##</sup> The fact that our study showed favourable results (where others do not) can be attributed to two factors. Firstly, many of the unidimensional interventions in the meta-analysis focus solely on improving one aspect of care for people with dementia (eg, formation of a network).<sup>##REF##32223022##32##</sup> The DementiaNet programme, on the other hand, is based on the theory that integrated care can only be achieved by focusing simultaneously on multiple aspects of integrated dementia care.<sup>##UREF##2##13##</sup> This approach is more likely to create networks in which sustainable interprofessional collaboration is maintained over a longer period of time.<sup>##UREF##2##13##</sup> Secondly, for those programmes that apply a multidimensional strategy, results come mostly from studies in the controlled setting of a randomised control trial (RCT) or in small uncontrolled groups, both only followed for a short period of time. However, dementia care in daily practice settings is likely to be different from that in RCT settings<sup>##REF##30127705##33##</sup> and the formation of sustainable collaborations in networks requires time before beneficial effects are achieved.</p>", "<p> Thanh et al show similar results for care networks in Alberta, Canada in their small-scale observational study: hospital care costs decreased by increasing the use of community services.<sup>##REF##32853159##19##</sup> The observed increase in primary care costs found in our study may be attributed to the same mechanisms. Stricter monitoring of patients and increased sharing of information on a patient’s health status between providers could result in earlier detection of increased frailty and health risks. Although this might result in some additional visits to primary care services, it prevents more costly inpatient hospital admissions. Another study found increased healthcare utilisation for certain types of outpatient hospital services in Germany.<sup>##REF##26750619##20##</sup> Although this seems to contradict our results, Germany is known to have relatively high numbers of consultation and hospitalisations due to the absence of a primary care-based gatekeeping system,<sup>##UREF##12##34##</sup> while GPs in the Netherlands serve as strong gatekeepers.<sup>##UREF##7##22##</sup> The additional outpatient visits found in Germany are, therefore, likely to be caused by the same mechanisms that cause an increase in primary care visits in the Dutch and Canadian setting. Such differences in outcomes depending on health system characteristics suggest that networks should be tailored towards the systems in which they are being implemented.</p>", "<p> Our study has several strengths, due to its use of claims data instead of RCT data or other types of observational data. This gives an unbiased, long-term, and comprehensive overview of the healthcare use of a certain group of patients. By looking at both curative and long-term care data, our study provides insight into almost the entire care trajectory of patients with dementia, ensuring that savings in one sector are not achieved by shifting costs to another sector. Mandatory and automatic enrolment in the curative and long-term care sector in the Netherlands ensures that all eligible patients of DementiaNet were included. As our cohort is representative of the Dutch population,<sup>##REF##32716516##35##</sup> these results are a reliable indication of what the DementiaNet programme could achieve throughout the Netherlands.</p>", "<p> Our study also has some limitations. Claims data contain no direct information on actual health status and diagnosis on the patient level, meaning we were unable to identify diagnosed patients or directly correct for unobserved health status. We tried to minimise errors of deriving this information from healthcare use in several ways by following a validated method<sup>##UREF##8##23##</sup> to identify patients with dementia based on specific pharmacy and care activity claims data (##SUPPL##0##Supplementary file 1##). In correcting for differences in disease severity and health status, we included co-variates that are known to be valid proxies for disease severity and progression of patients with dementia, such as age, number of co-morbidities, mortality, and year of diagnosis. Differences between groups for these proxies were mostly found to be non-significant (##TAB##0##Tables 1## and ##TAB##1##2##).</p>", "<p> Our entire cohort encompasses a large number of over 38 525 individuals, yet only a part of them participated in the DementiaNet programme’s community care networks. Such an unbalanced dataset could bias the results. Also, as participation was voluntary, there might have been unobserved baseline differences between participating primary care practices and the national control group. Although this would justify a before-after comparison, earlier studies show that such analyses can result in significant overestimations of outcomes.<sup>##REF##25025239##36##</sup> Alternatively, a mixed model design was selected to correct for this by allowing clustering of data within practices and control for possible unobserved practice variation at this level.</p>", "<p> Finally, DementiaNet networks have not been implemented throughout the Netherlands, but are clustered in a few regions and implemented in a stepwise approach across several years. This could lead to baseline differences between groups because of unmeasurable demographic differences between regions and short or long-term effects. Even though we did find some differences at baseline for the entire cohort and between different years of enrolment, groups were comparable for most proxies of health status at baseline. Moreover, the clustering per patient and correction for regional health office and SES in our mixed models should reduce the impact of such potential differences. The fact that results for total healthcare costs and hospital admissions across years of DementiaNet enrolment are comparable also does not indicate any differences in short or long-term effects.</p>", "<p> This study demonstrates that DementiaNet’s approach, with formation of local community care networks, is most likely effective in lowering admission risks and hospital care costs for patients with dementia. Combined with earlier favourable results on quality of care and network collaboration shown in several studies,<sup>##REF##29949608##14##, ####UREF##3##15##, ##UREF##4##16####4##16##</sup> the DementiaNet programme seems to be a value-adding initiative that is able to generate higher quality of care at the same costs. Although DementiaNet’s approach specifically focussed on the setup of community care networks for patients with dementia, this programme and its networks may be able to add value for a larger group of patients. After all, professionals active in DementiaNet networks share various other patient groups with complex care needs that could benefit from care coordination through community care networks, like frail older adults or patients in need of palliative care.</p>", "<p> Within the Netherlands, the results of this study can be a direct encouragement to set up similar networks throughout the country. Until now, setting up a network within the DementiaNet programme was a bottom-up approach that was initiated by network participants on a voluntary basis. The results of this study justify an approach in which broader implementation of such networks is encouraged. Guaranteed, long-term financial support and inclusion in nationwide guidelines on dementia care can assist this process of national uptake. Networks could be funded by redistributing funds from the identified 20% savings in hospital care towards primary care, but such processes are highly complex and require agreements between payers and providers across all levels of care. Internationally, policy-makers may want to actively encourage the establishment of similar DementiaNet community care networks through comparable mechanisms. However, international differences in healthcare systems requires networks to be tailored to the local needs in dementia care and evaluated separately.</p>" ]	[ "<title>Discussion and Conclusion</title>", "<p> This study aimed to assess the long-term impact of DementiaNet’s community care network approach on admission risks and healthcare for patients with dementia and demonstrates its potential as a strategy to achieve more sustainable and integrated dementia care, resulting in beneficial effects for both admission risks and hospital care costs over a period of up to five years. Our results indicate that participation in the DementiaNet programme could result in fewer hospitalisations but could also prevent more serious intensive care admissions and admissions into nursing homes. This study also shows that, besides reducing admission risks and in-hospital nursing days, the DementiaNet programme does not seem to increase total healthcare costs and can reduce annual hospital care costs by as much as 19.7%, which, in absolute terms, far exceeds the 10.2% increase in primary care costs.</p>", "<p> A recent meta-analysis of the effects of psychosocial interventions concludes that care coordination strategies could decrease nursing home admission rates of patients with dementia.<sup>##REF##32223022##32##</sup> Although this seems in line with our results, both studies on which this pooled effect is based concern unidimensional, hospital-initiated case management-like programmes instead of community network approaches.<sup>##REF##32223022##32##</sup> All other strategies in this meta-analysis, both unidimensional and multidimensional, failed to show results.<sup>##REF##32223022##32##</sup> The fact that our study showed favourable results (where others do not) can be attributed to two factors. Firstly, many of the unidimensional interventions in the meta-analysis focus solely on improving one aspect of care for people with dementia (eg, formation of a network).<sup>##REF##32223022##32##</sup> The DementiaNet programme, on the other hand, is based on the theory that integrated care can only be achieved by focusing simultaneously on multiple aspects of integrated dementia care.<sup>##UREF##2##13##</sup> This approach is more likely to create networks in which sustainable interprofessional collaboration is maintained over a longer period of time.<sup>##UREF##2##13##</sup> Secondly, for those programmes that apply a multidimensional strategy, results come mostly from studies in the controlled setting of a randomised control trial (RCT) or in small uncontrolled groups, both only followed for a short period of time. However, dementia care in daily practice settings is likely to be different from that in RCT settings<sup>##REF##30127705##33##</sup> and the formation of sustainable collaborations in networks requires time before beneficial effects are achieved.</p>", "<p> Thanh et al show similar results for care networks in Alberta, Canada in their small-scale observational study: hospital care costs decreased by increasing the use of community services.<sup>##REF##32853159##19##</sup> The observed increase in primary care costs found in our study may be attributed to the same mechanisms. Stricter monitoring of patients and increased sharing of information on a patient’s health status between providers could result in earlier detection of increased frailty and health risks. Although this might result in some additional visits to primary care services, it prevents more costly inpatient hospital admissions. Another study found increased healthcare utilisation for certain types of outpatient hospital services in Germany.<sup>##REF##26750619##20##</sup> Although this seems to contradict our results, Germany is known to have relatively high numbers of consultation and hospitalisations due to the absence of a primary care-based gatekeeping system,<sup>##UREF##12##34##</sup> while GPs in the Netherlands serve as strong gatekeepers.<sup>##UREF##7##22##</sup> The additional outpatient visits found in Germany are, therefore, likely to be caused by the same mechanisms that cause an increase in primary care visits in the Dutch and Canadian setting. Such differences in outcomes depending on health system characteristics suggest that networks should be tailored towards the systems in which they are being implemented.</p>", "<p> Our study has several strengths, due to its use of claims data instead of RCT data or other types of observational data. This gives an unbiased, long-term, and comprehensive overview of the healthcare use of a certain group of patients. By looking at both curative and long-term care data, our study provides insight into almost the entire care trajectory of patients with dementia, ensuring that savings in one sector are not achieved by shifting costs to another sector. Mandatory and automatic enrolment in the curative and long-term care sector in the Netherlands ensures that all eligible patients of DementiaNet were included. As our cohort is representative of the Dutch population,<sup>##REF##32716516##35##</sup> these results are a reliable indication of what the DementiaNet programme could achieve throughout the Netherlands.</p>", "<p> Our study also has some limitations. Claims data contain no direct information on actual health status and diagnosis on the patient level, meaning we were unable to identify diagnosed patients or directly correct for unobserved health status. We tried to minimise errors of deriving this information from healthcare use in several ways by following a validated method<sup>##UREF##8##23##</sup> to identify patients with dementia based on specific pharmacy and care activity claims data (##SUPPL##0##Supplementary file 1##). In correcting for differences in disease severity and health status, we included co-variates that are known to be valid proxies for disease severity and progression of patients with dementia, such as age, number of co-morbidities, mortality, and year of diagnosis. Differences between groups for these proxies were mostly found to be non-significant (##TAB##0##Tables 1## and ##TAB##1##2##).</p>", "<p> Our entire cohort encompasses a large number of over 38 525 individuals, yet only a part of them participated in the DementiaNet programme’s community care networks. Such an unbalanced dataset could bias the results. Also, as participation was voluntary, there might have been unobserved baseline differences between participating primary care practices and the national control group. Although this would justify a before-after comparison, earlier studies show that such analyses can result in significant overestimations of outcomes.<sup>##REF##25025239##36##</sup> Alternatively, a mixed model design was selected to correct for this by allowing clustering of data within practices and control for possible unobserved practice variation at this level.</p>", "<p> Finally, DementiaNet networks have not been implemented throughout the Netherlands, but are clustered in a few regions and implemented in a stepwise approach across several years. This could lead to baseline differences between groups because of unmeasurable demographic differences between regions and short or long-term effects. Even though we did find some differences at baseline for the entire cohort and between different years of enrolment, groups were comparable for most proxies of health status at baseline. Moreover, the clustering per patient and correction for regional health office and SES in our mixed models should reduce the impact of such potential differences. The fact that results for total healthcare costs and hospital admissions across years of DementiaNet enrolment are comparable also does not indicate any differences in short or long-term effects.</p>", "<p> This study demonstrates that DementiaNet’s approach, with formation of local community care networks, is most likely effective in lowering admission risks and hospital care costs for patients with dementia. Combined with earlier favourable results on quality of care and network collaboration shown in several studies,<sup>##REF##29949608##14##, ####UREF##3##15##, ##UREF##4##16####4##16##</sup> the DementiaNet programme seems to be a value-adding initiative that is able to generate higher quality of care at the same costs. Although DementiaNet’s approach specifically focussed on the setup of community care networks for patients with dementia, this programme and its networks may be able to add value for a larger group of patients. After all, professionals active in DementiaNet networks share various other patient groups with complex care needs that could benefit from care coordination through community care networks, like frail older adults or patients in need of palliative care.</p>", "<p> Within the Netherlands, the results of this study can be a direct encouragement to set up similar networks throughout the country. Until now, setting up a network within the DementiaNet programme was a bottom-up approach that was initiated by network participants on a voluntary basis. The results of this study justify an approach in which broader implementation of such networks is encouraged. Guaranteed, long-term financial support and inclusion in nationwide guidelines on dementia care can assist this process of national uptake. Networks could be funded by redistributing funds from the identified 20% savings in hospital care towards primary care, but such processes are highly complex and require agreements between payers and providers across all levels of care. Internationally, policy-makers may want to actively encourage the establishment of similar DementiaNet community care networks through comparable mechanisms. However, international differences in healthcare systems requires networks to be tailored to the local needs in dementia care and evaluated separately.</p>" ]	[ "<p>\n<bold>Background:</bold> People with dementia are increasingly living at home, relying on primary care providers for most healthcare needs. Suboptimal collaboration and communication between providers could cause inefficiencies and worse patient outcomes. Innovative strategies are needed to address this growing disease burden and rising healthcare costs. The DementiaNet programme, a community care network approach targeted at patients with dementia in the Netherlands, has been shown to improve patient’s quality of care. However, very little is known about the impact of DementiaNet on admission risks and healthcare costs. This study addresses this knowledge gap.\n</p>", "<p><bold>Methods:</bold> A longitudinal cohort analysis was performed, using medical and long-term care claims data from 38 525 patients between 2015-2019. The primary outcomes were risk of hospital admission and annual total healthcare costs. Mixed-model regression analyses were used to identify changes in outcomes.\n</p>", "<p><bold>Results:</bold> Patients who received care from a DementiaNet community care network showed a general trend in lower risk of admission for all types of admissions studied (ie, hospital, emergency ward, intensive care, crisis, and nursing home). Also, the intervention group showed a significant reduction of 12% in nursing days (relative risk [RR] 0.88; 95% CI: 0.77– 0.96). No significant differences were found for total healthcare costs. However, we found effects in two sub-elements of total healthcare costs, being a decrease of 19.7% (95% CI: 7.7%–30.2%) in annual hospital costs and an increase of 10.2% (95% CI: 2.3%–18.6%) in annual primary care costs.\n</p>", "<p><bold>Conclusion:</bold> Our study indicates that DementiaNet’s community care network approach may reduce admission risks for patients with dementia over a long-term period of five years. This is accompanied by a decrease in nursing days and savings in hospital care that exceed increased primary care costs. This improvement in integrated dementia care supports wider scale implementation and evaluation of these networks.</p>", "<p>\n<bold>Citation:</bold> Remers TE, Kruse FM, van Dulmen SA, et al. Effects of DementiaNet’s community care network approach on admission rates and healthcare costs: a longitudinal cohort analysis. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7700. doi:10.34172/ijhpm.2023.7700</p>" ]	[ "<title>Acknowledgements</title>", "<p> We thank Esther Hendriks and Marit Tanke (VGZ) for their perseverance in realising approval and execution of the merging of curative and long-term care data. Also, we thank all those at VGZ and at the Department of Geriatrics who have helped us in the design and execution of the research, especially Marieke Perry and Minke Nieuwboer. Lastly, thanks to Nicholas Crawford for his phenomenal help in proofreading and language checking of this manuscript.</p>", "<title>Ethical issues</title>", "<p> A recognized medical ethics review committee determined that this research is in accordance with the Declaration of Helsinki and exempted from the Dutch law on medical scientific research in humans (application number: 2020-6201).</p>", "<title>Competing interests</title>", "<p> All authors have completed the disclosure form and declare: financial support from the Dutch Ministry of Health, Welfare and Sport for the submitted work for TER, FMK, SAvD, and PPJ. Financial support was given to the research group – not directly to researchers. MFM reported receiving personal fees from Coöperatie Volksgezondheidszorg (VGZ).</p>", "<title>Funding</title>", "<p> This work was supported by the Dutch Ministry of Health, Welfare and Sport (VWS). Whilst VWS provided funds for the research, it was not actively involved in any part of the design and conduct of the study.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nA Graphic Representation of the Composition of the Study Cohort.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Comparison of Patient Characteristics Amongst Curative Care Claims Data Between Patients Included in Community Care Networks Participating in the DementiaNet Programme and the Control Group Receiving Usual Dementia Care\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Patient Characteristic</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Intervention (n = 485)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Control (n = 38 040)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P</bold></italic><bold> Value</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Age at diagnosis (y)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">76.9 (SD 9.9)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">78.1 (SD 9.3)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.006<sup>a</sup></td></tr><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Gender (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male: 48.1%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male: 46.0%</td><td rowspan=\"2\" style=\"text-align:center;vertical-align:middle;\" colspan=\"1\">.375<sup>b</sup></td></tr><tr><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Female: 52.0%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Female: 54.0%</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Comorbidities at diagnosis (n)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.1 (SD 1.7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.1 (SD 1.7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.849<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mortality during study period (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">42.7%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">46.4%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.104<sup>b</sup></td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"5\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Year of diagnosis (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Before 2015: 139 (29%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Before 2015: 11 735 (31%)</td><td rowspan=\"5\" style=\"text-align:center;vertical-align:middle;\" colspan=\"1\">.760<sup>b</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2015: 90 (19%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2015: 6619 (17%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2016: 85 (18%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2016: 6425 (17%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2017: 91 (19%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2017: 6661 (18%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2018: 80 (16%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2018: 6600 (17%)</td></tr><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">SES (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Low: 36.9%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Low: 34.7%</td><td rowspan=\"3\" style=\"text-align:center;vertical-align:middle;\" colspan=\"1\"><.001<sup>b</sup></td></tr><tr><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Middle: 11.5%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Middle: 31.8%</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">High: 51.5%</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">High: 33.6%</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Comparison of Patient Characteristics Amongst Long-term Claims Data Between Patients Included in Community Care Networks Participating in the DementiaNet Programme and the Control Group Receiving Usual Dementia Care\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Patient Characteristic</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Intervention (n = 485)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Control (n = 38 040)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P</bold></italic><bold> Value</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Age at diagnosis (y)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">79.7 (SD 8.0)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">80.8 (SD 7.7)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.038<sup>a</sup></td></tr><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Gender (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male: 47.2%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male: 37.9%</td><td rowspan=\"2\" style=\"text-align:center;vertical-align:middle;\" colspan=\"1\">.003<sup>b</sup></td></tr><tr><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Female: 52.8%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Female: 62.1%</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Comorbidities at diagnosis (n)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.1 (SD 1.7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.2 (SD 1.7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.481<sup>a</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mortality during study period (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">54.0%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">58.9%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.116<sup>b</sup></td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"5\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Year of diagnosis (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Before 2015: 85 (34%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Before 2015: 3667 (39%)</td><td rowspan=\"5\" style=\"text-align:center;vertical-align:middle;\" colspan=\"1\">.440<sup>b</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2015: 56 (22%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2015: 1820 (19%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2016: 43 (17%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2016: 1515 (16%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2017: 42 (17%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2017: 1378 (15%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2018: 26 (10%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2018: 1045 (11%)</td></tr><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">SES (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Low: 43.3%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Low: 29.4%</td><td rowspan=\"3\" style=\"text-align:center;vertical-align:middle;\" colspan=\"1\"><.001<sup>b</sup></td></tr><tr><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Middle: 8.2%</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Middle: 38.6%</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">High: 48.5%</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">High: 32.0%</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Admission Risk Comparisons for Patients Included in Community Care Networks Participating in the DementiaNet Programme and the Control Group Receiving Usual Dementia Care, Adjusted for Comorbidity, Socioeconomic Status, Gender, and Age\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Type of Admission </bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Risk for Intervention Compared to Control (95% CI)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P</bold></italic><bold> Value</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Hospital admission<sup>a</sup> (n = 37 205)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">OR 0.83 (0.67–1.03)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.096</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Emergency department visit<sup>a</sup>(n = 37 205)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">OR 0.88 (0.72–1.08)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.234</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Intensive care unit admission<sup>b</sup>(n = 37 205)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">OR 0.59 (0.34–1.01)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.055</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Number of in-hospital nursing days<sup>c</sup> (n = 17 798)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">RR 0.88 (0.77–0.96)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.01 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Primary care emergency admissions<sup>c</sup> (n = 28 792)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">OR 0.75 (0.43–1.32)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.320</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Admission to nursing home setting<sup>d</sup> (n = 9677)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">OR 0.96 (0.80–1.15)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">.656 </td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T4\"><label>Table 4</label><caption><title>Annual Cost Comparisons for Patients Included in Community Care Networks Participating in the DementiaNet Programme and the Control Group Receiving Usual Dementia Care, Adjusted for Comorbidity, Year of Diagnosis, Socioeconomic Status, Gender, and Age\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Cost Category</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Change Per Year for Intervention Compared to Control (95% CI)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P</bold></italic><bold> Value</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Total healthcare costs<sup>a</sup> (n= 9378)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">- 3.6% (-10.4% – +3.2%) </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">.303</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Total curative care costs<sup>b</sup> (n = 38 525)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">- 3.0% (-13.0% – +8.2%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.58</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Hospital care costs<sup>b</sup> (n = 37 205)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">- 19.7% (-7.6 – -30.3%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.01</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Primary care costs<sup>b</sup> (n = 38 267)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">+ 10.2% (+2.3% – +18.6%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.010</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">District nursing care costs<sup>b</sup> (n = 28 792)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">+ 0.10% (-14.7% – +18.5%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.949</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Pharmaceutical costs<sup>b</sup> (n= 37 751)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">- 4.1% (-11.7% – +4.1%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.318</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Long-term care costs (n= 9677)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">+1.0% (-6.5% – +8.6%)</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">.789</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT2\" position=\"float\"><sec id=\"bx2\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>This study finds that local community-based care networks created under the DementiaNet programme lower both admission risks and hospital care costs for people with dementia, and show such effects are maintained over a long-term period of up to five years. </p></list-item><list-item><p>Combined with previously demonstrated improvements in quality of care, the DementiaNet program has great potential to improve dementia care. </p></list-item><list-item><p>Further implementation of DementiaNet’s community care network approach, both nationally and internationally could therefore assist the transition of current fragmented dementia care into integrated care processes. </p></list-item><list-item><p>As the composition and functioning of care networks strongly depends on health system characteristics, international settings need to tailor these community care networks to their different systems. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> To this day, the organisation of dementia care remains suboptimal in many countries, with fragmentation being one of the main challenges. Patients with dementia are often treated by a wide range of healthcare professionals and providers, making effective communication difficult. Improving communication and collaboration between the different care providers can improve the wellbeing and health of patients and can lessen the care burden for informal caregivers. The findings of this study show that community care networks for patients with dementia created within the DementiaNet programme can both be cost-effective – potentially lowering healthcare costs and improve health outcomes in terms of admission risks and nursing days.</p></sec></boxed-text>", "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>\n<bold>Box 1.</bold> Brief Summary of System Characteristics of the Curative and Long-term Care in the Netherlands<sup>##UREF##7##22##</sup>\n</title><p>\n<bold>Curative Care</bold></p><p> Dutch inhabitants are compulsorily insured for all curative care ranging from care provided by GPs and hospital care to prescription drugs. Although taking up insurance is mandatory, inhabitants can choose their own healthcare insurance company, with four major insurer groups covering 90% of all Dutch inhabitants.</p><p>\n<bold>Long-term Care</bold></p><p> Dutch inhabitants are automatically insured for long term care with income-related premiums. The long-term system care system covers a wide range of services delivered to patients requiring around the clock care either in their own homes or in nursing homes, including costs for permanent nursing home residency, home care, daytime activities, and medical devices. Long-term care is being arranged on a regional basis by 31 regional care offices. By law, the insurance company with the largest share of patients in a region has to arrange all care for patients in that specific region; regardless of the patient’s insurer for curative care.</p><p>----------------</p><p> Abbreviation: GPs, general practitioner.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 1. Selection Criteria & Methods for Deriving Admission Risk Outcomes and Confounders From Claims Data.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 2. Comparison of Baseline Characteristics and Outcomes Per Year of DementiaNet Entry.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 3. Sensitivity Analyses.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: SES, socioeconomic status; SD, standard deviation.</p><p>\n<sup>a</sup> One-way ANOVA; <sup>b</sup> Pearson’s chi-squared test.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: SES, socioeconomic status; SD, standard deviation.</p><p>\n<sup>a</sup> One-way ANOVA; <sup>b</sup> Pearson’s chi-squared test.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: CI, confidence interval; RR, relative risk; OR, odds ratio.</p><p>\n<sup>a</sup>Mixed effects logistic regression model with binary distribution (yes/no) and correction for treatment year.</p><p>\n<sup>b</sup>Mixed effects logistic regression model with binary distribution (yes/no).</p><p>\n<sup>c</sup>Mixed effects logistic regression model with Poisson distribution (no. inpatient days).</p><p>\n<sup>d</sup>Logistic regression model with binary distribution (yes/no) and correction for treatment year.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviation: CI, confidence interval.</p><p>\n<sup>a</sup> Curative and long-term care combined.</p><p>\n<sup>b</sup> Log-transformed outcome variable because of skewed distribution.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7700-g001\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7700-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7700-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7700-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["5"], "mixed-citation": [" World Health Organization (WHO). Global Action Plan on the Public Health Response to Dementia 2017-2025. WHO; 2017. "]}, {"label": ["9"], "mixed-citation": [" Campbell J, Dussault G, Buchan J, et al. A Universal Truth: No Health Without a Workforce. Geneva: Global Health Workforce Alliance, World Health Organization; 2013. "]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Nieuwboer", "Richters", "van der Marck"], "given-names": ["MS", "A", "MA"], "article-title": ["Triple aim improvement for individuals, services and society in dementia care: the DementiaNet collaborative care approach"], "source": ["Z GerontolGeriatr"], "year": ["2017"], "volume": ["50"], "issue": ["Suppl 2"], "fpage": ["78"], "lpage": ["83"], "pub-id": ["10.1007/s00391-017-1196-4"]}, {"label": ["15"], "person-group": ["\n"], "surname": ["Oostra", "Harmsen", "Nieuwboer", "Rikkert", "Perry"], "given-names": ["DL", "A", "MS", "M", "M"], "article-title": ["Care integration in primary dementia care networks: a longitudinal mixed-methods study"], "source": ["Int J Integr Care"], "year": ["2021"], "volume": ["21"], "issue": ["4"], "fpage": ["29"], "pub-id": ["10.5334/ijic.5675"]}, {"label": ["16"], "mixed-citation": [" Oostra DL, Nieuwboer MS, Melis RJF, Remers TEP, Olde Rikkert MGM, Perry M. DementiaNet facilitates a sustainable transition toward integrated primary dementia care: a long-term evaluation. Alzheimers Dement. 2023. "], "pub-id": ["10.1002/alz.13154"]}, {"label": ["18"], "person-group": ["\n"], "surname": ["Ha", "Chan", "Yap"], "given-names": ["NHL", "I", "P"], "article-title": ["Mixed-method evaluation of CARITAS: a hospital-to-community model of integrated care for dementia"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["10"], "fpage": ["e039017"], "pub-id": ["10.1136/bmjopen-2020-039017"]}, {"label": ["21"], "mixed-citation": [" Nijhof E, Romp M, van Schip-Wagter E. Verzekerden in beeld 2021 - Inzicht in het overstapseizoen. Vektis; 2021. "]}, {"label": ["22"], "person-group": ["\n"], "surname": ["Kroneman", "Boerma", "van den Berg", "Groenewegen", "de Jong", "van Ginneken"], "given-names": ["M", "W", "M", "P", "J", "E"], "article-title": ["Netherlands: health system review"], "source": ["Health Syst Transit"], "year": ["2016"], "volume": ["18"], "issue": ["2"], "fpage": ["1"], "lpage": ["240"]}, {"label": ["23"], "mixed-citation": [" van den Pol H, Luijk R, Leegwater E. Zorggebruik van mensen met dementie in beeld - zorggebruikindicatorendementienetwerken. Vektis; 2019. "]}, {"label": ["24"], "mixed-citation": [" Majumder MS, Rose S. Health Care Claims Data May Be Useful For COVID-19 Research Despite Significant Limitations. Health Aff Blog. October 6, 2020. "], "pub-id": ["10.1377/forefront.20201001.977332"]}, {"label": ["25"], "mixed-citation": [" Mot ES, Aouragh A, de Groot M, Mannaerts H. The Dutch System of Long-Term Care. Citeseer; 2010. "]}, {"label": ["31"], "person-group": ["\n"], "surname": ["Douven", "Burger", "Schut"], "given-names": ["R", "M", "E"], "article-title": ["Grote prijsverschillen ziekenhuiszorg, ondanks concurrentie"], "source": ["Econ Stat Ber"], "year": ["2018"], "volume": ["103"], "issue": ["4762"], "fpage": ["276"], "lpage": ["279"]}, {"label": ["34"], "mixed-citation": [" European Observatory on Health Systems and Policies (OECD). Germany: Country Health Profile 2019. Paris: OECD Publishing; 2019. "], "pub-id": ["10.1787/36e21650-en"]}]	{ "acronym": [], "definition": [] }	36	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 28; 12:7700	oa_package/9f/9c/PMC10699814.tar.gz
PMC10699816	0	[ "<title>Background</title>", "<p> The number and proportion of the population aged 65 years and above in Taiwan is rapidly rising. According to the population projections report from the National Development Council, Taiwan officially entered the stage of an “aged society,” as Taiwanese people aged 65 years and above accounted for more than 14% of the country’s total population at the end of March 2018. It is estimated that the percentage of people who are 65 years of age or older is projected to reach 20% in 2025, making it a “superaged society.”<sup>##UREF##0##1##</sup> More surprising is that it will take only 7 years for Taiwan to advance from the “aged society” stage to the “superaged society” stage. In comparison, 11 years will be needed for Japan, 15 years for the United States, 29 years for France, and 51 years for the United Kingdom. At the same time, the disability rate in the general population in Taiwan has continued to grow, and the disabled population is estimated to increase from more than 750 000 in 2010 to approximately 1 200 000 by 2031.<sup>##UREF##1##2##</sup> Therefore, the demand for healthcare services, including medical and long-term care, will inevitably increase. Unfortunately, less or unsuitable access to healthcare resources often results in unmet medical and long-term care needs and fragmented healthcare. It is imperative to adopt a plan of action to introduce more flexible, accessible, continuous and comprehensive patient-centered healthcare services for eligible elderly or disabled individuals.</p>", "<p> In response to the challenges of unmet healthcare service needs and to construct a complete local home healthcare system, publicly-financed integrated homecare launched by the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan, in 2016 has been proposed to strengthen the connection between medical treatments and healthcare resources and improve the continuity of healthcare delivery. The Integrated Homecare services, which encompass the stages of “homecare,” “intensive homecare,” and “hospice care,” are delivered through contracted homecare teams composed of regulated health professionals, mainly family physicians and registered nurses. When advanced medical and healthcare services are necessary, dentists, Chinese medicine practitioners, pharmacists, respiratory therapists or other medical personnel are further linked. Under the regulation of Integrated Homecare, if a patient living at home has a definite need for medical or nursing services, but it is difficult to reach out the essential services because of limited self-care ability with a score of less than 60 for the Barthel activities of daily living (ADL) index or specific illnesses conditions, the patient would be eligible to apply the reimbursed homecare items, including physician and nursing homecare, clinical diagnosis and treatment, the provision of medical supplies and general nursing care and laboratory tests, etc. Intensive homecare covers the reimbursed homecare items and additional special skilled nursing services, such as replacing nasogastric tubes, tracheostomy tubes, Foley catheters and wound care. Moreover, the hospice care stage refers to patients qualified for the homecare reimbursement receiving the hospice and palliative care under terminal illness or end-stage disease.<sup>##UREF##2##3##</sup> According to the 2019 Health and Welfare Report published by the Ministry of Health and Welfare, Taiwan, more than 1200 contracted medical service institutions form professional integrated homecare teams, providing care for over 49 000 qualifying individuals in 2018.<sup>##UREF##3##4##</sup> Since the demand for healthcare has skyrocketed, substantial growth in homecare services is expected in the foreseeable future.</p>", "<p> Although the public health strategy of increased accessibility of comprehensive home or community-based healthcare services and emergency home visits have been commonly adopted to reduce overcrowding of emergency departments (EDs),<sup>##UREF##4##5##, ####REF##25452824##6##, ##REF##30843316##7##, ##REF##16541823##8##, ##REF##32610762##9##, ##REF##35658332##10##, ##REF##28264943##11##, ##REF##26514717##12##, ##REF##26560094##13####26560094##13##</sup> scientific evidence on the association between home-based healthcare services and ED usage is surprisingly insufficient and controversial. Provision of integrated homecare services has been shown to be beneficial for reducing inappropriate ED visits,<sup>##REF##35658332##10##,##REF##26514717##12##,##REF##26560094##13##</sup> whereas contrary argument exhibits unplanned or nonurgent ED visits often occur among patients receiving homecare services.<sup>##REF##32819144##14##,##REF##29712671##15##</sup> Given that reducing unnecessary ED visits is widely thought as an important goal of all primary care and specialty practices and a challenging and contentious issue for policy-makers, efforts to reduce and prevent unnecessary or avoidable ED visits should be informed by an understanding of the contributions of specific risk factors for ED utilizations in this population.</p>", "<p> Therefore, the objective of this study was to identify the risk factors for ED visits among patients receiving publicly-funded homecare services. As the first step in this work, the available independent measures were reviewed to explore personal demographic and medical information, caregiver characteristics and behaviors related to homecare services and ED visits that would or would not be related to the utilizations of ED. Next, these candidate independent measures were reduced into a more economical set of risk factors correlated with ED utilizations.</p>" ]	[ "<title>Methods</title>", "<title> Study Design and Setting </title>", "<p> This single-center, retrospective observational study was based on a review of charts from patients receiving the publicly-financed integrated homecare programs in Kaohsiung Armed Forces General Hospital, which is a regional hospital located in southern Taiwan and is a dedicated institution coordinating and offering appropriate healthcare services for eligible elderly or disable individuals. Moreover, both the study protocol and the process of retrospective chart review were approved by the institutional review board of the Kaohsiung Armed Forces General Hospital, Taiwan (KAFGHIRB 109-056). Because of the nature of this retrospective study and data de-identification, the requirement for informed consent was waived.</p>", "<title> Participants</title>", "<p> Patients eligible for reimbursement under integrated homecare programs between January 1, 2020 and December 31, 2020, and over the age of 18 years were initially recruited into the retrospective cohort study. If patients were receiving hospice care services, did not complete the assessments regarding the personal demographic information, health status, physical functions, medications, nutrition, conscious levels, and comorbidities etc, or did not receive more than three months of homecare services, they were removed from the current study. The patients who had visited the ED once during the study period were registered in the case group.</p>", "<title> Data Sources</title>", "<p> The whole data analyzed in the current retrospective study were mainly retrieved by from two major information sources. One is the hospital information system database, which is the official digitized records for patients’ socio-demographics, medical information and details on homecare services and ED utilizations. Moreover, as patients were initially enrolled in the publicly-financed integrated homecare programs, each of them formally received a series of standardized assessments for comprehensively evaluating health status, physical functions, medications, nutrition, conscious levels, and comorbidities etc, which were also documented in the hospital information system, and updated quarter-yearly or if there is a significant change in clinical status. Caregiver and nurse characteristics were obtained from another information source, the structured questionnaires. Theses collected data identifying beneficiaries, caregivers and dedicated nurses were encrypted to ensure privacy and then constructed multiple-linked population-based health administrative datasets.</p>", "<title> Variables </title>", "<p> The variables used for analysis in the present retrospective study were mainly comprised of the patients’ demographics and medical information, caregiver and nurse characteristics, and behaviors on homecare service and ED visits. Apart from sex and age, patients’ medical information included nasogastric intubation, Foley catheter insertion and skin pressure ulcer, bedridden status, number of prescribed drugs and scores on the Glasgow Coma Scale, Barthel ADL Index, and Charlson Comorbidity Index. Caregiver and nurse characteristics involved full or part-time care pattern, caregiver’s age, sex, nationality, and working experience of dedicated nurses. Finally, behaviors related to homecare services and ED visits were number of ED utilizations within the period of data collection, duration of introducing homecare services, previous one-year experience with ED utilizations. Of these variables, patients’ demographics and medical information, behaviors related to homecare services, and ED utilizations were retrieved from the hospital information system databases. Caregiver and nurse characteristics were further gathered through structured questionnaires from patients, family members, caregivers and dedicated nurses. All charts in the current work were reviewed and appropriateness by two of the co-authors (WYC and CCY). In unclear cases, the other co-author was consulted (TCY).</p>", "<title> Statistical Analysis</title>", "<p> Descriptive statistics were initially used to feature the personal demographic and medical information and summarize the characteristics of caregivers and previous behaviors regarding homecare services and ED visits for all participants. Preliminary univariate analyses, including the independent <italic toggle=\"yes\">t </italic>test or Mann–Whitney U test for continuous variables and chi-square analysis or Fisher’s exact test for categorical variables, were conducted to define the potential determinants of ED utilizations. The potential determinants that achieved a <italic toggle=\"yes\">P</italic> value ≤.2 in the preliminary univariate analyses were further entered into the multivariate logistic regression model to identify the explanatory risk factors associated with ED utilization. To find the subset of potential determinants that best predict the ED utilizations and combat the pervasive overfitting or underfitting problems, the best subset selection approach was employed.<sup>##UREF##5##16##</sup> Subsequently, the parsimonious multivariate logistic regression model was selected based on with the minimum Akaike information criterion (AIC).<sup>##UREF##6##17##</sup> All analyses in the current work were conducted using R version 4.2.3 software and the threshold for statistical significance for all analyses was<italic toggle=\"yes\"> P</italic>< .05.</p>" ]	[ "<title>Results</title>", "<p> A total of 122 patients were identified and 12 of them did not receive more than three months of integrated homecare services. Of the remining 110 eligible participants, 2 patients were found to have insufficient clinical documentation to be included in the analysis. The cohort study finally contained 108 patients. A detailed description of the study flowchart can be found in Figure. Patients had a mean age of 80.8 (±14.1) years and were almost balanced between males (53.7%) and females (46.3%). There were 68 (63.0%) and 63 (58.3%) patients who underwent nasogastric intubation and Foley catheter insertion, respectively. The mean scores were 9.4 (±14.9) for the Barthel ADL Index and 7.1 (±2.1) for the Charlson Comorbidity Index. The average duration of receiving publicly-funded integrated homecare programs was 24.4 (±21.9) months. Of the 108 patients, 65 patients (60.2%) used ED services within the data collection period, with a mean number of 2.1 (±1.7) for ED utilizations. Other characteristics of patients contributing to the analysis can be found in ##TAB##0##Table 1##.</p>", "<p> The preliminary univariate analyses demonstrated that a higher proportion of participants with ED utilizations presented with nasogastric intubation (70.8% vs. 51.2%, <italic toggle=\"yes\">P</italic>= .032) or skin pressure ulcers (29.2% vs. 9.3%, <italic toggle=\"yes\">P</italic>= .011) compared with those without ED utilizations. In addition, the mean score for the Charlson Comorbidity Index and the number of ED visits over the year before the index period were significantly higher in the case group (<italic toggle=\"yes\">P</italic>< .05). The patients who did not utilize unplanned emergency medical resources during the study period received a longer duration of homecare services, with a mean length of 30.6 (±26.4) months (<italic toggle=\"yes\">P</italic>= .016). As achieving a <italic toggle=\"yes\">P</italic> ≤.2 in the preliminary univariate analyses, a total of 10 candidate determinants, including nasogastric intubation, Foley catheter insertion, skin pressure ulcer, bedridden status, Charlson Comorbidity Index, number of prescribed drugs, caregiver’s sex, duration of introducing homecare services, working experience of dedicated nurses and previous one-year experience with ED utilizations were included into the multivariate logistic regression. Finally, the best subset selection analysis directly yielded the optimal five-determinant model which was selected with the minimum AIC value of 123.41, revealing Charlson Comorbidity Index, caregiver’s sex, duration of introducing homecare services, working experience of dedicated nurses, and number of ED utilizations within previous past year before enrollment as independent risk factors for ED visits (##TAB##1##Table 2##). ##TAB##2##Table 3## summarizes the details regarding the risk factors related to ED utilizations based on the best subset selection analysis. The parsimonious multivariate logistic regression model satisfied the omnibus test of model coefficients (<italic toggle=\"yes\">P</italic>< .001) and the Hosmer–Lemeshow test (<italic toggle=\"yes\">P</italic>= .521), indicating a good fit model. Patients having higher scores for the Charlson Comorbidity index (odds ratio [OR] = 1.33, 95% confidence interval [CI] = 1.05 to 1.70) and prior experience with ED utilizations in the past one year (OR = 1.54, 95% CI = 1.14 to 2.10) had significantly higher risk for unplanned ED utilizations during the data collection timeframe. Moreover, receiving homecare services offered by male caregiver (OR = 0.18, 95% CI = 0.05 to 0.66), longer duration of introducing home care services (OR = 0.97, 95% CI = 0.95 to 1.00) and prolonged working experience of dedicated nurse (OR = 0.89, 95% CI = 0.79 to 0.99) were significantly associated with a lower risk for ED visits.</p>" ]	[ "<title>Discussion</title>", "<p> As the explosive growth in healthcare demand for healthcare services, provision of integrated home and community-based care services is assumed to ensure continuity of healthcare delivery, reduce unnecessary or avoidable visits to the hospital or ED.<sup>##UREF##4##5##, ####REF##25452824##6##, ##REF##30843316##7##, ##REF##16541823##8##, ##REF##32610762##9##, ##REF##35658332##10##, ##REF##28264943##11####28264943##11##</sup> Nonetheless, concerns about the appropriateness of ED utilizations among the population receiving homecare services still persist.<sup>##REF##25371236##18##</sup> In the current study, we aimed to examine personal demographic and medical information, caregiver characteristics and behaviors related to homecare services and ED visits to explore the risk factors for ED visits among patients receiving publicly-funded homecare services. The preliminary univariate analyses showed that the presences of nasogastric intubations and skin pressure ulcers, more severe comorbid condition, a shorter duration for receiving homecare services and high use of ED services within one year prior to data collection were associated with unplanned ED utilizations among patients receiving publicly-funded integrated homecare services. Notably, to the authors’ knowledge, our study is the first attempt to leverage best subset selection regression approach to stratify the risk of utilizing ED sources among patients receiving publicly-funded homecare services. Selecting the variables with <italic toggle=\"yes\">P</italic>≤ .2 in the preliminary univariate analyses, the satisfactory parsimonious five-determinant model was registered, disclosing Charlson Comorbidity Index, caregiver’s sex, duration of introducing homecare services, working experience of dedicated nurses and number of prior ED utilizations in the past one year to be the most predictive of the likelihood of unplanned ED utilizations. Considering these results, the risk stratification prediction model may be feasible for early identifying recipients receiving publicly-funded integrated homecare services at risk for ED visits.</p>", "<p> It is generally acknowledged that Charlson Comorbidity Index is the commonly-used gold-standard measure to assess comorbidity in clinical scenarios<sup>##REF##3558716##19##</sup> and a proxy for multimorbidity and morbidity burden in primary care and community settings.<sup>##REF##22412005##20##</sup> Individuals with higher levels of comorbidities are more susceptible to sudden health deteriorations.<sup>##REF##24195643##21##</sup> As might be expected, our results from the univariate analyses revealed that patients receiving homecare services with the experience of ED visits had higher scores for the Charlson Comorbidity index. The findings from the best subset selection regression analysis conducted in the present work parallel other previous investigations that substantially confirmed comorbidity being as an independent predictive factor for hospital mortality, ED utilization and recidivism for elders.<sup>##REF##30622198##22##,##REF##31521468##23##</sup></p>", "<p> Another relevant indicator of unplanned ED visits is represented by the duration of provision of healthcare services. Our study not only found that the patients who did not utilize unplanned emergency medical resources within the observation period received a longer time in integrated homecare programs but also displayed duration of receiving home care services could be used to determine the likelihood of unplanned ED utilizations. Consistent with our finding, a before-after retrospective cohort study conducted in Vancouver, Canada, in a sample of 246 infirm participants aged over 55 years, showed that ED visit rates after enrollment in integrated home-based primary cares did not significantly decrease but tended toward stabilization.<sup>##REF##29622006##24##</sup> Another time series analyses in Italy, consisting of 39 822 recipients receiving integrated home cares also reported 45%, 17%, and 64% reduction in ED visits after introducing short, intermediate and long duration of integrated home cares, respectively.<sup>##REF##35658332##10##</sup> Accordingly, continuously accessing integrated homecare services could be beneficial for risk mitigation of unplanned ED utilizations.</p>", "<p> Moreover, our study identified the characteristics of caregiver or dedicated nurse, including caregiver’s sex and working experience as independent risk factors unplanned or nonurgent ED visits among patients receiving homecare services. Previous studies have reported that female caregiver perceive caregiving as more burdensome because of socialization and role expectations<sup>##REF##2180010##25##</sup> and different coping strategies for caregiving situation,<sup>##REF##25651586##26##,##UREF##7##27##</sup> which may account for the lower risk of unplanned or nonurgent ED visits among patients receiving homecare services provided by male caregiver. On the other hand, a nurse-centric survey from the National Database of Nursing Quality Indicators<sup>TM</sup> (NDNQI)<sup>®</sup> in 2006 concluded the relationship between nurse experience and quality of care.<sup>##REF##21848348##28##</sup> In line with this, our multivariate logistic regression results presented that for every increase of one year in average working experience of dedicated nurse, the risk of unexpectedly using ED recourses was lowered by 1.1% lower.</p>", "<p> Our result also supports the common notion, indicating that past use of healthcare services is one of the important variables influencing subsequent healthcare utilizations among the geriatric population.<sup>##REF##31277582##29##, ####REF##26931325##30##, ##UREF##8##31####8##31##</sup> The finding of the present work based on the best subset selection regression analysis demonstrated that a higher number of past ED visits was predictive of the likelihood of ED utilization during the index period. In other words, patients with one year of previous experience with ED utilizations were more likely to visit emergency services unexpectedly. Research from a medical center in Taipei, Taiwan, has also reported that multiple previous ED visits appeared to be one of the risk factors for readmissions or ED utilization among patients receiving home healthcare.<sup>##UREF##9##32##</sup> Analogous findings were obtained from Franchi et al, who noted that a higher number of past ED visits was another predictor significantly associated with frequent ED use, showing that seniors with four or more department visits had a 30-fold higher risk of having the same number of ED utilization in the subsequent year.<sup>##REF##26931325##30##</sup></p>", "<p> Of note, empirical data have disclosed that nasogastric intubation-induced aspiration would be a potentially serious complication and a significant risk factor for unplanned emergency readmission.<sup>##REF##3086812##33##,##REF##10394080##34##</sup> The present work found that more than 60% of participants (68/108) receiving publicly-funded integrated homecare services had nasogastric intubations and further manifested significantly higher proportion of patients having nasogastric intubation visited the ED than those who did not. Since the demand for nasogastric intubation in disabled older homecare residents in Taiwan continues to grow,<sup>##REF##12110075##35##,##UREF##10##36##</sup> effective education strategies are urgently needed to manage accurate nasogastric tube feeding and prevent unplanned or accidental extubation and ED utilization for this reason.</p>", "<p> The present findings should be read while considering some embedded limitations; first, given that our single-center, retrospective design just collected the specific targets, only patients who received homecare services integrated by a dedicated regional hospital in southern Taiwan were recruited for this study. The relatively small sample size and the sample specificity, therefore could lack the representativity of whole home healthcare systems in Taiwan and the present work may not be suitable for extrapolation to other home healthcare systems. Second, published evidence indicated sharp increase in the number of patients who utilized ED or acute healthcare recourses as approaching death.<sup>##REF##34728661##37##,##REF##21644868##38##</sup> As we limited the retrospective cohort study to patients receiving more than three months of publicly-funded integrated homecare services within the observation period, patient facing a rapid deterioration in health with imminent death in an emergency medicine setting and receiving less than three months of homecare services were removed from the current database. Our inability to consider another important clinical issue regarding imminent death in an emergency medicine setting might probably bias the findings in unpredictable ways. Additionally, approximately 70% (80/108) of the participants of this study were eligible for social welfare assistance, and further effort is needed to highlight whether governmental medical subsidies would influence the behaviors in seeking ED sources. Finally, we reviewed charts of patients enrolled in a regional hospital’s publicly-financed integrated homecare programs. Records regarding the use of EDs in other hospitals were unavailable, and the results would likely be underestimated.</p>" ]	[ "<title>Conclusion</title>", "<p> In addition to the presences of nasogastric intubations and skin pressure ulcers, more severe comorbid condition, a shorter duration for receiving homecare services and high use of ED services within one year prior to data collection were highlighted to be associated with unplanned ED utilizations among patients receiving publicly-funded integrated homecare services, specially, we identified the optimal parsimonious five-determinant model, disclosing Charlson Comorbidity Index, caregiver’s sex, duration of introducing homecare services, working experience of dedicated nurses, and number of prior ED utilizations in the past one year to be the most predictive of the likelihood of unplanned ED utilizations among patients receiving publicly-funded integrated homecare services. The risk stratification-based prediction model could be incorporated into hospital information system for early warning patients at risk for ED visits. The evidence of demographic and clinical determinants of ED utilizations may also help government agencies propose supportive policies for improved access to integrated homecare resources and promote appropriate care recommendations to reduce unplanned or nonurgent ED visits among patients receiving homecare services.</p>" ]	[ "<p>\n<bold>Background:</bold> The public health strategy of increasing access to comprehensive home or community-based healthcare services and emergency home visits is intent on reducing the overcrowding of emergency departments. However, scientific evidence regarding the association between home-based healthcare services and emergency department uses is surprisingly insufficient and controversial so far. The present retrospective study identified the risk factors for emergency department visits among patients receiving publicly-funded homecare services.\n</p>", "<p><bold>Methods:</bold> The personal demographic and medical information, caregiver characteristics, and behaviours related to homecare services and emergency department visits from the medical records and structured questionnaires of 108 patients who were recipients of integrated homecare services in a regional hospital in southern Taiwan between January 1, 2020, and December 31, 2020, were collected. After screening the potential predictor variables using the preliminary univariate analyses, the multivariate logistic regression with best subset selection approach was conducted to identify best combination of determinants to predict unplanned emergency department utilizations.\n</p>", "<p><bold>Results:</bold> Best subset selection regression analysis showed Charlson Comorbidity Index (odds ratio (OR)=1.33, 95% CI=1.05 to 1.70), male caregiver (OR=0.18, 95% CI=0.05 to 0.66), duration of introducing homecare services (OR=0.97, 95% CI=0.95 to 1.00), working experience of dedicated nurses (OR=0.89, 95% CI=0.79 to 0.99) and number of emergency department utilizations within previous past year before enrollment (OR=1.54, 95% CI=1.14 to 2.10) as significant determinants for unplanned emergency department visits.\n</p>", "<p>\n<bold>Conclusion:</bold> The present evidence may help government agencies propose supportive policies to improve access to integrated homecare resources and promote appropriate care recommendations to reduce unplanned or nonurgent emergency department visits among patients receiving homecare services.</p>", "<p>\n<bold>Citation:</bold> Chiu WY, Yeh TC, Yang CC. Factors associated with emergency department visits among patients receiving publicly-funded homecare services: a retrospective chart review from southern Taiwan regional hospital. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7377. doi:10.34172/ijhpm.2023.7377</p>" ]	[ "<title>Ethical issues</title>", "<p> Ethical approval was obtained by the institutional review board of the Kaohsiung Armed Forces General Hospital, Taiwan (KAFGHIRB 109-056).</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Disclaimer</title>", "<p> The manuscript has never been published before in any other journal and will not be submitted to another journal during the period it is under review or after it is accepted by the Journal. The authors agree to follow the Journal’s submission instructions.</p>", "<title>Funding</title>", "<p> This work was supported by Kaohsiung Armed Forces General Hospital, Taiwan and the National Science and Technology Council, R.O.C. (Taiwan) (MOST 111-2221-E-037-003-MY2).</p>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nFlowchart for Participant Screening and Enrollment.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Personal Characteristics and Univariate Analyses of Collected Variables for All Participants\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Total</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Patients With ED Utilizations (n = 65)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Patients Without ED Utilizations (n = 43)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P </bold></italic><bold>Value</bold><sup>e</sup>\n</td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"5\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\">Basic demographic and medical information</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean age (y)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80.8 ± 14.1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">81.5 ± 12.2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">79.7 ± 16.6</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.506<sup>b</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male, n (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">58 (53.7)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">36 (55.4)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">22 (51.2)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.410<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Welfare receipt</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80 (74.1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">51 (78.5)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">29 (67.4)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.201<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Glasgow Coma Scale</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12.4 ± 3.1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12.3 ± 3.2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12.7 ± 2.9</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.452<sup>b</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Nasogastric intubation, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">68 (63.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">46 (70.8)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">22 (51.2)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<bold>.032</bold><sup>c</sup>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Foley catheter insertion, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">63 (58.3)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">35 (53.8)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">28 (65.1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.168<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Skin pressure ulcer, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">23 (21.3)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">19 (29.2)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4 (9.3)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<bold>.011</bold><sup>d</sup>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Bedridden, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">41 (38.0)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">22 (33.8)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">19 (44.2)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.189<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Barthel ADL index</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9.4 ± 15.0</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8.5 ± 15.1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10.6 ± 4.57</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.487<sup>b</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Charlson Comorbidity Index</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7.1 ± 2.1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7.4 ± 2.1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6.5 ± 2.0</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<bold>.030</bold><sup>b</sup>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Polypharmacy<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">87 (80.6)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">54 (83.1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">23 (53.5)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.416<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No. of prescribed drugs</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6.7 ± 2.9</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7.1 ± 2.9</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6.1 ± 2.9</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.096<sup>b</sup></td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"5\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">Caregiver/Nurse characteristics</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Full-time caregiver, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80 (74.1)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">50 (76.9)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">30 (69.8)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.271<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Age ≥65 years, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">22 (20.4)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13 (20)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9 (20.9)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.546<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male caregiver, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">19 (17.6)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9 (13.8)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10 (23.3)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.159<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Foreign nationality, No. (%)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">46 (42.6)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">29 (44.6)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">17 (39.5)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.374<sup>c</sup></td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean year of working experience for dedicated nurse (y)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10.2 ± 4.2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9.7 ± 4.1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10.9 ± 4.3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.148<sup>b</sup></td></tr><tr style=\"background-color:#eeeeee\"><td colspan=\"5\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">Behaviors on home care service and ED visit</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No. of ED utilizations within the period of data collection (min-max)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.1 ± 1.7 (1-9)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean duration of receiving home care services (mon)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">24.4 ± 21.9</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">20.3 ± 17.3</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">30.6 ± 26.4</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<bold>.016</bold><sup>b</sup>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">No. of ED utilizations over the past year</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1.2 ± 1.6</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2.4 ± 2.5</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.9 ± 1.1</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold><.001</bold><sup>b</sup>\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Best Subset Selection Approach for Screening Best Combination of Predictor Variables\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n</td><td colspan=\"10\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Number of Variables Included</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>1</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>2</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>3</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>4</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>5</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>6</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>7</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>8</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>9</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>10</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Variables<sup>a</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Nasogastric intubation</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Foley catheter insertion</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Skin pressure ulcer</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Bedridden</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Charlson Comorbidity Index</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No. of prescribed drugs</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male caregiver</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean year of working experience for dedicated nurse</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean duration of introducing home care services</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No. of ED utilizations over the past year</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">✓</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">AIC</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">132.54</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">130.12</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">128.16</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">126.37</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">123.41</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">123.52</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">123.67</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">125.02</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">126.65</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">128.46</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Multivariate Logistic Regression Analysis of Factors That Can Independently Predict Uses of Emergency Medical Resources Within the Data Collection Period\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>OR</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>95% CI</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P</bold></italic><bold> Value</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Charlson Comorbidity Index</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1.33</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1.05-1.70</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n<bold>.021</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Male caregiver</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.18</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.05-0.66</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<bold>.010</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean duration of introducing home care services (mon)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.97</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.95-1.00</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<bold>.015</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mean year of working experience of dedicated nurse (y)</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.89</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.79-0.99</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n<bold>.030</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">No. of ED utilizations over the past year</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1.54</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1.14-2.10</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>.006</bold>\n</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Policy-maker should be aware that provision of continuous and comprehensive integrated homecare model would reduce unnecessary or avoidable visits to the emergency department (ED). </p></list-item><list-item><p>Patients who did not utilize unplanned emergency medical resources received a longer time in integrated homecare publicly-funded homecare programs. </p></list-item><list-item><p>The optimal parsimonious five-determinant model, comprising of Charlson Comorbidity Index, caregiver’s sex, duration to introduce homecare services, working experience of dedicated nurses and number of ED visits within previous past year before enrollment could predict unplanned ED utilizations among patients receiving publicly-funded integrated homecare services. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> Increased accessibility of comprehensive home or community-based healthcare services and emergency home visits would reduce overcrowding of emergency departments (EDs). Efforts to reduce and prevent unnecessary or avoidable ED visits should be informed by an understanding of the contributions of specific risk factors for ED utilization for patients receiving integrated home care. The current work authenticated that providing a continuous and comprehensive integrated homecare model would potentially reduce unnecessary or avoidable visits to the EDs. The evidence of demographic and clinical determinants of ED utilization may help government agencies propose supportive policies for improved access to integrated homecare resources and promote appropriate care recommendations to reduce unplanned or nonurgent ED visits among patients receiving homecare services.</p></sec></boxed-text>" ]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p> Abbreviations: ADl, activities of daily living; ED, emergency department; N/A, not applicable.</p><p>\n<sup>a</sup>Polypharmacy was defined as regular use of at least five prescribed drugs.</p><p>\n<sup>b</sup><italic toggle=\"yes\">P</italic> values comparing patients with ED utilizations and those without ED utilizations within the data collection period were obtained from independent <italic toggle=\"yes\">t</italic> test.</p><p>\n<sup>c</sup><italic toggle=\"yes\">P</italic> values comparing patients with ED utilizations and those without ED utilizations within the data collection period were obtained from chi-square analysis.</p><p>\n<sup>d</sup><italic toggle=\"yes\">P</italic> values comparing patients with ED utilizations and those without ED utilizations within the data collection period were obtained from Fisher’s exact test.</p><p>\n<sup>e</sup>A <italic toggle=\"yes\">P </italic>value of less than.05 was considered significant.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: ED, emergency department; AIC, Akaike information criterion.</p><p>\n<sup>a</sup>Variables that achieved a <italic toggle=\"yes\">P</italic> ≤ .2 in the preliminary univariate analyses were entered into the multivariate logistic regression analyses with best subset selection approach to determent the parsimonious model.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: OR, odds ratio; ED, emergency department; CI, confidence interval.</p><p>\n<italic toggle=\"yes\">Note: </italic>Omnibus test of model coefficients: <italic toggle=\"yes\">P</italic> < .001; Hosmer–Lemeshow test: <italic toggle=\"yes\">P</italic> = .521.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7377-g001\" position=\"float\"/>" ]	[]	[{"label": ["1"], "mixed-citation": [" National Development Council (R.O.C.) Taiwan. Trend in the Percentage of Elderly Population. National Development Council; 2020. [Chinese]. "]}, {"label": ["2"], "mixed-citation": [" National Development Council (R.O.C.) Taiwan. Population Projections for Republic of China (Taiwan): 2014-2061. National Development Council; 2013. [Chinese]. "]}, {"label": ["3"], "mixed-citation": [" National Health Insurance Administration, Ministry of Health and Welfare, (R.O.C.) Taiwan. 2020-2021 Handbook of Taiwan\u2019s National Health Insurance. 2019. "]}, {"label": ["4"], "mixed-citation": [" National Health Insurance Administration, Ministry of Health and Welfare, (R.O.C.) Taiwan. Taiwan Health and Welfare Report. 2019. [Chinese]. "]}, {"label": ["5"], "mixed-citation": [" College of Family Physicians of Canada. A Vision for Canada: Family Practice \u2013 the Patient\u2019s Medical Home. Mississauga, ON: College of Family Physicians of Canada; 2011. "]}, {"label": ["16"], "person-group": ["\n"], "surname": ["Hastie", "Tibshirani", "Tibshirani"], "given-names": ["T", "R", "R"], "article-title": ["Best subset, forward stepwise or lasso? Analysis and recommendations based on extensive comparisons"], "source": ["Stat Sci"], "year": ["2020"], "volume": ["35"], "issue": ["4"], "fpage": ["579"], "lpage": ["592"], "pub-id": ["10.1214/19-STS733"]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Liao", "Cavanaugh", "McMurry"], "given-names": ["JG", "JE", "TL"], "article-title": ["Extending AIC to best subset regression"], "source": ["Comput Stat"], "year": ["2018"], "volume": ["33"], "issue": ["2"], "fpage": ["787"], "lpage": ["806"], "pub-id": ["10.1007/s00180-018-0797-8"]}, {"label": ["27"], "person-group": ["\n"], "surname": ["Calasanti", "Bowen"], "given-names": ["T", "ME"], "article-title": ["Spousal caregiving and crossing gender boundaries: maintaining gendered identities"], "source": ["J Aging Stud"], "year": ["2006"], "volume": ["20"], "issue": ["3"], "fpage": ["253"], "lpage": ["263"], "pub-id": ["10.1016/j.jaging.2005.08.001"]}, {"label": ["31"], "person-group": ["\n"], "surname": ["McCusker", "Cardin", "Bellavance", "Belzile"], "given-names": ["J", "S", "F", "E"], "article-title": ["Return to the emergency department among elders: patterns and predictors"], "source": ["AcadEmerg Med"], "year": ["2000"], "volume": ["7"], "issue": ["3"], "fpage": ["249"], "lpage": ["259"], "pub-id": ["10.1111/j.1553-2712.2000.tb01070.x"]}, {"label": ["32"], "person-group": ["\n"], "surname": ["Lee", "Lee", "Yang", "Lee"], "given-names": ["HC", "TY", "YC", "YS"], "article-title": ["Risk factors of one-year readmission or emergency room revisit in patients receiving home health care"], "source": ["Taiwan J Fam Med"], "year": ["2018"], "volume": ["28"], "issue": ["4"], "fpage": ["208"], "lpage": ["218"], "pub-id": ["10.3966/168232812018122804003"]}, {"label": ["36"], "mixed-citation": [" Ministry of Health and Welfare, (R.O.C.) Taiwan. The nasogastric tube feeding rate in Taiwan. 2021. [Chinese]. "]}]	{ "acronym": [], "definition": [] }	38	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 11; 12:7377	oa_package/9f/a4/PMC10699816.tar.gz
PMC10699817	0	[ "<title>Background</title>", "<p> Over the past two decades, an increasing number of pay-for-performance (P4P) programs, which use financial incentives to better motivate physicians and improve the quality of healthcare, have been adopted worldwide.<sup>##REF##16908917##1##, ####REF##16595409##2##, ##REF##20731816##3##, ##REF##23380190##4##, ##REF##28114600##5####28114600##5##</sup> A P4P program is expected to enhance the quality of care by offering incentives to providers. Financial incentives reward certain services based on pre-determined benchmarks. These programs generally provide incentives to healthcare providers to improve the process of care (eg, checking the glycated hemoglobin [HbA1c] levels of patients with diabetes) and intermediate outcomes (eg, controlling the HbA1c levels of patients with diabetes). The measures are based on the recommendations of clinical practice guidelines. Good adherence to clinical guidelines can improve health outcomes for patients. Therefore, considering the incentives offered under P4P programs, healthcare providers might devote more effort to specific conditions or indicators that are rewarded and pursue better care outcomes for patients.<sup>##REF##16908917##1##</sup></p>", "<p> However, P4P programs may have potential unintended consequences,<sup>##REF##16908917##1##,##REF##16595409##2##,##REF##23380190##4##</sup> such as spillover effects on neglecting conditions or activities that are not directly rewarded.<sup>##REF##23380190##4##</sup> Holmstrom and Milgrom proposed the “multitasking problem” to illustrate the possibility of spillover effects.<sup>##UREF##0##6##</sup> In a P4P scheme, healthcare providers might pay more attention to indicators tied to financial incentives and neglect those that are not incentivized. Therefore, P4P programs may improve the performance of incentivized items at the expense of the unfavorable performance of non-incentivized items, resulting in a decline in the quality of care for patients. This phenomenon is called a “negative spillover effect.”</p>", "<p> The problem of multitasking might be alleviated if the activities undertaken in a process are similar or co-occur, because certain conditions or indicators rely on similar inputs.<sup>##REF##20490360##7##,##REF##21667575##8##</sup> This means that, under a P4P program, non-incentivized activities may be indirectly rewarded when they share commonalities with incentivized activities. This phenomenon is called a “positive spillover effect” (or halo effect). Therefore, commonalities in production among a set of activities are crucial for generating positive or negative spillover effects from an incentive program.</p>", "<p> Although the intended effects of P4P programs have been well documented,<sup>##REF##16908917##1##, ####REF##16595409##2##, ##REF##20731816##3##, ##REF##23380190##4##, ##REF##28114600##5####28114600##5##</sup> little is known about their spillover effects, and the results tend to be inconclusive. Some studies have found that P4P programs have a positive spillover effect on non-incentivized conditions or indicators,<sup>##REF##17625132##9##, ####REF##17550669##10##, ##UREF##1##11##, ##UREF##2##12####2##12##</sup> whereas others have found negative spillover effects, because of the possible neglect of non-incentivized aspects of care by healthcare providers over the long term.<sup>##REF##19625717##13##,##REF##21712336##14##</sup> Some studies have found no spillover effect at all of P4P programs.<sup>##REF##21667575##8##,##REF##17551130##15##</sup> The aforementioned discrepancies in the findings might be attributed to variations in the types of P4P programs implemented, the quality of the methodology used, and differences in the research setting.</p>", "<p> Most empirical studies on the spillover effects of P4P programs have been performed in the United States<sup>##REF##21667575##8##,##UREF##1##11##,##REF##17551130##15##</sup> or the United Kingdom.<sup>##REF##17625132##9##,##REF##17550669##10##,##REF##19625717##13##,##REF##21712336##14##</sup> The spillover effects of P4P programs in the United States have tended to be small, which might be attributable to the diluting effect of the small incentive size based on multiple payers and the phenomenon in which payers often consider only a fraction of the targeted healthcare providers.<sup>##REF##16595409##2##,##REF##20731816##3##</sup> The P4P programs in the United Kingdom have been implemented nationally. Most of these programs are designed for primary care settings and reward general practitioners based on the quality-of-service delivery. However, healthcare systems in many Asian countries such as Japan, Korea, and Taiwan lack general practitioners (as gatekeepers) or formal referral mechanisms and are mainly specialist-based care.</p>" ]	[ "<title>Methods</title>", "<p> This study used a natural experimental design with population-based longitudinal data to examine the long-term spillover effects of a P4P program. The analysis was based on claims data for healthcare utilization from 2016 to 2020 in Taiwan.</p>", "<title> Pay-for-Performance Program for Diabetes Care</title>", "<p> Since the end of 2001, Taiwan’s single-payer, the National Health Insurance Administration (NHIA), has implemented nationwide P4P programs for several chronic conditions. For the P4P program for diabetes care, physicians who specialize in metabolic disorders or endocrinology or those who have completed training for the diabetes shared care program can voluntarily participate in the P4P program for diabetes care. Participating physicians can recruit patients for the program. The P4P program pays participating physicians three fees: the P4P management fee for the initial enrollment visit, an extra fee for a comprehensive follow-up visit, and an annual evaluation fee. The required and recommended services include a medical history examination, physical examination (for example, ophthalmoscopic or foot examination), laboratory evaluation (for example, HbA1c check or cholesterol checks), management plan, and diabetes self-management education, which are clearly defined in the P4P program for diabetes care.<sup>##UREF##3##16##</sup></p>", "<p> Outcome-based quality indicators have been gradually incorporated into the P4P program for diabetes care. Between 2001 and 2006, the financial incentives of the diabetes P4P program focused only on participation or process-based care (eg, performing HbA1c or cholesterol checks). In late 2006, the NHIA implemented a new strategy to better reward the health outcomes by paying an additional bonus for improvement in intermediate clinical outcome measures. A composite score was developed for each participating physician based on measures including the complete follow-up visit rate and control of HbA1c and low-density lipoprotein cholesterol (LDL-C) levels. Under this scheme, physicians receive an extra outcome-based reward (NT$ 1000 or US$ 33 per patient) if their composite scores rank among the top 25% of participating physicians. This plan is called the “pay for excellence” incentive. In 2009, the NHIA introduced a “pay-for-improvement” incentive to encourage physicians to focus on improving the composite scores of patients. Physicians receive an extra reward (NT$ 500 or US$ 17 per patient) if the composite score of a patient improves or is maintained over two years.<sup>##UREF##3##16##</sup> In short, both process-based (eg, HbA1c check) and intermediate clinical outcome-based indicators (eg, proper control of HbA1c) for the recommended examination and laboratory tests have been incorporated into the diabetes P4P program. However, not all the intermediate clinical outcome indicators of the examinations/tests are incentivized in the program.<sup>##UREF##3##16##</sup></p>", "<title> Participants</title>", "<p> Adult patients (aged 20 or older) diagnosed with type-2 diabetes were identified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) code E11. Because clinical data for intermediate outcomes (eg, HbA1c level) became available starting in 2015, we included only patients with at least three diabetes-related physician visits and laboratory test results every year from 2016 to 2020. Patients with diabetes who were enrolled in the nationwide P4P program in 2017 were included in the intervention group. The index date for each patient was defined as the date of enrollment in the P4P program between January 1, 2017 and December 31, 2017. The study included only participants who remained in the program throughout the observation period from 2017 to 2020.</p>", "<p> Selection bias cannot be ruled out because the patients enrolled in the program were purposively selected by their physicians and voluntarily enrolled in the P4P program.<sup>##REF##12785560##17##,##REF##22232099##18##</sup> To minimize the potential impact of selection bias, we adopted a two-step sample selection: identifying patients visiting the same group of physicians and using the propensity score matching (PSM) approach to select patients. In the first step, we identified the most frequently visited physicians for the diabetes care of the 9119 patients enrolled in the P4P program. All diabetic patients who visited the shortlisted set of physicians were identified. Patients who had never been enrolled in the P4P program were considered suitable for the comparison group. A total of 2649 physicians were consulted by 9119 patients (pre-matched) in the intervention group, and 21 651 patients (pre-matched) were selected via PSM in the comparison group.</p>", "<p> Subsequently, in the second step, we used a PSM approach to select appropriate patients to form the comparison group.<sup>##UREF##4##19##</sup> For each patient, we created a propensity score that estimated the probability of their enrollment in the P4P program based on their characteristics using a generalized estimating equations (GEEs) model considering the effects of patient clustering among particular physicians.<sup>##UREF##5##20##</sup> The characteristics of patients considered in the matching process included their age, sex, Charlson comorbidity index (CCI) score,<sup>##REF##1607900##21##</sup> diabetes complication severity index (DCSI) score,<sup>##REF##18197741##22##</sup> likelihood of hospitalization in the previous year, and baseline HbA1c values. The characteristics of healthcare providers included in the model were the accreditation level<sup>##REF##10894199##23##</sup> and location of the hospital or community clinic that was most frequently visited by a given patient.</p>", "<p> Based on the propensity scores, we used the caliper matching method with 1:2 matching between the intervention and comparison groups. Finally, 7688 patients (post-matched) were enrolled from the P4P program, and the PSM process yielded 15 376 patients (post-matched) in the comparison group. In addition, we calculated absolute standardized differences in baseline characteristics between the intervention and comparison groups. Standardized differences less than 10% indicated acceptable matching.<sup>##REF##11297888##24##, ####REF##19757444##25##, ##REF##21818162##26####21818162##26##</sup></p>", "<p> The observation period ranged from one year before the index date in 2017 to three years of subsequent follow-up. As the subjects in the comparison group did not have an index date unlike those enrolled in the P4P program, they were assigned a pseudo-index date of their matched counterparts in the intervention group. In all, 23 064 patients and 92 256 patient years were included in the analysis. The unit of analysis was the number of patient-years.</p>", "<title> Measurement of Variables</title>", "<p> In terms of dependent variables, four intermediate clinical outcome indicators were included in this study: two incentivized and two non-incentivized indicators under the P4P scheme. In the analysis, the two incentivized indicators measured whether the patient had proper control of their HbA1c (HbA1c <7%) and LDL-C levels (LDL-C <100 mg/dL) during the study period. High-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels are also crucial for the management of dyslipidemia in patients with diabetes.<sup>##REF##14693930##27##</sup> Therefore, we included two non-incentivized indicators to measure whether the patient had proper control over their HDL-C (HDL-C >40 mg/dL) and TG levels (TGs <200 mg/dL).</p>", "<p> The leading independent variables were patient enrollment in the P4P program, time dummy variables for the three years after the index date, and three interaction terms for the previously described variables. The following covariates were controlled in the regression models: patient characteristics (sex, age, CCI score, DCSI score, and likelihood of hospitalization in the previous year) and healthcare provider characteristics (accreditation level and location).</p>", "<title> Statistical Analyses</title>", "<p> To examine the spillover effects of the P4P program, we fitted the GEEs with difference-in-differences (DID) estimation to longitudinal data that considered the correlation between repeated observations for the same patients and patients within the same matched pairs as well as considered the unobserved time-invariant characteristics for patients.<sup>##UREF##5##20##</sup> The likelihood of the patient having proper control on the four intermediate clinical outcome indicators was analyzed using a logit link function and had a binominal distribution. The specifications are as follows:</p>", "<p>\n<italic toggle=\"yes\">logit Y</italic><sub>it</sub><italic toggle=\"yes\"> = β</italic><sub>0</sub> + <italic toggle=\"yes\">β</italic><sub>1</sub> × <italic toggle=\"yes\">P</italic>4<italic toggle=\"yes\">P</italic><sub>it</sub><italic toggle=\"yes\"> + β</italic><sub>2</sub> × <italic toggle=\"yes\">Year</italic>1<sub>it</sub><italic toggle=\"yes\"> + β</italic><sub>3</sub> × <italic toggle=\"yes\">Year</italic>2<sub>it</sub><italic toggle=\"yes\"> + β</italic><sub>4</sub> × <italic toggle=\"yes\">Year</italic>3<sub>it</sub><italic toggle=\"yes\"> + β</italic><sub>5</sub> × <italic toggle=\"yes\">P</italic>4<italic toggle=\"yes\">P</italic><sub>it</sub> × <italic toggle=\"yes\">Year</italic>1<sub>it</sub> + <italic toggle=\"yes\">β</italic><sub>6</sub><italic toggle=\"yes\"> × P</italic>4<italic toggle=\"yes\">P</italic><sub>it</sub> × <italic toggle=\"yes\">Year</italic>2<sub>it</sub> + <italic toggle=\"yes\">β</italic><sub>7</sub> × <italic toggle=\"yes\">P</italic>4<italic toggle=\"yes\">P</italic><sub>it</sub><italic toggle=\"yes\"> × Year</italic>3<sub>it</sub> + <italic toggle=\"yes\">β</italic><sub>8</sub> × <italic toggle=\"yes\">X</italic><sub>it</sub> + <italic toggle=\"yes\">β</italic><sub>9</sub> × <italic toggle=\"yes\">Z</italic><sub>i</sub> + <italic toggle=\"yes\">ε</italic><sub>it</sub></p>", "<p> where <italic toggle=\"yes\">Y</italic><sub>it</sub> is the likelihood of good control on an intermediate clinical outcome for patient<italic toggle=\"yes\">i</italic>during period<italic toggle=\"yes\"> t. </italic>The <italic toggle=\"yes\">P</italic>4<italic toggle=\"yes\">P</italic><sub>it </sub>dummy indicates whether the patient was enrolled in the P4P program. <italic toggle=\"yes\">Year</italic>1<sub>it</sub>, <italic toggle=\"yes\">Year</italic>2<sub>it</sub>, and <italic toggle=\"yes\">Year</italic>3<sub>it</sub> are dummy variables that indicate observations for over 3 years after the index date of the P4P program. The DID estimates of the effects of the P4P program are captured by the coefficients <italic toggle=\"yes\">β</italic><sub>5</sub>, <italic toggle=\"yes\">β</italic><sub>6</sub>, and <italic toggle=\"yes\">β</italic><sub>7</sub> on the three interaction terms <italic toggle=\"yes\">P</italic>4<italic toggle=\"yes\">P</italic><sub>it</sub><italic toggle=\"yes\"> × Year</italic>1<sub>it</sub>, <italic toggle=\"yes\">P</italic>4<italic toggle=\"yes\">P</italic><sub>it</sub><italic toggle=\"yes\"> × Year</italic>2<sub>it</sub>, and <italic toggle=\"yes\">P</italic>4<italic toggle=\"yes\">P</italic><sub>it</sub><italic toggle=\"yes\"> × Year</italic>3<sub>it</sub>, respectively. Parameters <italic toggle=\"yes\">X</italic><sub>it</sub> and <italic toggle=\"yes\">Z</italic><sub>i</sub> represent a set of variables that measure time-variant and time-invariant covariates (participant’s sex). All statistical analyses were performed using the SAS version 9.4 (SAS Institute) and Stata version 15.1 (StataCorp).</p>" ]	[ "<title>Results</title>", "<title> Descriptive Analysis</title>", "<p>\n##TAB##0##Table 1## lists the baseline characteristics of the pre- and post-matched participants in the intervention and comparison groups. In the pre-matched sample, patients diagnosed with diabetes in the intervention group were younger, had higher DCSI and CCI scores, and controlled their baseline HbA1c levels less well. Furthermore, they had a higher likelihood of hospitalization in the previous year and tended to receive care at a medical center/regional hospital. The PSM process resulted in a more balanced distribution of the characteristics of patients and their care providers in the intervention and comparison groups. All absolute standardized differences were less than 10%, indicating acceptable matching results.</p>", "<p> Figure presents the changes in the outcome measures over the study period. For the incentivized indicators, proper control of HbA1c levels was lower in the intervention group than in the comparison group in the baseline year (43.59% vs. 45.05%). After the first year of the P4P program, the rate of proper control of HbA1c increased in the intervention group (49.08%) and was higher than that in the comparison group (46.85%). For proper control of LDL-C, the rates in the intervention and comparison groups increased after the intervention (ranging from 56.18% to 70.51% in the intervention group; 57.30% to 66.77% in the comparison group). For non-incentivized indicators, we found that the rates of proper control on HDL-C steadily increased in both the intervention and comparison groups over four years. Finally, we found a noticeable increase in the rate of proper control of TG levels in the intervention group after enrollment, compared with a slight increase in the comparison group.</p>", "<title> Results From Regression Models</title>", "<p>\n##TAB##1##Table 2## lists the results obtained from the DID estimates in the GEEs model. For the incentivized indicator HbA1c, patients enrolled in the P4P program were more likely than their counterparts to have proper control of their HbA1c levels during the post-P4P period. The odd ratios (ORs) of the interaction terms were positive and significant from the first to third years after the intervention (OR was 1.166 in the first year [95% confidence interval [CI]: 1.106-1.230], 1.168 in the second year [95% CI: 1.103-1.236], and 1.138 in the third year [95% CI: 1.073-1.206]). In respect of the proper control of LDL-C, we also found that the DID parameters were positive and significant, with OR being 1.199 (95% CI: 1.128-1.273), 1.232 (95% CI: 1.155-1.314), and 1.231 (95% CI: 1.150-1.318) for the three years after the intervention.</p>", "<p> For the non-incentivized indicator TGs, the result was similar to that of the aforementioned incentivized indicators. Patients in the P4P program were more likely than their counterparts to have proper control of their TG levels in the first and second years after the P4P program (OR of 1.114 [95% CI: 1.044-1.189], 1.122 [95% CI: 1.047-1.202]). However, there was no significant effect in the third year after the P4P program (OR of 1.051 [95% CI: 0.980-1.128]). Conversely, we found no spillover effects of the P4P program on the non-incentivized HDL-C control in the three years after the P4P program (OR of 1.036 in the first year [95% CI: 0.985-1.089]; 0.986 in the second year [95% CI: 0.936-1.040]; and 0.974 in the third year [95% CI: 0.922-1.029]) (##TAB##1##Table 2##).</p>", "<title> Sensitivity Analysis</title>", "<p> Sensitivity analyses were performed to validate the robustness of the findings. First, we used a continuous scale of the intermediate clinical outcome variables instead of a binary one. The analyses yielded results similar to those described earlier (##SUPPL##0##Supplementary file 1##, Table S1). Second, we performed analyses stratified by sex and found partly similar results (Table S2). Third, we performed analyses stratified by the status of multiple chronic conditions (<2 chronic conditions or ≥2 chronic conditions, excluding diabetes). In this study, the number of chronic conditions was measured using nine common chronic conditions that often require ongoing medication management, including hypertension, heart disease, cerebrovascular disease, pulmonary disease, chronic renal disease, arthritis/degenerative joint diseases, depression/anxiety-associated diseases, and cancer. Most of the results were similar to previous findings, except for patients with ≥2 chronic conditions, in terms of TG outcomes (Table S3). Finally, we used random-intercept models with DID estimation to consider unobserved time-invariant covariates and considered the correlation between repeated observations for the same patient. Instead of the odds ratios, we calculated the average marginal effects for all estimates and used bootstrapping with 100 replications to acquire standard errors (Table S4). Previously, a similar approach has been used in the econometric literature. These sensitivity analyses yielded results similar to our main results.</p>" ]	[ "<title>Discussion</title>", "<title> Effect of P4P Programs on Incentivized Outcomes</title>", "<p> The effect of a P4P program on intermediate clinical outcomes tended to be inconclusive in a previous systematic review.<sup>##REF##28114600##5##</sup> For example, under the Quality of Outcome Framework (QOF) in the United Kingdom, Vamos et al<sup>##REF##21810950##28##</sup> and Alshamsan et al<sup>##REF##22585887##29##</sup> performed an interrupted time series analysis and found that the trend in the proper control of HbA1c in patients with diabetes after the introduction of the QOF worsened relative to the pre-QOF trend. In contrast, we found that the P4P program for diabetes had a positive long-term impact on incentivized intermediate outcomes, including proper control of HbA1c and LDL-C levels in patients. Several possible explanations can explain this outcome. First, the universal QOF scheme is designed for primary care settings to reward general practitioners for achieving quality indicators. However, in Taiwan, P4P programs are designed with disease-specific incentives and rewards are given to specialists to achieve pre-determined targets. In other words, focusing on the management of diabetes care based on clinical guideline-recommended services (eg, medication management) could lead to better glycemic control. Second, the P4P scheme for diabetes in Taiwan provides multiple incentives. From 2001 to 2006, incentives were exclusively based on process-of-care outcomes (eg, receipt of HbA1c testing). Incentives targeting intermediate clinical outcomes (eg, proper control of HbA1c) were incorporated in 2006, and a bonus for improvement in intermediate clinical outcomes was introduced in 2009. Combining multiple incentive designs might better motivate the care providers toward improving intermediate clinical outcomes.<sup>##REF##16908917##1##</sup></p>", "<title> Spillover Effect of P4P Programs on Non-incentivized Outcomes</title>", "<p> Previous studies have raised concerns about the unintended effects of P4P programs.<sup>##REF##16908917##1##,##REF##16595409##2##,##REF##23380190##4##</sup> However, research on the spillover effects of P4P programs on non-incentivized clinical outcomes is limited, and the findings tend to be inconclusive.<sup>##REF##21667575##8##, ####REF##17625132##9##, ##REF##17550669##10##, ##UREF##1##11##, ##UREF##2##12##, ##REF##19625717##13##, ##REF##21712336##14##, ##REF##17551130##15####17551130##15##</sup> This study focused on whether the intended improvement might spill over to other non-incentivized aspects of care, resulting in a decline in the overall quality of care among patients with diabetes. Under the P4P program for diabetes care in Taiwan, checks of patient TGs and HDL-C (a process of care) are incentivized, but control of patients’ TG and HDL-C levels (intermediate clinical outcomes) are not incentivized. For patients with diabetes, a high TG or low HDL-C level is associated with a higher risk of vascular complications.<sup>##REF##29874886##30##</sup> Therefore, controlling patients’ TG and HDL-C levels is essential for diabetes management, which in turn affects the overall health outcome. The findings from this study suggest that the P4P did not affect the control of non-incentivized HDL-C levels among the intervention group even three years after enrollment. However, we found that the P4P program had a positive spillover effect on TG control (another non-incentivized parameter) in the first and second years after the P4P program.</p>", "<p> The inconsistent findings of the spillover effects seem intriguing; however, when we consider “commonality in production,” these seem reasonable. In the P4P program, the multitasking problem can be mitigated when the procedures used by physicians to address the incentivized and non-incentivized indicators are similar.<sup>##REF##20490360##7##,##REF##21667575##8##</sup> We observed that the improvement in TG control (a non-incentivized outcome) occurred because it was addressed by physicians in a manner similar to that of HbA1c control (an incentivized outcome). The recommendations of the American Diabetes Association emphasize that lifestyle interventions and glycemic control are both beneficial for improving TG control.<sup>##REF##14693930##27##</sup> For example, metformin is a first-line pharmacological agent used for glycemic control in type-2 diabetes, and evidence has shown that metformin can significantly decrease TG levels in patients with diabetes.<sup>##REF##15189360##31##</sup> In other words, for patients enrolled in the P4P program for diabetes care, physicians might regularly monitor their blood glucose levels and improve their glycemic control using medications such as metformin, which also improves the TG level. However, the improvement in HDL-C control was not affected by the use of similar treatments. The effects of metformin on HDL-C levels are less evident.<sup>##REF##17638715##32##,##UREF##6##33##</sup> Lifestyle interventions such as weight loss, exercise, and diet control are better ways to manage HDL-C levels.<sup>##REF##14693930##27##</sup> Therefore, our findings support the idea that commonalities among a set of activities are crucial for financial incentive programs to generate positive or no spillover effects.<sup>##REF##21667575##8##,##UREF##2##12##</sup></p>", "<title> Limitations</title>", "<p> This study had some limitations. First, the participants were not randomly assigned to the intervention or comparison groups, which may have caused selection bias. In this study, we used two-step sample selection strategies to minimize selection bias: selecting patients from the same physician and using PSM. Although the PSM matching strategy may have increased the similarity of participants in the intervention and comparison groups at baseline, it does not ensure that the two groups were similar before the intervention. Owing to the lack of available intermediate clinical outcome data, we performed a placebo DID analysis using the participants’ diabetes-related hospitalizations as proxies to examine the parallel trend assumption before the intervention. During 2007 and 2016 (before the P4P intervention in 2017), the placebo DID demonstrated small and insignificant changes in hospitalization for diabetes-related conditions, which implied similar trends in the two groups before the intervention (Table S5).<sup>##UREF##7##34##</sup> Finally, the participants in this study were representative of patients with at least three diabetes-related physician visits and laboratory test results, which might not represent all diabetes patients in Taiwan.</p>" ]	[ "<title>Conclusion</title>", "<p> This is one of the first studies to evaluate the long-term spillover effects of a P4P program on intermediate clinical outcomes under a single-payer healthcare system. This study provides evidence showing that the P4P program has significantly improved incentivized outcome measures. In addition, the P4P program has a positive spillover effect on a non-incentivized outcomes when the related measure is treated in a manner similar to that of the incentivized indicators. However, this study found no spillover effect on non-incentivized outcomes when the related measure is not treated in a manner similar to that of incentivized indicators. We speculate that the problem of multitasking can be mitigated if a set of indicators is addressed using similar treatment measures. Therefore, we suggest that the incentive design of P4P programs should consider “commonality in procedure” to facilitate positive spillover effects and avoid negative spillover effects. Future investigations are necessary to examine the spillover effects of a financial incentive program with both “targeted vs. non-targeted conditions” and “incentivized vs. non-incentivized indicators” under various health-care settings and adopt a more extended follow-up.</p>" ]	[ "<p>\n<bold>Background:</bold> Several studies have examined the intended effects of pay-for-performance (P4P) programs, yet little is known about the unintended spillover effects of such programs on intermediate clinical outcomes. This study examines the long-term spillover effects of a P4P program for diabetes care.\n</p>", "<p><bold>Methods:</bold> This study uses a nationwide population-based natural experimental design with a 3-year follow-up period under Taiwan’s universal coverage healthcare system. The intervention group consisted of 7688 patients who enrolled in the P4P program for diabetes care in 2017 and continuously participated in the program for three years. The comparison group was selected by propensity score matching (PSM) from patients seen by the same group of physicians. Each patient had four records: one pertaining to one year before the index date of the P4P program and the other three pertaining to follow-ups spanning over the next three years. Generalized estimating equations (GEEs) with difference-in-differences (DID) estimations were used to consider the correlation between repeated observations for the same patients and patients within the same matched pairs.\n</p>", "<p><bold>Results:</bold> Patients enrolled in the P4P program showed improvements in incentivized intermediate clinical outcomes that persisted over three years, including proper control of glycated hemoglobin (HbA1c) and low-density lipoprotein cholesterol (LDL-C). We found a slight positive spillover effect of the P4P program on the control of non-incentivized triglyceride [TG]). However, we found no such effects on the non-incentivized high-density lipoprotein cholesterol (HDL-C) control.\n</p>", "<p><bold>Conclusion:</bold> The P4P program has achieved its primary goal of improving the incentivized intermediate clinical outcomes. The commonality in production among a set of activities is crucial for generating the spillover effects of an incentive program.</p>", "<p>\n<bold>Citation:</bold> Chen CC, Chien KL, Cheng SH. Examining the long-term spillover effects of a pay-for-performance program in a healthcare system that lacks referral arrangements. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7571. doi:10.34172/ijhpm.2023.7571</p>" ]	[ "<title>Ethical issues</title>", "<p> This study was approved by the Institutional Review Board of Fu Jen Catholic University (C106074).</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> The study was supported by grants from the National Science and Technology Council (NSTC 112-2410-H-002 -039 -MY3) in Taiwan. The funding source had no role in the study.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nDistribution of Intermediate Clinical Outcome Measures by Intervention Status Over Study Period. Abbreviations: P4P, pay-for-performance; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Characteristics of Patients With Diabetes in the Pre- and Post-matched Samples at Baseline\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>Characteristics</bold>\n</td><td colspan=\"5\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Pre-matched Sample</bold>\n</td><td colspan=\"5\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Post-matched Sample</bold>\n</td></tr><tr><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Intervention Group</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Comparison Group</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Intervention Group</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Comparison Group</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>No.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>%</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>No.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>%</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Absolute Standardized Differences</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>No.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>%</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>No.</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>%</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Absolute Standardized Differences</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">All</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">9119</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">21651</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">7688</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">15376</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Gender</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Female</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4338</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">47.57</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9949</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">45.95</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3525</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">45.85</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7079</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">46.04</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Male</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4781</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">52.43</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">11 702</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">54.05</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4163</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">54.15</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">8297</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">53.96</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Age group</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\"><60</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3523</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">38.63</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7746</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">35.78</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.06</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3029</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">39.40</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5576</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">36.26</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.06</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">60-74</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4351</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">47.71</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9740</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">44.99</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.05</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3446</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">44.82</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7349</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">47.8</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.06</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">75+</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1245</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">13.65</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4165</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">19.24</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.15</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1213</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">15.78</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2451</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">15.94</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DCSI score</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 0</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3139</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">34.42</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">8249</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">38.10</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2897</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">37.68</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5544</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">36.06</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 1</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2092</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">22.94</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5047</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">23.31</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1818</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">23.65</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3637</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">23.65</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 2+</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3888</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">42.64</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">8355</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">38.59</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.08</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2973</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">38.67</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">6195</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">40.29</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CCI score</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 1</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4463</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">48.94</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">11022</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">50.91</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3814</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">49.61</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7767</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">50.51</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 2</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3721</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">40.8</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">8535</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">39.42</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3073</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">39.97</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">6193</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">40.28</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 3+</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">935</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">10.25</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2094</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9.67</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">801</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">10.42</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1416</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9.21</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.04</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Hospitalization in the previous year</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7374</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">80.86</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">18 481</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">85.36</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.12</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">6494</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">84.47</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">13 088</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">85.12</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1745</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">19.14</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3170</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">14.64</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.12</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1194</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">15.53</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2288</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">14.88</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.02</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Control of HbA1c at baseline period</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Poor control (HbA1c ≥7)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5724</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">62.77</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">11 182</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">51.65</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.23</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4337</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">56.41</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">8449</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">54.95</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Better control (HbA1c <7)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3395</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">37.23</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">10 469</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">48.35</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.23</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3351</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">43.59</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">6927</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">45.05</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.03</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mean value of HbA1c at baseline (mean SD)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7.65</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.38</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7.28</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.21</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.29</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7.35</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.08</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7.29</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.09</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.06</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Accreditation level</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medical center/regional hospital</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3766</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">41.3</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">7045</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">32.54</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.18</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2938</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">38.22</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5368</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">34.91</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.07</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">District hospital/clinics</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5353</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">58.7</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">14 606</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">67.46</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.18</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4750</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">61.78</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">10 008</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">65.09</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.07</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Location of hospitals</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Taipei and northern regions</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4258</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">46.69</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">11 910</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">55.01</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.17</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4045</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">52.61</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">8072</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">52.5</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Central and southern regions</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2820</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">30.92</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5810</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">26.83</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.09</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2227</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">28.97</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4425</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">28.78</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.00</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Kao-ping and eastern regions</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2041</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">22.38</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3931</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">18.16</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.11</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1416</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">18.42</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2879</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">18.72</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.01</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Adjusted Estimations of the Effects of the Pay-for-Performance Program on the Incentivized and Non-incentivized Intermediate Clinical Outcomes\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Characteristics</td><td colspan=\"6\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Incentivized Items</bold>\n</td><td colspan=\"6\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Non-incentivized Items</bold>\n</td></tr><tr><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>HbA1c (<7%)</bold>\n</td><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>LDL-C (<100 mg/dL)</bold>\n</td><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>HDL-C (>40 mg/dL)</bold>\n</td><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>TGs (<200 mg/dL)</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>OR</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>95% CI</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>OR</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>95% CI</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>OR</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>95% CI</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>OR</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>95% CI</bold>\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">P4P group (reference group: comparison group)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.948 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.897 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.002 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.970 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.918 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.026 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.071 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.009 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.138 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.018 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.951 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.090 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Period (reference group: pre-P4P period)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Post-P4P 1 year</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.069 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.038 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.100 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.208 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.169 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.247 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.030 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.001 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.059 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.014 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.978 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.052 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Post-P4P 2 year</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.010 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.979 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.042 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.225 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.182 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.269 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.090 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.058 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.123 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.063 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.023 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.105 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Post-P4P 3 year</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.047 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.013 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.081 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.436 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.384 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.491 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.198 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.161 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.236 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.138 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.094 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.185 </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Interaction term between P4P group and period (reference group: comparison group in pre-P4P period)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">P4P group×Post-P4P 1 year</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.166 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.106 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.230 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.199 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.128 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.273 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.036 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.985 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.089 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.114 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.044 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.189 </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">P4P group×Post-P4P 2 year</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.168 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.103 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.236 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.232 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.155 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.314 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.986 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.936 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.040 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.122 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.047 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.202 </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">P4P group×Post-P4P 3 year</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.138 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.073 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.206 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.231 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.150 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.318 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.974 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.922 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.029 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.051 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.980 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.128 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Male</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.880 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.843 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.918 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.211 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.162 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.263 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.325 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.308 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.342 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.809 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.766 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.855 </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Age group (reference group: <60)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">60-74</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.354 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.300 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.410 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.239 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.189 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.292 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.196 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.147 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.247 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.557 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.482 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.635 </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">75+</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.301 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.230 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.376 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.559 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.472 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.652 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.038 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.977 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.103 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.864 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.737 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2.001 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DCSI score (reference group: score 0)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 1</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.946 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.912 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.981 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.189 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.142 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.238 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.950 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.916 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.986 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.974 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.931 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.019 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 2</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.938 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.904 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.974 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.296 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.245 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.349 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.914 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.880 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.950 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.982 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.938 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.029 </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CCI score (reference group: score 1)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 2</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.061 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.030 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.093 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.991 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.959 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.023 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.957 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.929 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.987 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.016 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.980 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.054 </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Score 3+</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.128 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.073 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.185 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.976 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.925 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.030 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.886 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.842 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.933 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.987 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.926 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.053 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Hospitalization in the previous year (reference group: no)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.078 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.046 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.112 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.016 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.982 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.052 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.967 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.938 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.997 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.965 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.928 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.004 </td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medical center/regional hospital (reference group: district hospital/clinics)</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.960 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.930 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.991 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.084 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.047 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.122 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.955 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.924 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.987 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.053 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.012 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.097 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Location of hospitals (reference group: Kao-ping and eastern) </td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Taipei and northern regions</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.725 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.686 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.767 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.831 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.786 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.878 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.001 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.938 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.069 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.850 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.791 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.913 </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Central and southern regions</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.841 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.792 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.894 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.970 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.913 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.030 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.018 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.948 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.093 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.967 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">0.893 </td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.047 </td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>This study suggests that the pay-for-performance (P4P) program for diabetes care has achieved its primary objective of improving incentivized intermediate clinical outcomes such as glycated hemoglobin (HbA1c) and low-density lipoprotein cholesterol (LDL-C). </p></list-item><list-item><p>It also suggests that a non-incentivized measure (triglycerides, TGs) was also improved owing to the “commonality in procedure” phenomenon. </p></list-item><list-item><p>Policy-makers may need to evaluate the spillover effects of a financial incentive program on non-targeted conditions and non-incentivized indicators in various healthcare settings. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> Several studies have investigated the intended effects of pay-for-performance (P4P) programs in various health systems, yet little is known about the unintended spillover effects of such programs. The single-payer Taiwanese universal health scheme launched a P4P program for diabetes care in 2001. This study demonstrates that the P4P program significantly improves incentivized intermediate clinical outcome measures, such as glycated hemoglobin (HbA1c) and low-density lipoprotein cholesterol (LDL-C), and the effect persist over three years. In addition, the results of this study suggest a positive spillover effect of the P4P program on non-incentivized triglyceride (TG) control. These findings support the phenomenon of commonality in production among a set of activities crucial for generating spillover effects of an incentive program.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1 contains Tables S1-S5.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: DCSI, Diabetes Complication Severity Index; CCI, Charlson Comorbidity Index; SD, standard deviation; HbA1c, glycated hemoglobin.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: OR, odds ratio; CI, confidence interval; P4P, pay-for-performance; DCSI, Diabetes Complication Severity Index; CCI, Charlson Comorbidity Index; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TGs, triglycerides.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7571-g001\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7571-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["6"], "person-group": ["\n"], "surname": ["Holmstrom", "Milgrom"], "given-names": ["B", "P"], "article-title": ["Multitask principal-agent analyses: incentive contracts, asset ownership, and job design"], "source": ["J Law Econ Organ"], "year": ["1991"], "volume": ["7"], "fpage": ["24"], "lpage": ["52"], "pub-id": ["10.1093/jleo/7.special_issue.24"]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Sutton", "Elder", "Guthrie", "Watt"], "given-names": ["M", "R", "B", "G"], "article-title": ["Record rewards: the effects of targeted quality incentives on the recording of risk factors by primary care providers"], "source": ["Health Econ"], "year": ["2010"], "volume": ["19"], "issue": ["1"], "fpage": ["1"], "lpage": ["13"], "pub-id": ["10.1002/hec.1440"]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Sherry", "Bauhoff", "Mohanan"], "given-names": ["TB", "S", "M"], "article-title": ["Multitasking and heterogeneous treatment effects in pay-for-performance in health care: evidence from Rwanda"], "source": ["Am J Health Econ"], "year": ["2017"], "volume": ["3"], "issue": ["2"], "fpage": ["192"], "lpage": ["226"], "pub-id": ["10.1162/AJHE_a_00072"]}, {"label": ["16"], "mixed-citation": [" Cheng SH, Lin YY. Pay-for-performance programs in Taiwan. In: Hu TW eds. Health Care Policy in East Asia: A World Scientific Reference. Volume 4: Health Care System Reform and Policy Research in Taiwan. New Jersey: World Scientific; 2020:157-180. "], "pub-id": ["10.1142/10794-vol4"]}, {"label": ["19"], "person-group": ["\n"], "surname": ["Rosenbaum", "Rubin"], "given-names": ["PR", "DB"], "article-title": ["The central role of the propensity score in observational studies for causal effects"], "source": ["Biometrika"], "year": ["1983"], "volume": ["70"], "issue": ["1"], "fpage": ["41"], "lpage": ["55"], "pub-id": ["10.1093/biomet/70.1.41"]}, {"label": ["20"], "mixed-citation": [" Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. Hoboken, NJ: John Wiley & Sons; 2004. "]}, {"label": ["33"], "person-group": ["\n"], "surname": ["Chaudhuri", "Dandona"], "given-names": ["A", "P"], "article-title": ["Effects of insulin and other antihyperglycaemic agents on lipid profiles of patients with diabetes"], "source": ["Diabetes ObesMetab"], "year": ["2011"], "volume": ["13"], "issue": ["10"], "fpage": ["869"], "lpage": ["879"], "pub-id": ["10.1111/j.1463-1326.2011.01423.x"]}, {"label": ["34"], "mixed-citation": [" Huntington-Klein N. The Effect: An Introduction to Research Design and Causality. 1st ed. Boca Raton, FL: CRC Press; 2022. "]}]	{ "acronym": [], "definition": [] }	34	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 9; 12:7571	oa_package/f0/0e/PMC10699817.tar.gz
PMC10699818	0	[ "<title>Introduction</title>", "<p> Like many other countries around the world, Pakistan recognises the importance of an essential package of health services (EPHS) for achieving universal health coverage (UHC) and Sustainable Development Goal 3 (Good Health and Well-being).<sup>##UREF##0##1##,##UREF##1##2##</sup> The country’s long-term development strategy for health (‘Vision 2025’) reiterates the need for a revised intervention package that offers protection against financial hardship to individuals and communities when accessing health interventions.<sup>##UREF##2##3##</sup></p>", "<p> The Disease Control Priorities 3 (DCP3) initiative provides long-term support to Pakistan in the development and implementation of its EPHS. The DCP3 Country Translation project responds to the increasing need of low- and lower middle-income countries for technical guidance and support in benefit package design and in accelerating progress towards UHC.<sup>##UREF##3##4##,##REF##29179954##5##</sup> Pakistan is one of the first countries globally to implement the project.</p>", "<p> DCP3 provides a review of evidence on the efficacy, effectiveness and cost-effectiveness of interventions and a model benefit package for UHC. A priority setting process is needed to translate this evidence into EPHS design in Pakistan. Increasingly, decision-makers are urged to organise such processes in a fair, legitimate manner, with legitimacy referring to the reasonableness of decisions as perceived by stakeholders and being an important prerequisite for broad societal support.<sup>##REF##11090498##6##,##UREF##4##7##</sup></p>", "<p> Deliberative processes in healthcare are seen by many as a promising approach to achieve such legitimate decision-making for its merits in facilitating well-informed and inclusive decisions.<sup>##REF##12765705##8##, ####UREF##5##9##, ##UREF##6##10##, ##REF##35667778##11####35667778##11##</sup> Scholars have emphasized the advantages of incorporating diverse perspectives, evidence, and careful analysis into the decision-making process. Through open discussions and collaboration, the deliberative approach fosters stakeholder engagement, promoting a sense of ownership and acceptance of decisions, which enhances the likelihood of successful implementation. Potential drawbacks include its time-consuming nature and resource requirements, particularly in time-sensitive or resource-limited situations, difficulties in reaching consensus and risk of manipulation or dominance by powerful stakeholders.<sup>##UREF##5##9##</sup> Deliberative processes are implemented by a range of governmental bodies in western countries that develop recommendations on the reimbursement of health interventions.<sup>##UREF##6##10##</sup></p>", "<p> As part of a series on the DCP3 implementation in Pakistan, this paper reports on the priority setting process used in the development of the EPHS in Pakistan in the period 2019-2020, employing evidence-informed deliberative processes (EDPs). The EDP framework is a practical and stepwise tool for priority setting, with the dual aim to optimise the legitimacy of benefit package decisions, and related outcomes in terms of eg, population health and financial risk protection.<sup>##REF##28237205##12##, ####UREF##7##13##, ##UREF##8##14##, ##REF##34923809##15####34923809##15##</sup> In the framework, the concept of legitimacy is translated into four elements – stakeholder involvement, ideally operationalised through stakeholder participation with deliberation; evidence-informed evaluation; transparency; and appeal.<sup>##UREF##8##14##</sup> The practical guidance on EDPs provides recommendations on how these elements can be implemented in each step of a decision-making process of EPHS design, based on a review of practices of countries around the world.<sup>##UREF##8##14##</sup> Several other frameworks on priority setting are available,<sup>##UREF##4##7##,##UREF##9##16##, ####UREF##10##17##, ##UREF##11##18##, ##UREF##12##19####12##19##</sup> and the EDP framework can be considered complementary because of its explicit focus on stakeholder participation, including detailed practical guidance.</p>", "<p> A separate challenge for any priority setting process is how policy-makers can integrate benefit package decisions across the three axes of UHC, ie, to decide whether it should first expand the interventions package, improve population coverage for interventions, or reduce co-payments for interventions.<sup>##UREF##4##7##</sup> This issue has been addressed within the EDP framework<sup>##UREF##7##13##</sup> and this paper reports on its implementation in Pakistan.</p>", "<p> The research question in this paper is: how was the EDP framework implemented in the context of EPHS design in Pakistan and what is the stakeholders’ feedback on this process? The paper starts with the description of the process including the institutional context and the operationalisation of the EDP framework for EPHS design in Pakistan. We subsequently report on the survey used to assess stakeholder satisfaction with the priority setting process and survey results. We conclude by putting these results in a broader perspective. This paper is part of a series of papers on the development of the EPHS in Pakistan.<sup>##UREF##13##20##, ####UREF##14##21##, ##UREF##15##22##, ##UREF##16##23####16##23##</sup></p>" ]	[]	[ "<title> Survey Results</title>", "<p> Out of 139 invited TWG/NAC members, 35 responded to the survey (25%). Respondents were overall positive about the process followed, with average scores for most questions of around 4 (+/-around 0.8) (##TAB##0##Table##). They were relatively critical (ie, here arbitrarily defined as items that received an average score of ≤ 3.7) as to whether (<italic toggle=\"yes\">i</italic>) all important stakeholders were involved; (<italic toggle=\"yes\">ii</italic>) there was sufficient time to understand the evidence; (<italic toggle=\"yes\">iii</italic>) the evidence was sufficiently sensitive to the context of Pakistan; and (<italic toggle=\"yes\">iv</italic>) the process and methods used had improved compared to previous approaches for HBP design in Pakistan. In their answers to open-ended questions, respondents mentioned, among others, they would value a more inclusive stakeholder involvement by inviting healthcare providers, clinicians, provincial representatives and ‘people working on the ground’; better communication in terms of document sharing and follow-up steps; better definitions and explanations of decision criteria; the inclusion of other criteria such as complementarity of interventions, and more attention for specific criteria such as feasibility; the use of local evidence and more transparency on evidence collection; a better stakeholder involvement in the appraisal phase. A thematic analysis of responses to open-ended questions is provided in ##SUPPL##4##Supplementary file 5##.</p>" ]	[ "<title>Discussion</title>", "<p> This paper described the implementation of the EDP framework in Pakistan and collected stakeholder feedback on this process. The use of EDPs may have contributed to the legitimacy of the UHC-EPHS decision process in Pakistan in three ways. First, the process involved more than 150 stakeholders through their participation as members in TWGs and/or the NAC. The meetings were organised in such a way that each member had equal chances to provide input in the deliberations and TWG members were granted voting power. In other words, stakeholders’ values were central in deliberations in various stages of the decision-making process. Second, the process was evidence-informed, ie, the discussions not only relied on formal evidence but also used expert judgements where relevant and necessary. TWG and NAC members brought in valuable expertise, especially on the practical implementation of interventions, and this added to the credibility of the decision-making process as a whole. Third, the use of EDPs contributed to transparency of decisions because final decisions were published, and the many involved stakeholders now have an understanding of the process. Our process evaluation survey indicates that stakeholders were generally and overall positive on these matters.</p>", "<p> The EPHS design process as described in this paper for the country of Pakistan shares many similarities with benefit package design/revision processes in other countries. A recent review of processes in Afghanistan, Ethiopia, Pakistan, Somalia, Sudan, and Zanzibar (Tanzania) identified that these countries follow largely the same steps – such as installing an advisory committee, selecting interventions for evaluation and selecting decision criteria – but also often differ in the practical operationalisation of the steps, eg, in the type of stakeholders that are being involved or in the choice of decision criteria.<sup>##UREF##18##25##</sup> While there is no single ‘best practice’ in the operationalisation of these steps, countries’ experiences can inspire other countries in the design of their process. This was also the case in Pakistan where the EPHS process as described in this paper was based on existing local decision-making processes but also influenced by practices of other countries through the use of the EDP framework.<sup>##UREF##8##14##</sup></p>", "<p> There were several practical challenges to the implementation of each of the steps of the EDP framework. Firstly, on the<italic toggle=\"yes\"> advisory committees (step A)</italic>, TWG and NAC members were generally satisfied with stakeholder involvement, but suggested participation could be improved in terms of its inclusive recruitment, specifically regarding representation by the provinces. In future applications of EDPs, efforts should be made to more proactively invite both sub-national stakeholders as well as public and patient representatives in advisory committees, or to elicit input from them through other means such as surveys. Broader stakeholder representation will further improve the legitimacy of the decision-making process, although it should be realised that this may involve higher organisational costs.</p>", "<p> In addition, not all TWG and NAC members may have the capacity to fully grasp the presented evidence. We did train members and provided them with instructions, criteria explanation sheets, evidence briefs and explicit rounds for clarification questions. This may have been successful – in our survey, TWG and NAC members reported to have a fairly good understanding of the criteria and related evidence although they also identified areas for improvement.</p>", "<p> Second, on the<italic toggle=\"yes\"> decision criteria (step C)</italic>, the UHC BP secretariat identified and selected a broad range of criteria through a stakeholder survey. Respondents were generally satisfied about the use of criteria, but also mentioned that these could be better defined and operationalized, such as ‘burden of disease avoided by the intervention.’ Although the project team pilot-tested criteria terminology and definitions among a sample of TWG and NAC members, this warrants more attention in future applications.</p>", "<p> Third, regarding the <italic toggle=\"yes\">assessment </italic>of interventions (<italic toggle=\"yes\">step D1</italic>), the Pakistan DCP team faced several challenges in compiling evidence. Due to both capacity and time constraints, the contextualisation of evidence using best practice translation methods was not always feasible, requiring the development of novel rapid ways of collating and analysing Pakistan specific data (as was the case with cost estimates)<sup>##UREF##13##20##</sup> or translating international evidence to the local context (as was the case with cost-effectiveness data).<sup>##UREF##15##22##</sup> While respondents generally agreed that the used methods to assess the evidence were acceptable, they mentioned that gathering more local evidence would be an improvement to the process.</p>", "<p> In addition, evidence is ideally collected on all decision criteria. In the current approach, the assessment of interventions in terms of their ‘feasibility,’ ‘equity,’ ‘financial risk protection,’ and ‘social and economic impact’ was based entirely on TWG and NAC members’ judgements as part of the appraisal process. This raises the risk that certain complex criteria, such as ‘equity’ were considered less thoroughly or objectively.</p>", "<p> Fourth, in the<italic toggle=\"yes\"> appraisal </italic>of interventions <italic toggle=\"yes\">(step D2)</italic>, several aspects may have compromised the decision-making processes by the TWGs and NAC. Not all committee members had background knowledge to fully understand and interpret the presented evidence (eg, on cost-effectiveness of interventions). We did make efforts to instruct them with evidence briefs and explicit rounds for clarification questions, but it is not clear whether this was sufficient; while TWG and NAC members reported in our survey to have a good understanding of the evidence, we also observed that few committee members referred to evidence on cost-effectiveness, for example, to develop their judgment. In addition, several TWG and NAC members observed a shortage of expertise in some disease areas in their committees. Moreover, in the TWGs, time for appraisal was generally short, and only some 15-20 minutes were available for deliberation on each intervention. Furthermore, we observed that some facilitators and members were dominant during group meetings, which resulted in less balanced deliberations. These aspects are all known challenges to the use of deliberative process in healthcare decision-making.<sup>##REF##12765705##8##, ####UREF##5##9##, ##UREF##6##10##, ##REF##35667778##11####35667778##11##</sup> Nevertheless, TWG and NAC members were overall positive about the appraisal process.</p>", "<p> Fifth, the overall decision-making process was heavily disrupted by the COVID-19 pandemic. All TWG and NAC meetings were held on site until February 2020 but were conducted largely online afterwards. This may have compromised stakeholder participation, especially provincial engagement, and the quality of the decision-making process.</p>", "<p> An important limitation of our evaluation of the EDP implementation is the online survey that we conducted among participants. It resulted in broad notions of their satisfaction but precluded detailed insights into their experiences and perceptions of the strengths and weaknesses of the EDP framework. A more thorough approach might have revealed, for example, asymmetry of information and/or unequal power dynamics, but this would have required personal interviews and/or non-participant observations during the deliberations. Another limitation is the limited response (25%) to the online survey. We may have missed important perspectives from those who did not respond.</p>", "<p> An important contribution of this paper is how policy-makers can integrate benefit package decisions across the three axes of UHC.<sup>##UREF##4##7##,##UREF##7##13##</sup> In the appraisal sub-step D2.1, decisions were made on the priority categories of interventions. In sub-step D2.2, fiscal space was considered, and decisions were made whether the intervention package should be expanded, or population coverage should be improved. To our knowledge, this is the first paper that has explicitly articulated these trade-offs into a set of scenarios and translated the complex interplay between benefit package design, UHC dimensions, and health system constraints into a series of practical steps. This aspect and other features of the EDP framework could serve as an example for other countries that wish to undertake health benefit package design or revision.</p>" ]	[ "<title>Conclusion</title>", "<p> Despite several challenges, implementation of the priority setting process may have improved the legitimacy of decision-making by involving stakeholders through participation with deliberation and being evidence-informed and transparent. Important lessons were learned that can be beneficial for other countries designing their own health benefit package.</p>" ]	[ "<p>\n<bold>Background:</bold> The Disease Control Priorities 3 (DCP3) project provides long-term support to Pakistan in the development and implementation of its universal health coverage essential package of health services (UHC-EPHS). This paper reports on the priority setting process used in the design of the EPHS during the period 2019-2020, employing the framework of evidence-informed deliberative processes (EDPs), a tool for priority setting with the explicit aim of optimising the legitimacy of decision-making in the development of health benefit packages.\n</p>", "<p><bold>Methods:</bold> We planned the six steps of the framework during two workshops in the Netherlands with participants from all DCP3 Pakistan partners (October 2019 and February 2020), who implemented these at the country level in Pakistan in 2019 and 2020. Following implementation, we conducted a semi-structured online survey to collect the views of participants in the UHC benefit package design about the prioritisation process.\n</p>", "<p><bold>Results:</bold> The key steps in the EDP framework were the installation of advisory committees (involving more than 150 members in several Technical Working Groups [TWGs] and a National Advisory Committee [NAC]), definition of decision criteria (effectiveness, cost-effectiveness, avoidable burden of disease, equity, financial risk protection, budget impact, socio-economic impact and feasibility), selection of interventions for evaluation (a total of 170), and assessment and appraisal (across the three dimensions of the UHC cube) of these interventions. Survey respondents were generally positive across several aspects of the priority setting process.\n</p>", "<p><bold>Conclusion:</bold> Despite several challenges, including a partial disruption because of the COVID-19 pandemic, implementation of the priority setting process may have improved the legitimacy of decision-making by involving stakeholders through participation with deliberation, and being evidence-informed and transparent. Important lessons were learned that can be beneficial for other countries designing their own health benefit package such as on the options and limitations of broad stakeholder involvement.</p>", "<p>\n<bold>Citation:</bold> Baltussen R, Jansen M, Akhtar SS, et al. The use of evidence-informed deliberative processes for designing the essential package of health services in Pakistan. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8004. doi:10.34172/ijhpm.2023.8004</p>" ]	[ "<title>Description of the Priority Setting Process</title>", "<title> Institutional Context</title>", "<p> The priority setting process was implemented by the Health Planning, System Strengthening and Information Analysis Unit of the Ministry of National Health Services, Regulations and Coordination (MNHSR&C), with technical support from the DCP3 Country Translation initiative, referred to as the UHC-EPHS Secretariat. Additional partners included the Community Health Sciences Department of Aga Khan University and Health Services Academy, London School of Hygiene & Tropical Medicine, World Health Organization (WHO) and Radboud University Medical Center (Radboudumc).</p>", "<title> Operationalisation of the EDP Framework</title>", "<p> We operationalised the steps of the EDP framework for the Pakistan context during two separate workshops at Radboudumc in the Netherlands, with participants from all DCP3 Pakistan project partners (October 2019 and February 2020). These steps are shown in ##FIG##0##Figure 1##; of which steps A-D were realised during the present project and steps E-F are to be implemented in a subsequent stage. All procedures, templates and instructions were pilot tested and trainings for facilitators were organised prior to implementation at the UHC-EPHS workshops in Islamabad, Pakistan (November 2019 and February 2020).</p>", "<title> Step A: Installing Advisory Committees</title>", "<p> Supported by DCP3 partners, the UHC-EPHS Secretariat designed a governance structure for the EPHS based around three connected stages of deliberation around priorities (##FIG##1##Figure 2##).</p>", "<p> The first stage concerned the involvement of four already existing Technical Working Groups (TWGs) for specific disease clusters: reproductive, maternal, neonatal, child, and adolescent health (36 members), non-communicable diseases (38 members), communicable diseases (51 members), and health services access (26 members). These TWGs normally advise the MNHSR&C on various aspects of their respective disease areas, representing relevant stakeholders. This time they were tasked with reviewing the technical aspects of a range of interventions for potential inclusion into the UHC-EPHS, and broadly allocating services into priority categories.</p>", "<p> The second stage involved the establishment of a National Advisory Committee (NAC), whose mandate was to interpret the recommendations of the various TWGs and combine them into an overall set of recommendations. The NAC had 15 formal members.</p>", "<p> The third stage involved a high-level meeting of the Steering Committee (SC) responsible for reviewing the NAC recommendations and approving or revising them, and providing advice to the Minister of Health, who is responsible for making the final decision to implement the UHC-EPHS. An International Advisory Group (IAG) advised the SC. Terms of reference were drafted and adopted for each entity in the governance structure endorsed by the SC (shown in ##FIG##1##Figure 2##). Conflict of interest declaration forms were drafted for completion by TWG and NAC members.</p>", "<title> Step B: Selecting Interventions</title>", "<p> In a workshop in April 2019, the MNHSR&C, jointly with representatives from the provincial departments of health and other key stakeholders, reviewed the availability, coverage, and relevance of the DCP3 Essential UHC package (EUHC) in Pakistan. The DCP3 EUHC package is a model benefit package for UHC which lower- and middle-income countries are recommended to consider for the development of their national health benefit packages. Participants concluded that 170 (78%) out of the 218 EUHC services were relevant and feasible for Pakistan and should be assessed for possible inclusion in the UHC-EPHS, while others may be assessed and included at a later stage. None of the services currently provided in Pakistan were omitted at this stage.<sup>##UREF##17##24##</sup></p>", "<p> Thereafter, the UHC-EPHS Secretariat further defined the selected DCP3 services in terms of processes and required resources, and the TWG members reviewed them before and during the UHC-EPHS workshops (November 2019 and February 2020).</p>", "<title> Step C: Defining Decision Criteria</title>", "<p> In October-November 2019, the MNHSR&C conducted a survey on the use of decision criteria with the aim to develop consensus on the importance and definition of criteria for the prioritization of interventions by TWG and NAC members. It was sent electronically to all TWG and NAC members invited for the November meeting, with responses received from 52 members (response rate 52%). The following seven criteria were selected: effectiveness, burden of disease, health gain for money spent (defined as “cost-effectiveness” in the survey), equity, financial risk protection, budget impact, socio-economic impact, and feasibility. Details on the survey, its results and criteria definitions are provided in ##SUPPL##0##Supplementary file 1##.</p>", "<title> Step D1: Assessment </title>", "<p> Assessment refers to the collection of evidence on the interventions considered. The UHC-EPHS Secretariat collected the available evidence on three criteria: budget impact (composed of individual intervention costs), cost-effectiveness, and burden of disease. Note that the criterion ‘burden of disease’ was used in the first meeting of the TWGs (TWG1) but was changed to ‘avoidable burden of disease by the intervention’ from the second meeting (TWG2) onwards as the latter criterion reflects both the burden of disease and the potential size of health gains. This was considered appropriate by the UHC-EPHS Secretariat, as burden of disease then directly relates to the intervention. This criterion then replaced the ‘Effectiveness’ criterion. The process of developing the evidence base is reported elsewhere.<sup>##UREF##13##20##,##UREF##15##22##,##UREF##16##23##</sup> No quantitative evidence was collected for the remaining criteria for two reasons: effectiveness was not considered explicitly since all EUHC interventions were widely proven to be effective, while the others have insufficient data to make a quantitative assessment. These criteria were qualitatively assessed during the appraisal stage using expert opinion of the TWG members.</p>", "<title> Step D2: Appraisal </title>", "<p> Appraisal concerns the interpretation of the results of the assessment in a broader perspective and formulates a recommendation to inform decision-makers. This step involved the complex trade-off across the three UHC dimensions<sup>##UREF##7##13##</sup> and was split into two sub-steps.</p>", "<title> Appraisal Sub-step D2.1 – The Division of Interventions Into Priority Categories (Unconstrained by Fiscal Space)</title>", "<p> The first sub-step involved the division of the 170 interventions into categories of ‘high priority,’ ‘medium priority’ and ‘low priority,’ reflecting their relative importance for the health system in Pakistan. To arrive at these categories, the TWGs interpreted the results of the assessment stage for each intervention and deliberated in Nov 2019 (TWG1 on community and primary care interventions) and in Feb 2020 (TWG2 on first level and referral hospital care) (see ##FIG##2##Figure 3##). Each TWG covered between 28–51 interventions. At the meetings, the TWGs were split in smaller groups so each group could focus on smaller sets of around 10 interventions.</p>", "<p> Each TWG was allocated a trained facilitator, who had received instructions on how to follow a stepwise deliberative process. Each small group meeting started with an introduction, followed by a deliberative process for each intervention, which included reading of the intervention description, a round of clarification questions and answers, and an initial voting, in which each TWG members categorised the intervention as a high, medium or low priority. Based on their votes, the facilitator invited each TWG member to share his/her argumentation followed by group deliberation. Subsequently, members gave their last vote, and the rapporteur summarised the final voting results and argumentation. Several templates were available to facilitate this process, such as ‘evidence sheets’<sup>##UREF##7##13##</sup> (also see ##SUPPL##1##Supplementary file 2##, Figure S3) and ‘criteria explanation sheet.’ Voting was a crucial element of the deliberative process: it required TWG members to provide argumentation to justify their votes and thereby stimulated a more in-depth discussion; and it provided TWG members maximum influence on the decision-making process. To illustrate, ##SUPPL##2##Supplementary file 3## provides the instructions to the TWG facilitator on the deliberative process.</p>", "<title> Appraisal Sub-step D2.2 – Making Choices Among High Priority Interventions (Accounting for Fiscal Space Constraints)</title>", "<p> Over the course of several meetings, the NAC subsequently reviewed TWG recommendations. An initial NAC meeting (NAC1) held in November 2019 reviewed TWG recommendations on community and health centre interventions. ##SUPPL##1##Supplementary file 2## provides the instruction to the NAC chair on the process. A second NAC meeting (NAC2), held in June 2022, had the complex task to further prioritise the list of interventions across all levels of the health system (community, health centre, primary hospitals, and referral hospitals) within the available fiscal space, taking into account coverage. To inform these decisions, the UHC-EPHS Secretariat prepared evidence on various packages with alternative assumptions on fiscal space, coverage levels, and co-payment levels; and taking into account the appropriate time horizon of NAC recommendations (0 to 10 years). Some packages also represented specific trade-offs, eg, explicitly prioritising high priority community interventions. During this second meeting, the NAC recommended two packages: a reduced package of interventions for immediate implementation (the immediate implementation package, or IIP) and a full EPHS to be implemented over a longer time horizon. The NAC recommendations on the IIP from the second meetings were reviewed by the IAG in July 2020, which suggested further changes. Lastly, the final iterations of both IIP and full EPHS were reviewed and approved by the UHC-EPHS SC and the Inter-Ministerial Health and Population Council in October 2020.</p>", "<p>\n##FIG##2##Figure 3## shows the timeline of the different stages of the appraisal process.</p>", "<title>Feedback on Process</title>", "<title> Survey Design on Stakeholder Satisfaction</title>", "<p> We developed a semi-structured online survey to collect, ex-post, the views of EDP participants about the process that was followed. The survey was structured around the EDP steps (<italic toggle=\"yes\">i</italic>) stakeholder involvement (reflecting the step ‘installing advisory committee’), (<italic toggle=\"yes\">ii</italic>) selection of decision criteria, (<italic toggle=\"yes\">iii</italic>) evidence collection (reflecting the step ‘assessment’), and (<italic toggle=\"yes\">iv</italic>) appraisal. In addition, participants were asked about their satisfaction, acceptance and perceptions of the relevance of the process and its outcomes.</p>", "<p> For each theme, participants were asked to indicate to what extent they agreed with a set of statements using a five-point Likert scale. In addition, they were invited to respond to a series of open-ended questions on how these themes could be improved upon for future use. The survey was pretested with members of the DCP secretariat. ##SUPPL##3##Supplementary file 4## contains the survey questions.</p>", "<title>Acknowledgements</title>", "<p> We express our gratitude to all TWG, NAC, and SC members who participated in the meetings and provided valuable feedback. In addition, we thank the IAG for providing constructive feedback on the materials and methods; and the WHO and the Bill & Melinda Gates Foundation for supporting this work.</p>", "<title>Ethical issues</title>", "<p> Ethical approvals were obtained from the London School of Hygiene and Tropical Medicine (21257) and Aga Khan University (2019-1992-5190); MoH clearance is being sought.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This paper is part of a series of papers coordinated by the DCP3 Country Translation Project at the London School of Hygiene and Tropical Medicine, which is funded by the Bill & Melinda Gates Foundation [Grant OPP1201812]. The sponsor had no involvement in paper design; collection, analysis and interpretation of the data; and in the writing of the paper.</p>", "<title>\nSupplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nThe Six Steps of the Evidence-Informed Deliberative Process Framework.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nThe Universal Health Coverage Essential Package of Health Services Governance Structure. Note: Arrows represent the flow of information. Reporting obligations are represented by larger arrows. Abbreviations: DCP3, Disease Control Priorities 3; EPHS, essential package of health services; UHC, universal health coverage.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nTimeline of Stages and Dates of the Appraisal Process. Abbreviations: DCP3, Disease Control Priorities 3; UHC, universal health coverage.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table</label><caption><title>Views Regarding the Used Evidence-Informed Deliberative Process\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Topic</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Statements </bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Average (Standard Deviation)</bold>\n<sup>a</sup>\n</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"8\" style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Stakeholder involvement</td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">It is clear to me how stakeholders were selected to participate in the EPHS design</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.96)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">All important stakeholders were involved in the EPHS design</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.7 (1.09)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">My involvement in the EPHS design was valuable</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.0 (0.72)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Involved stakeholders had equal opportunities to contribute during meetings</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.3 (0.77)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Deliberation amongst stakeholders contributed to the development of my own opinions</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.75)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Views of involved stakeholders have been adequately taken into account in the EPHS design</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.2 (0.82)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The NAC meeting in June 2020 was organized online, and this limited my understanding of the process</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">2.9 (1.06)<sup>b</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The NAC meeting in June 2020 was organized online, and this limited my involvement in the process</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.2 (1.11)<sup>b</sup></td></tr><tr><td rowspan=\"10\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">The (use of) decision criteria</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The criterion of ‘health gain for money spent’ was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.91)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The criterion of ‘avoidable burden of disease by the intervention’ was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.83)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The criterion of ‘budget impact’ was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.87)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The criterion of ‘feasibility’ was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.81)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The criterion of ‘equity’ was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.78)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The criterion of ‘social and economic impact’ was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.91)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The criterion of ‘financial risk protection’ was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.0 (0.88)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The decision criteria are an adequate reflection of the most important values for EPHS design</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.89)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The trade-offs between different criteria were clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.90)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Each criterion was adequately taken into account in the EPHS design</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.8 (0.91)</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"6\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">The (use of) evidence</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The evidence presented was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.75)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There was sufficient time to understand the evidence on each intervention</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.7 (0.87)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The evidence presented was relevant to design the EPHS</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.80)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">It is clear to me how the evidence was developed</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.8 (0.82)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">I am generally satisfied with the methods used to assess the evidence</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.8 (0.82)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The evidence presented was sufficiently sensitive to the context of Pakistan</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.6 (0.90)</td></tr><tr><td rowspan=\"5\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">The appraisal process</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There was sufficient time to deliberate on each intervention</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.90)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Each intervention was evaluated according to the same standards</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.81)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The process for taking decisions about the inclusion of interventions into the EPHS was clear to me</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.0 (0.70)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">I am satisfied with how decisions were taken about the inclusion of interventions in the EPHS</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.85)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The interventions under discussion were relevant to the context of Pakistan</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.1 (0.70)</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"5\" style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Satisfaction, acceptance and relevance of the process and outcomes</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The process and methods used have improved compared to previous approaches for EPHS design in Pakistan</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.4 (0.80)<sup>c</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The final content of the EPHS is acceptable for the context of Pakistan</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">4.0 (0.72)<sup>c</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">I am satisfied with the outcomes of the EPHS process</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.76)<sup>c</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The outcomes of the EPHS process are relevant to my setting/area</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3.9 (0.75)<sup>c</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">It is clear to me how the outcomes of the EPHS process will be used moving forward</td><td style=\"text-align:center;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">1.9 (0.93)<sup>c</sup></td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Pakistan recognises the importance of achieving universal health coverage (UHC), and the need for a revised essential package of health services (EPHS) to support this. </p></list-item><list-item><p>In 2018, Pakistan initiated the development of a national EPHS by drawing on the Disease Control Priorities 3 (DCP3) evidence and approach, and implemented a national level priority setting process in 2019-2020. </p></list-item><list-item><p>Implementation of the priority setting process resulted in a revised EPHS may have improved the legitimacy of the decision-making process and the decisions themselves by involving stakeholders through evidence-based deliberation and being transparent. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> This paper describes the process used by the government of Pakistan to establish the ‘Universal health coverage essential package of health services (UHC-EPHS)’ during the period 2019-2020. With this package of health services, the government aims to achieve UHC, ie, that all people have access to the full range of quality health services they need, when and where they need them, without financial hardship. The process involved a project team comprising scientists who collected evidence on eg, costs and health effects of the services. It also involved more than 150 stakeholders such as medical practitioners and policy-makers from different regions of the country, who interpreted this evidence and made recommendations to the government. This comprehensive decision-making process may contribute to the provision of health services that are most needed by the people of Pakistan.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 1. Survey on Decision Criteria and Presentation Sheet.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 2. Appraisal Sub-step D2.2 – Instructions for the NAC Chair.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 3. Appraisal Sub-step D2.1 – Instructions for the TWG Facilitator.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl4\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 4. Priority Setting Process Evaluation Survey.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl5\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 5. Full Results of Priority Setting Process Evaluation Survey.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: NAC, National Advisory Committee; EPHS, Essential Package of Health Services.</p><p>\n<sup>a</sup>Scores reflect average responses to neutral questions on the listed themes, with responses ranging from 1 (‘fully disagree’) to 5 (‘fully agree’).</p><p>\n<sup>b</sup>Seven respondents were excluded (n = 28) due to only participating in the TWGs.</p><p>\n<sup>c</sup>One respondent was excluded (n = 34) due to self-reported inability to answer these questions.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-8004-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8004-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8004-g003\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-8004-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-8004-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-8004-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-8004-s004.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-8004-s005.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" United Nations. Sustainable Development Goals. Goal 3: Ensure Healthy Lives and Promote Well-Being for All at All Ages. 2016. "], "uri": ["http://www.un.org/sustainabledevelopment/health/"]}, {"label": ["2"], "mixed-citation": [" Government of Pakistan. National Initative for Sustainable Development Goals. "], "uri": ["https://www.sdgpakistan.pk/"]}, {"label": ["3"], "mixed-citation": [" Planning Commission Ministry of Planning, Development & Reform. Pakistan 2025: One Nation - One Vision. Islamabad. "], "uri": ["https://www.pc.gov.pk/uploads/vision2025/Pakistan-Vision-2025.pdf"]}, {"label": ["4"], "mixed-citation": [" Disease Control Priorities Project, Third Edition. University of Washington. "], "uri": ["http://dcp-3.org/"]}, {"label": ["7"], "mixed-citation": [" World Health Organization (WHO). WHO Consultative Group on Equity and Universal Health Coverage. Making Fair Choices on the Path to UHC. Geneva: WHO; 2016. "]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Safaei"], "given-names": ["J"], "article-title": ["Deliberative democracy in health care: current challenges and future prospects"], "source": ["J HealthcLeadersh"], "year": ["2015"], "volume": ["7"], "fpage": ["123"], "lpage": ["136"], "pub-id": ["10.2147/jhl.s70021"]}, {"label": ["10"], "mixed-citation": [" Bond K, Stiffell R, Ollendorf DA. Principles for deliberative processes in health technology assessment. Int J Technol Assess Health Care. 2020:1-8. "], "pub-id": ["10.1017/s0266462320000550"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Baltussen", "Jansen", "Bijlmakers", "Tromp", "Yamin", "Norheim"], "given-names": ["R", "MP", "L", "N", "AE", "OF"], "article-title": ["Progressive realisation of universal health coverage: what are the required processes and evidence?"], "source": ["BMJ Glob Health"], "year": ["2017"], "volume": ["2"], "issue": ["3"], "fpage": ["e000342"], "pub-id": ["10.1136/bmjgh-2017-000342"]}, {"label": ["14"], "mixed-citation": [" Oortwijn W, Jansen M, Baltussen R. Evidence-Informed Deliberative Process: A Practical Guide for HTA Bodies for Legitimate Benefit Package Design. Nijmegen: Radboud University Medical Center; 2021. "], "uri": ["https://www.radboudumc.nl/global-health-priorities"]}, {"label": ["16"], "mixed-citation": [" Terwindt F, Rajan D, Soucat A. Priority-setting for national health policies, strategies and plans. In: Strategizing National Health in the 21st Century: A Handbook. Geneva: World Health Organization; 2016. "]}, {"label": ["17"], "mixed-citation": [" Glassman A, Giedion U, Smith PC. What\u2019s In, What\u2019s Out: Designing Benefits for Universal Health Coverage. Washington, DC: Brookings Institution Press, Center for Global Development; 2017. "]}, {"label": ["18"], "mixed-citation": [" International Decision Support Initiative (iDSI). The HTA Toolkit. 2018. Available from: "], "uri": ["http://www.idsihealth.org/HTATOOLKIT/"]}, {"label": ["19"], "mixed-citation": [" Castro H, Suharlim C, Kumar R. Moving LMICs Toward Self-Reliance: A Roadmap for Systematic Priority Setting for Resource Allocation. Available from: "], "uri": ["https://msh.org/resources/a-roadmap-for-systematic-priority-setting-and-health-technology-assessment-hta-a-practical/"]}, {"label": ["20"], "mixed-citation": [" Raza W, Zulfiqar W, Shah MM, et al. Costing interventions for developing an Essential Package of Health Services: application of a rapid method and results from Pakistan. Int J Health Policy Manag 2023; Forthcoming. "]}, {"label": ["21"], "mixed-citation": [" Torres-Rueda S, Vassall A, Zaidi R, et al. The use of evidence to design an Essential Package of Health Services in Pakistan: a review and analysis of prioritisation decisions at different stages of the appraisal process. BMJ Glob Health 2023; Forthcoming. "]}, {"label": ["22"], "mixed-citation": [" Huda M, Kitson N, Saadi N, et al. Assessing global evidence on cost-effectiveness to inform development of Pakistan\u2019s Essential Package of Health Services. Int J Health Policy Manag 2023; Forthcoming. "]}, {"label": ["23"], "mixed-citation": [" Alwan A, Siddiqi S, Safi M, et al. Addressing the UHC challenge using the Disease Control Priorities-3 approach: learning from the Pakistan experience. Int J Health Policy Manag 2023; Forthcoming. "]}, {"label": ["24"], "mixed-citation": [" Ministry of National Health Services, Regulations and Coordination. Review of Essential Health Services in Pakistan Based on Disease Control Priorities-3. April 2019. Available at: "], "uri": ["http://www.nhsrc.gov.pk/"]}, {"label": ["25"], "person-group": ["\n"], "surname": ["Baltussen", "Mwalim", "Blanchet"], "given-names": ["R", "O", "K"], "article-title": ["Decision-making processes for essential packages of health services: experience from six countries"], "source": ["BMJ Glob Health"], "year": ["2023"], "volume": ["8"], "issue": ["Suppl 1"], "fpage": ["e010704"], "pub-id": ["10.1136/bmjgh-2022-010704"]}]	{ "acronym": [], "definition": [] }	25	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 24; 12:8004	oa_package/db/4b/PMC10699818.tar.gz
PMC10699819	0	[]	[]	[]	[]	[]	[ "<p>\n<bold>Citation:</bold> Borst RAJ, Wehrens R, Bal R. The knowledge translation pizzadilemma: a response to recent commentaries. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8296. doi:10.34172/ijhpm.2023.8296</p>" ]	[ "<p>\n<italic toggle=\"yes\">Rules of Taste Enforce Structures of Power</italic>.</p>", "<p>\n<bold>Susan Sontag</bold><sup>##UREF##0##1##</sup></p>", "<p> There is a special place on the internet, which is devoted to pizza metaphors and quotes. Somehow, the seven insightful commentaries<sup>##REF##37579403##2##–##REF##36243949##8##</sup> on our paper remind us of that place – in a good way. We thank the authors of these commentaries for investing their time and efforts in writing such eloquent and often generous reflections on our review that was published in this Journal.<sup>##REF##35279039##9##</sup> In this response we seek to draw out potential cross-pollinations, but also address nuances that we feel might not have come across so clearly in the original paper. To set the stage for our response, we will first return to our pizza metaphor.</p>", "<p> Generally speaking, most people know what ‘a pizza’ looks like – that is: an oven-baked, relatively flat piece of dough that usually resembles a circular shape. Yet when you ask different people what constitutes a ‘good’ pizza, the answers are less univocal: pizzas need to have a thick crust, a thin crust, must be cheesy, or not, definitely do not have pineapple on them, or might include pineapple as a mere guilty pleasure after all. Some people may dislike pizzas entirely. We believe that it is not far-fetched to extend this to the past and current debates on our ‘pizza,’ namely: knowledge translation (KT). There is recurring sentiment in the literature which suggests that KT is one ‘thing’ – a thing that can be tinkered with, and which can be attuned to the preferences of its practitioner or scholar; much like the dough and toppings of a pizza. Most KT scholars and practitioners will have a preferred ‘flavour’ of KT and some may discredit anyone who dares to add ‘pineapple’ to their flavour.</p>", "<p> In the pizza-like understandings of KT, there are core ingredients of KT. Yet while reading some commentaries on our paper, we could not help but wonder: are we understanding ‘KT’ in a comparable way after all? Could it be that our flavour of KT is not a pizza at all? Ødemark,<sup>##REF##37579418##6##</sup> for instance, argues that we are prescribing a sequential form of KT – which we certainly did not intend to. Interestingly, Sturmberg<sup>##REF##36243949##8##</sup> relates our thinking to the notion of ‘complex adaptive organisations,’ even though this is not the area that our paper addresses. Our pizza might simply have too many toppings (which some people, arguably, also prefer) and starts to resemble a casserole. In the likely event that this represents our failure to express our position on KT in a clear and concise way, we will briefly expand on what we see as KT and how that affects our suggestion to study practices of (sustaining work in) KT.</p>", "<p> In our work, we see KT as a descriptor of a loosely demarcated phenomenon whereby actors in various ways, and through different means, seek to build relations and relay knowledge into different practices with the overall aim of affecting those practices. Such a perspective, as Oliver<sup>##REF##37579363##7##</sup> argues, liberates KT from its linear shackles, for instance by not merely stating that relations are important, but by showing what it actually means to build such relations in KT work. Inspired by the commentaries, we feel that it is important to tease out two more contributions to the KT literature here. First, when we speak of ‘translation’ in our review, that does not include any presumptions about directionality or gradience, yet it does signify a displacement– when knowledge is translated, it does not stay at the same place. Ødemark’s<sup>##REF##37579418##6##</sup> argument that the ‘receiving end’ is not an empty void, in need of enlightenment, is of crucial importance here. Hence translation connotes more a process of weaving things together, or relaying (cf. Haraway<sup>##UREF##1##10##</sup>), than of transmitting. Beside displacement, translation also implies transformation: by being translated, knowledge – which necessarily includes embodied, tacit, experiential, <italic toggle=\"yes\">and</italic> scientific knowledge – does not stay the same in form and nature.<sup>##UREF##2##11##,##UREF##3##12##</sup> Instead, it becomes part of a new network, which requires the creation of new connections that were not there before – such work indeed <italic toggle=\"yes\">also </italic>needs to be done alongside the <italic toggle=\"yes\">“production and dissemination of new knowledge in ways that enhance its utility to end-users.”</italic><sup>##REF##37579403##2##</sup> This is particularly important considering that translations are never neutral and have the potential to affect the lives and well-being of citizens worldwide.<sup>##REF##37579417##4##</sup></p>", "<p> Second, when we speak of practices, we do not necessarily refer to the commonly use triad of ‘research, policy, and practice’. ‘Practice,’ in our understanding, signifies actors who are practising something, which might include situated actions in (health)care, research, or policy. It is about studying activities of actors and how they transpire in certain processes. Above all, what counts as KT is empirically defined as any activity related to the translation of knowledge. Depending on where such practices are studied, this means that KT may now comprise much more, including very mundane interactions, and not only the application of a set of tools specifically designed for KT.<sup>##UREF##4##13##,##REF##35114559##14##</sup> Finally, and to be clear: in our understanding KT is certainly not confined to clinical settings at all, although we do acknowledge that this is what has historically and – to our opinion – problematically imprinted much of the field. We therefore enthusiastically welcome the plea of Edelman and Topp<sup>##REF##37579403##2##</sup> to extend our thinking to ‘non-clinical settings’ and that such populations also necessitate different forms of KT. Kothari and Cameron<sup>##REF##37579457##3##</sup> eloquently capture that this also includes <italic toggle=\"yes\">“rebalance[ ing ] the power of underserved voices or hidden knowledge through KT work”</italic> – they are absolutely right in noting that any process of doing and sustaining KT does not solely rely on researchers or explicit ‘knowledge producers,’ but revolves in the wider constellation of caretakers, community members, or other – often underserved – voices. Following how KT travels and is provided meaning locally thus forms an important area of future study (cf. Abrahamsson and Mol<sup>##UREF##5##15##</sup>).</p>", "<p> Having laid out our perspective on KT, we feel that it appropriate to briefly state here that we ourselves are not KT practitioners (at least not in the strict sense). We do, however, study different <italic toggle=\"yes\">practices</italic> of KT. Similarly, our analyses do not aim to provide a prescriptive model for how KT ought to be done, but a description of how KT is practised and what we might learn from that. It would, however, be dishonest to argue that our conclusions are entirely harmless and do not include, albeit implicit, a plea for practising KT in a different way. In line with Meier,<sup>##REF##37579463##5##</sup> we feel that it is time to empirically open-up KT (cf. Borst et al<sup>##REF##35114559##14##</sup>) and expand it beyond ‘common-taste’ KT (our words). Such expansions and extensions also allow for understanding the role of contestation in processes of KT – not merely about the tools and instruments that are used, but also about what is, and is not, considered as valid knowledge. Finally, we wholeheartedly welcome Oliver’s<sup>##REF##37579363##7##</sup> plea to study and describe <italic toggle=\"yes\">“what it takes” </italic>to do certain KT work, rather than staying with narrow frameworks and indicator sets. Instead, we may find inspiration in empirically disentangling more undervalued aspects of KT – which may appear boring, but actually provide insight into crucial underlying mundane work.</p>", "<title>Acknowledgements</title>", "<p> The authors would like to thank Alexandra Edelman, Stephanie Topp, Anita Kothari, Jacqui Cameron, Tanja Kuchenmüller, Laura dos Santos Boeira, Ninna Meier, John Ødemark, Kathryn Oliver, and Joachim Sturmberg for writing such stimulating commentaries – we will happily share a pizza with them should that occasion arise.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["1"], "mixed-citation": [" Sontag S. On Women. 1st edition. Rieff D, ed. New York: Picador, Farrar, Straus and Giroux; 2023. "]}, {"label": ["10"], "mixed-citation": [" Haraway DJ. Staying with the Trouble: Making Kin in the Chthulucene. Durham, London: Duke University Press; 2016. "]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Freeman"], "given-names": ["R"], "article-title": ["What is \u201ctranslation\u201d?"], "source": ["Evid Policy"], "year": ["2009"], "volume": ["5"], "issue": ["4"], "fpage": ["429"], "lpage": ["447"], "pub-id": ["10.1332/174426409x478770"]}, {"label": ["12"], "mixed-citation": [" Latour B. Circulating reference: sampling the soil in the Amazon Forest. In: Latour B, ed. Pandora\u2019s Hope: Essays on the Reality of Science Studies. Cambridge, MA: Harvard University Press; 1999:24-79. "]}, {"label": ["13"], "mixed-citation": [" Borst RAJ. Mundane Knowledge Translation: Revealing the Work that Underlies Evidence-Informed Policy [dissertation]. Erasmus Universiteit Rotterdam; 2023. "]}, {"label": ["15"], "mixed-citation": [" Abrahamsson S, Mol A. Foods. In: Adey P, Bissell D, Hannam K, Merriman P, Sheller M, eds. The Routledge Handbook of Mobilities. Routledge Handbooks. London: Routledge; 2014:278-287. "]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 18; 12:8296	oa_package/35/b3/PMC10699819.tar.gz
PMC10699820	0	[ "<title>Background</title>", "<p> For more than two decades the eastern region of the Democratic Republic of Congo (DRC) has experienced violent armed conflicts.<sup>##UREF##0##1##,##UREF##1##2##</sup> In 2020, there were 120 active armed groups in the region.<sup>##UREF##2##3##</sup> Power disputes, interethnic conflict, territorial conquest, and the control of natural resource sites are among the multifaceted causes of these conflict.<sup>##UREF##3##4##, ####UREF##4##5##, ##UREF##5##6##, ##UREF##6##7####6##7##</sup> The consequences are a protracted crisis with both direct (deaths, abductions, property damage, and population relocation)<sup>##REF##19153907##8##, ####REF##19491603##9##, ##UREF##7##10##, ##UREF##8##11####8##11##</sup> and indirect effects. Several studies demonstrate indirect effects on the population’s well-being and education, psychological affects such post-traumatic stress disorder, and economic repercussions.<sup>11–14</sup></p>", "<p> The health sector is among the most severely impacted by this chronic crisis. The demand for healthcare is affected by poverty and, above all, by the continuous displacement of the population exposing the population to acute life-threatening diseases (diarrhoea, malnutrition, cholera, and measles outbreaks).<sup>##REF##31822891##15##</sup> On the other side, attacks on medical workers, their kidnapping, and the destruction of medical facilities have a detrimental effect on the performance of the health system in terms of healthcare provision for the population.<sup>##UREF##12##16##, ####REF##21122098##17##, ##REF##34906188##18##, ##UREF##13##19####13##19##</sup> The measuring of performance, a multidimensional concept,<sup>##REF##10178368##20##</sup> is frequently done in low-income countries using only one dimension, goal accomplishment, without exploring other dimensions like coping or value maintenance.</p>", "<p> To deal with the shocks of armed conflict, coping mechanisms have been put in place, often with the assistance of international organisations. These mechanisms include de-escalation training for health workers to deal with attacks,<sup>##UREF##14##21##</sup> the World Health Organization (WHO) initiative to monitor attacks on the health system in order to adapt humanitarian actions<sup>##UREF##15##22##</sup> and the International Committee of the Red Cross platform on violence against health workers.<sup>##UREF##16##23##</sup> Non-governmental organisations (NGOs) have taken on other components, such as the reconstruction of schools destroyed by conflict and the protection and social reintegration of civilians.<sup>##UREF##17##24##,##UREF##18##25##</sup></p>", "<p> The Congolese health system is organised into three levels: the national normative level, the intermediate level, which serves as a supervisory level in each of the country’s 26 provinces, and the operational level, which is represented by the health zone (HZ) or health district.<sup>##UREF##19##26##</sup></p>", "<p> Armed conflicts, mainly concentrated in the Eastern part of DRC, has a negative impact on population well-being,<sup>##UREF##20##27##</sup> causes a high number of deaths<sup>##UREF##21##28##</sup> and other adverse effects such as sexual violences.<sup>##UREF##22##29##,##UREF##23##30##</sup> Although this is a major issue in eastern DRC, few studies have assessed the impact that armed conflict can have on the health system. The available literature focuses primarily on healthcare workers and facilities attacks,<sup>##REF##25476862##31##,##UREF##24##32##</sup> or the effect on services utilisation.<sup>##REF##34511092##33##,##REF##21059195##34##</sup> The few studies in South Kivu that show certain mechanisms of adaptation of the health system to changing contexts (mobilisation of resources, rationalisation of health centre management, application of new standards, and dynamic community participation) in order to provide appropriate care to the population were conducted in HZs that had experienced little armed conflict since 2013.<sup>##UREF##25##35##,##UREF##26##36##</sup></p>", "<p> The aim of this study is twofold: firstly, to characterise the traumatic factors that interfered with the provision of care, and secondly, to determine which coping mechanisms were put in place by the HZs to maintain an acceptable level of performance (according to the regulations in force in the DRC during the period of armed conflict).</p>" ]	[ "<title>Methods</title>", "<title> Study Design and Period</title>", "<p> This is a multiple case study. The reason for choosing this particular design is that it enabled us to examine how various HZs, that were adversely affected by armed conflict were able to adapt in order to continue providing care to the population.<sup>##UREF##27##37##</sup> By comparing the different cases, it was possible to better understand why and how the HZs implemented these adaptation mechanisms to remain effective.<sup>##UREF##27##37##</sup> The study was conducted from July to October 2022. The raw quantitative data collected ranged from 2013 to 2018.</p>", "<title> Study Settings, Cases Selection, and Description</title>", "<p> The study was conducted in the eastern DRC province of South Kivu. In 2020, it had a population of 6 565 000, the majority of whom resided in rural areas.<sup>##UREF##28##38##</sup> The operational level of the health system, the HZ, is subdivided into health areas with a geographical radius of 8000 to 15 000 km. Each of these health areas is covered by a health center and other optional health structures such as reference health centers and health posts. The health center (together with the optional structures) constitutes the first line of care in the HZ. The second line is the general referral hospital of the HZ. Especially in urban HZ, there may be optional secondary referral facilities (such as medical centers and clinics) and tertiary referral facilities (such as provincial and university hospitals).<sup>##UREF##29##39##</sup> Each HZ develops an operational action plan, which outlines the critical activities that must be completed over the course of the coming year.</p>", "<p> We made the decision to use the HZ as a “case” because it serves as the functional component of the Congolese healthcare system. In order to provide a good opportunity to comprehend the adaptation mechanisms put in place, the selection criteria were based on the idea that the HZs should be diversified according to the degree of damage caused by armed conflict. To achieve this, 4 of the 34 HZs in the South Kivu province were selected based on the typology developed in a prior study<sup>##UREF##20##27##</sup> (##FIG##0##Figure 1##). In order to exclude the periods of the two Kivu major wars (1996-2003) and those during which there were major rebellions in South-Kivu, we have chosen the period from 2013 (integration of the most influential armed group (Yakutumba) into the Congolese army)<sup>##UREF##5##6##</sup> to 2018 (election of a new political regime to the head of the county).</p>", "<p> This study used 2 criteria to determine the level of exposure to armed conflict between 2013 and 2018: (<italic toggle=\"yes\">a</italic>) the number of deaths directly related to armed conflict (battle-related death, BRD) using data from the Uppsala Conflict Data Program BRD Dataset, and (<italic toggle=\"yes\">b</italic>) the number of internally displaced persons (IDPs) from the United Nations Office for the Coordination of Humanitarian Affairs (UNOCHA) database. The HZs that had ≥50 000 IDPs and ≥5 BRD/100 000 population were considered unstable, those with ≥50 000 IDPs and <5 BRD/100 000 population were considered intermediate and those with <50 000 IDPs and <5 BRD/100 000 population were considered stable. The classification of stable HZs also took accessibility into account.</p>", "<p> The first case was the urban HZ of Kadutu, easily accessible by land, which was considered as “stable and accessible.” There is an anarchic emergence of health facilities in this HZ that offer a poorly defined care package that is not integrated into the health system. The HZ has not experienced any major armed conflict since 2013. This HZ was chosen on purpose from the 3 urban HZs (which have the same stability and geographic accessibility characteristics) in South Kivu province in accordance with our previous study.<sup>##UREF##20##27##</sup> The second case was the HZ of Idjwi, a rural island located 50 km from the shore of the city of Bukavu and accessible only by sea. Since the armed conflict in South Kivu began, this HZ has been spared because its difficult accessibility, which makes it landlocked compared to the rest of the HZs. So, it was considered as “stable and landlocked.” The third case was the HZ of Fizi, which is rural, can be accessed by road and sea, and had the highest number of BRDs and IDPs from 2013 to 2018. It was thus considered ‘unstable.’ The fourth case was the HZ of Bunyakiri, rural, accessible by road, which had many IDPs but few BRDs, and was considered as ‘intermediate.’ Rebels on the road hamper accessibility to this HZ (##TAB##0##Table 1##).</p>", "<title> Data Sources and Extraction</title>", "<p> To collect data, we combined both qualitative and quantitative methods. The qualitative approach allowed us to characterise the traumatic events that affected the HZs between 2013 and 2018 as well as the coping mechanisms put in place by these HZs. To collect this qualitative data, we used two types of methods: first, a review of the reports from the HZs available the provincial health division and from the NGOs that intervened in these HZs from 2013 to 2018. This review allowed us to identify some traumatic events and coping mechanisms for these events. After a quick analysis of the data from the reports review, we developed a guide to conduct subsequent semi-structured individual interviews to deepen the information from the review. The interview guide consisted of three main questions: (<italic toggle=\"yes\">i</italic>) what major traumatic events occurred in your HZ between 2013 and 2018? (<italic toggle=\"yes\">ii</italic>) which mechanisms did you put in place to deal with these events? and (<italic toggle=\"yes\">iii</italic>) how did you proceed to implement these mechanisms?</p>", "<p> The interviews targeted healthcare workers who had lived in HZs that had recorded traumatic events related to armed conflict (cases 3 and 4) from 2013 to 2018 and who had agreed to participate in our study. Interviewees were selected on the basis of their ability to answer the questions outlined in the interview guide. Using the snowball method, the first respondents (mainly those from the central office of the HZ) guided us to other healthcare worker in the HZ who might have additional information. The choice of this second sampling approach was justified by the delicate nature of the questions asked. The interviews were conducted by the first author (SML) in French or Swahili, in a room within the health facilities (hospital, health centre, and HZ office) and lasted 30 minutes on average. A total of 13 health staff were interviewed (7 in case 3 and 6 in case 4) including medical directors, nurse attendants and supervisors, midwives, the director of nursing at the general referral hospital, the general administrator of the HZ, and other support staff. A dictaphone was used to record the interviews, and the audio files were saved on a computer.</p>", "<p> The quantitative approach consisted of describing the level of performance attained by each case from 2013 to 2018 using health indicators. Due to the difficulty of collecting the data required to carry out a multidimensional measure of performance, we used a unidimensional measure of goal attainment.<sup>##REF##10178368##20##</sup> The goal was considered to be the standard (value set by the Ministry of Health) that had to be achieved in order to be considered “successful.”<sup>##UREF##30##40##</sup> To do this, we used routine health indicators collected at the HZ level. These paper-based data have been encoded in the national health information system (SNIS)<sup>##UREF##31##41##</sup>. Nevertheless, several data before 2017 were missing from this system. Using a pre-designed matrix, we collected additional data from the manually completed SNIS reports as well as from the annual reports archived at the central HZ office. Following consultation with the provincial health division experts and an assessment of the potential for indicators to be affected by armed conflict,<sup>##UREF##12##16##, ####REF##21122098##17##, ##REF##34906188##18##, ##UREF##13##19####13##19##,##REF##34511092##33##</sup> eight indicators were selected to measure the performance of the different cases, as well as the amount of NGO subsidies to the HZ (##TAB##1##Table 2##). These indicators addressed the three levels of the health system in the HZ: first level (health centre), second level (general referral hospital) and third level (HZ central office). Only the data on the amount of NGOs subsidies to the HZ for case 1 in 2017 could not be found.</p>", "<title> Data Analysis</title>", "<p> The quantitative data were coded and analysed using Microsoft Excel 2016. Trend analysis of key health performance indicators for the different cases was performed. The difference in standards attainment for these indicators for each case was plotted from 2013 to 2018.</p>", "<p> For the qualitative data, the audio files (in French and Swahili) from the interviews were transcribed into Word files (in French). We then carried out a thematic analysis<sup>##UREF##32##42##</sup> to describe the experiences (traumatic events and coping mechanisms) of health workers in HZs affected by armed conflict. The first phase consisted of familiarisation with the data. Then, a manual analysis of the transcripts was carried out by two persons separately (SML and CME) to establish codes. These different codes were grouped into two main themes: (<italic toggle=\"yes\">a</italic>) the traumatic events experienced by the health staff from 2013 to 2018; and (<italic toggle=\"yes\">b</italic>) the coping mechanisms implemented by these staff to maintain a good performance of the HZ. Regarding traumatic events, a timeline of traumatic events was developed from 2013 to 2018. To ensure maximum confidentiality in quoting the verbatims, only the interviewees’ title (nurse, physician, administrative, midwife, and support staff) and the type of HZ (case 3, case 4) were retained.</p>", "<p> Finally, a cross-case analysis<sup>##UREF##27##37##</sup> was carried out to link the context, the traumatic events, the coping strategies and the level of performance in each case.</p>" ]	[ "<title>Results</title>", "<title> Qualitative Results</title>", "<title> Main Traumatic Events in the Affected Health Zones From 2013 to 2018</title>", "<p>\n##FIG##1##Figure 2## shows the main traumatic events that occurred in the different HZs from 2013 to 2018. These events are classified into two groups: first, battle-related events (BREs), ie, armed conflicts and their consequences and non-battle related events (NBREs). The first group of events was not reported in the stable cases (cases 1 and 2) and refer to conflicts between armed groups. These were either battles between two ethnic groups in conflict, or between armed rebels and the Congolese army.</p>", "<p> The difference between these two types lied in the causes of confrontations. In the first case (inter-ethnic conflicts), the main cause was the possession of land and property (for example, the spoliation of the cattle of one group by another). In the second case (clash between armed rebels and Congolese army), the principal cause was the gain of power over a given territory. For both types of conflicts, there were direct consequences such as killings, rapes, property destruction (including health facilities) and internal displacement (people moving from neighbouring areas into already unstable HZs). Displaced persons mixed with the population of the HZ by settling with host families. The armed rebels could also settle along certain roads to loot, and even kidnap people.</p>", "<p> “<italic toggle=\"yes\">The main cause of these wars are inter-ethnic conflicts... In 2017, we can point to the conflict between herders and farmers, which took place in the middle plateau. The cows of the herders went to graze in the fields of the indigenous people of this area and there were clashes between these two peoples” </italic>(Nurse, case 3).</p>", "<p> “<italic toggle=\"yes\">Since I have been in the health zone (13 years)... I have witnessed many atrocities and movements of the population (internal displacements)... these movements have affected the functioning of the health zone in the event that a health area moves to another area; go and understand by deduction of mass displacement, promiscuity, malnutrition and the enclosure of a health area where people have been emptied out...” </italic>(Nurse, case 4).</p>", "<p> The second type, the NBRE, were occasionally observed in the stable cases (1 and 2). They consist of other events that have an impact on the functioning of the health system, including recurrent epidemics of cholera and measles as well as very high prevalences of malnutrition. It was also reported that health workers went on strike for long periods of time due to unpaid bonuses. In case 3, there were also recurring natural disasters (overflow of Lake Tanganyika destroying the road to the HZ).</p>", "<p> “<italic toggle=\"yes\">...These clashes are events that have marked our health zone. But in the meantime, we have the cholera epidemic which has become endemic. Recently we have also had a measles epidemic and what caused this measles epidemic was the nurses’ strike which lasted for 8 months to claim their salaries and bonuses...” </italic>(Nurse, case 3).</p>", "<p> “<italic toggle=\"yes\">...the overflowing of Lake Tanganyika which caused destruction of houses and even roads. This negatively affected the health zone. There were difficulties of displacement between Fizi and Uvira ” </italic>(Administrative, case 3).</p>", "<title> Adaptive Mechanisms Implemented by Affected Health Zones </title>", "<p> Interviewees and the various reports consulted both mentioned coping mechanisms for traumatic events. The first mechanism, essentially cited in Fizi (case 3), was the use of military nurses (from the DRC armed forces) to carry out preventive activities (eg, vaccination, distribution of mosquito nets) and supervision in some case 3’s health areas. The HZ management team provided these nurses with rapid training. Their remuneration was derived from the financial resources directly involved in the activities supported by the non-governmental partners. The HZs was sometimes forced to dip into its reserves to pay the military nurses. These mechanisms were created to provide care in a health area affected by armed conflict while the population was still present.</p>", "<p> “<italic toggle=\"yes\">To intervene in a health area in conflict, we have put in place a homemade strategy. We intervene through military collaboration. We contact the DRC military forces’s nurses and ask them to help us carry out supervisions and accompany mass activities such as vaccination, distribution of mosquito nets and other activities” </italic>(Physician, case 3).</p>", "<p> Secondly, the grant from NGOs was the most frequently cited mechanism by the respondents. NGOs support was mor frequently cited in Fizi (case 3) than in Bunyakiri (case 4). These NGOs not only provided financial but also technical support to the HZ. The first support consisted of a lump sum given to the central office of the HZ or to the general referral hospital for their functioning, a lump sum bonus paid to agents who intervene in a specific programme, and the provision of medical equipment and inputs to the health facilities and central office of the HZ. The second type of support included strengthening the skills of the health staff through continuous training or practical accompaniment by technical assistants. The HZ’s core team assessed displaced communities’ health needs and used this information to advocate to attract NGO funding. Unfortunately, the rebels occasionally kidnapped some of the NGO workers, often resulting in the cessation of support to the HZ.</p>", "<p> “<italic toggle=\"yes\">They (displaced persons or IDP) have IDP badges; on these badges it is marked IMC (International Medical Corps). When they arrive at the hospital, they just show the badge, and they get free treatment” </italic>(Midwife, base 3).</p>", "<p> “<italic toggle=\"yes\">It was on the road, at about 2 p.m …. the project manager of MSF (Médecins Sans Frontières ) and his entire team were kidnapped. This bad event was the precursor of the big unfortunate decision of MSF departure from the health zone. Alongside … was the total abortion of the Baraka hospital construction project” </italic>(Physician, case 3).</p>", "<p> The third coping mechanism identified was the relocation of the health facilities. It was either the health staff who moved to open a community site in non-conflict areas where the population had sought refuge when fleeing the war (mainly in Fizi, case 3). In this first case, when the situation calms, the population returns to its natural environment and the community site is closed. Alternatively, if the conflict is permanent, the central office of the HZ may decide to relocate the health facility, which is also vulnerable to destruction during the clashes (mainly in Bunyakiri, case 4).</p>", "<p> “<italic toggle=\"yes\">To facilitate accessibility and to ensure that quality care reaches the entire population of the district, we created healthcare sites in the health areas. There were community health sites, and we also set up health posts for all the people who are more than 5 kilometres away and who had difficulty accessing the health centres” </italic>(Nurse, case 3).</p>", "<p> “<italic toggle=\"yes\">...when the situation here in the health centre became critical at the time of the rebels, the general hospital moved…. What I can say about 2017 is that most of the health centres stopped functioning in their usual places and moved to other places...” </italic>(Support staff, case 4).</p>", "<p> The last mechanism mentioned by the interviewees, both in Fizi (case 3) and Bunyakiri (case 4) was the implementation of negotiation strategies with the belligerents. This involved carrying out as many activities as possible during calm periods and limiting actions during times of armed conflict. Sometimes, health staff would negotiate with rebel leaders to keep them out of conflict and secure healthcare sites. Community leaders usually mediated these negotiations.</p>", "<p> “<italic toggle=\"yes\">The health zone is in a territory that has long been called the “red zone”; we are already used to it. Clashes can take place today and the day after tomorrow we continue our activities” </italic>(Nurse, case 3).</p>", "<title> Comparative Trends in Key Performance Indicators and Case Analysis</title>", "<p>\n##FIG##2##Figure 3## shows the evolution of trends in performance indicators as well as the amount of NGO funding allocated to the HZs.</p>", "<p> The stable and accessible HZ (case 1) received the least amount of NGO subsidies. Its context is quite complex, with the emergence of several secondary level health facilities, often for profit, suffocating the health centres, and the presence of two tertiary level hospitals managed by ministry of health (Hôpital Provincial Général de Référence de Bukavu and the Ciriri Hospital). Periodic NBREs have been observed in case 1. Certain performance indicators, on the other hand, are poor (service utilisation rate <45%, bed occupancy rate <60% from 2013 to 2016, and an assisted delivery rate ≤ 70%). Nonetheless, case 1 is the most efficient in carrying out the operational action plan’s activities (90%-93% execution rate), except in 2018 (36%), and supervisions (>80% execution rate). Preventive activities (prenatal consultation, pentavalent vaccination) and in-hospital mortality remain within the acceptable norms.</p>", "<p> Because of its location the stable and remote HZ (case 2) (island in Lake Kivu) is the only one that has not experienced armed conflict in South Kivu. Only NBRE were reported in this HZs. The majority of the performance indicators are favourable (in-hospital mortality, low pentavalent 3 vaccine drop-out rate, assisted deliveries, supervisions, and antenatal consultations). The operational action plan has been implemented to more than 80%. The two indicators that did not meet the standard in this case were the service utilisation rate (52%-75.7%) and the bed occupancy rate (<80% except for 2017). NGO grants have been low except in 2014, with a peak of over US$ 400 000. This year saw a paradoxical decrease in the implementation of operational action plan activities (77.3%), an increase in the use of care services (75.7%), and an increase in supervision (91.7%).</p>", "<p> For case 3 (unstable HZ), three situations emerged: first, there was a drop in performance indicators when the HZ had many BREs and the amount of funding received from NGOs (ANGO) were low (2015). Second, even when the ANGO was low but the HZ was facing NBREs (2013, 2014, and especially 2018), the performance indicators tended to improve. Third, when the ANGO was high, regardless of the type of traumatic events (2016 and especially 2017), the trend in performance indicators improved until they exceeded the normality thresholds. During this period only the proportion of action plan activities completed (PAC) remained the weakest indicator. According to the respondents, action mechanisms were in place in all three situations but more so when there were fewer BREs and financial support was high.</p>", "<p> For case 4 (intermediate HZ), even though the ANGO are low and the HZ is facing BREs (2013 to 2014), the performance indicators (except for PAC) were still within the norms. According to interviewees, the HZ is used to absorb the shock of the chronic crisis and to put in place coping mechanisms that are not reliant on NGO subsidies (negotiation strategies, relocation of care sites). In comparison to Case 3, this subsidy was very low during this period. However, as in case 3, when there were more subsidies, the level of achievement of the indicators improved despite the type of traumatic events (2016 and 2017).</p>" ]	[ "<title>Discussion</title>", "<p> The objective of this study was to describe the traumatic events that occurred in HZs in chronic crisis due to armed conflict from 2013 to 2018, as well as the coping mechanisms put in place by these HZs to maintain good performance. Our findings indicate that the traumatic events that occurred during this time period that could have an impact on the health system BREs, consisting of clushes between armed groups and their direct consequences (deaths, kidnappings and relocation of health facilities), and NBREs, which included events such as epidemics, natural disasters and health personnel strikes. The HZs in affected by armed conflicts (cases 3 and 4) maintained an acceptable level of performance for some performance indicators but their level of PAC achievement remained low. The use of military nurses in the affected areas, the relocation of health facilities, attracting NGO funding and implementing negotiation strategies with the belligerents were among the coping mechanisms identified.</p>", "<p> The coping mechanisms put in place by the HZs in crisis depended on the traumatic events they experienced. The BREs were the events that had the greatest impact on the health system as they caused a drop in the performance of the indicators in these HZs. These results corroborate those of other studies that have shown the vulnerability of health systems during armed conflicts.<sup>##UREF##12##16##,##UREF##13##19##,##REF##34511092##33##,##UREF##33##43##</sup> The NBREs in crisis areas were additive factors to the BREs which could explain the destabilisation of the health system.<sup>##REF##31822891##15##</sup> In contrast, in stable HZs, these NBREs could be regarded as emergent and ephemeral events, leading to the rapid and effective implementation of appropriate measures. Maintaining good performance in this situation was dependent on the coping mechanisms put in place by the health workers, without external assistance. This would be explained by strong leadership and organisational governance within these HZs. However, with financial support from NGOs, the performance of health indicators improved. Indeed, the health system faces several challenges during armed conflicts, including the lack of appropriate support.<sup>##REF##28592283##44##</sup> In some African countries, such as the DRC, where resources allocated to the health sector remain below the 15% threshold set in the Abuja Declaration,<sup>##UREF##34##45##</sup> the majority of funding for this sector comes from external partners.<sup>##UREF##19##26##,##UREF##35##46##, ####UREF##36##47##, ##UREF##37##48####37##48##</sup> The government’s support is mainly focused on the payment of risk premiums to certain healthcare staff (mainly doctors and nurses).</p>", "<p> In the crisis HZs (cases 3 and 4), performance was better for certain indicators such as bed occupancy rates and use of curative services when compared to the stable HZs (cases 1 and 2). This could be explained by the urban health context,<sup>##REF##15760293##49##</sup> which is characterised not only by socio-economic degradation<sup>##UREF##38##50##</sup> but also by the disordered emergence of health facilities that are not integrated into the health system and offering a poorly defined care package for case 1. Furthermore, this HZ has two tertiary level hospitals for which the health system has no data collection framework, even though these are the most frequented health facilities.<sup>##UREF##29##39##</sup> The explanations for case 2 are, however different. The predominance of traditional medicine, difficult financial access to care, and the low technical level of the health facilities (which are underfunded) could all be explanatory factors for this situation. Also, the isolation of case 2 could be a major factor explaining the low level of these indicators.<sup>##UREF##39##51##,##UREF##40##52##</sup></p>", "<p> Finally, three indicators seem to reflect the state of crisis in the affected HZs: high intra-hospital mortality and high rate of pentavalent 3 vaccine drop-out, as well as a low rate of operational action plan completion. This can be explained firstly by the fact that there were no BREs but sporadic NBREs in the stable HZs from 2013 to 2018, so the drop-out rate for pentavalent 3 vaccine and in-hospital mortality could be low. Subsequently, in the event of a crisis, the HZs prioritises resolving health emergencies (management of war casualties and epidemics) and establishing coping mechanisms to the detriment of activities planned in the operational action plan.</p>", "<title> Study Strengths and Limitations </title>", "<p> The strength of this study is that it shows how the different coping mechanisms developed in crisis-affected HZs can contribute to maintaining its performance even during periods of conflict. On the other hand, tracing traumatic events over a period of 6 years allowed us for a better understanding of trends in the achievement of different performance indicators in the affected HZs. This was made possible by using a combination of methods to triangulate information.</p>", "<p> Nevertheless, some study limitations should be highlighted. The memory bias that some health workers may have in recalling traumatic events and coping mechanisms. This bias was offset by questioning other sources, including the reports review. The absence of some of the 8 selected indicators due to the fact that they were not encoded in the SNIS before 2017 was remedied by collecting the raw data at the HZ level. These raw data collected within SNIS reports as well as from the HZ annual reports, had already been verified at the annual HZ meeting. To minimize the risk of error, we had these data validated by the expert from the provincial health division in charge of health information system (DIHS2).</p>", "<p> Knowledge of the health system in the Eastern DRC and experience of previous studies in areas of armed conflict could influence the authors’ position on the opinions of the health workers interviewed. To minimise this bias, we drew up the interview guide on the basis of a preliminary literature review, the questions asked were open-ended to allow people to express themselves as much as possible, and the data were analysed by two separate authors (SML who conducted the interviews and CME) so as not to modify what the interviewees had to say. Finally, the results of the thematic analysis were reviewed by other authors (EP and GF) who were less familiar with the crisis context linked to the armed conflicts in eastern DRC.</p>" ]	[ "<title>Conclusion</title>", "<p> The chronic crisis caused by armed conflicts leads to traumatic events that affects the performance of the health system in South Kivu. In the face of this shock, health staff in the HZ have put in place coping mechanisms to continue providing healthcare to the population. These initiatives were facilitated in part by financial support from NGOs. In the event of chronic armed conflict, the HZ management team, with good leadership and organisational culture, and sufficient resources, could serve as the foundation for adapting this system. A study to define a resilience framework for the HZ in chronic armed conflict would be beneficial.</p>" ]	[ "<p>\n<bold>Background:</bold> The Eastern part of the Democratic Republic of Congo (DRC) has been affected by armed conflict for several years. Despite the growing interest in the impact of these conflicts on health service utilisation, few studies have addressed the coping mechanisms of the health system. The purpose of this study is to describe the traumatic events and coping mechanisms used by the health zones (HZs) in conflict settings to maintain good performance.\n</p>", "<p><bold>Methods:</bold> This multiple case study took place from July to October 2022 in four HZs in the South Kivu Province of DRC. HZs were classified into \"cases\" according to their conflict profile: accessible and stable (Case 1), accessible but remote (Case 2), unstable (Case 3), and intermediate (Case 4). Eight performance indicators and the amount of funding provided to the HZs by non-governmental organizations (NGOs) were recorded. A graph was created to compare their evolution from 2013 to 2018. A thematic analysis of qualitative data from individual interviews with selected health workers was conducted.\n</p>", "<p><bold>Results:</bold> Both battle-related events (war and its effects) and non-battle-related events (epidemics, disasters, strikes) were recorded according to the case conflict-profile. Although the cases (3 and 4) most affected by armed conflicts occasionally performed better than the stable ones (1 and 2), their operational action plan was poorly carried out. The coping mechanisms developed in cases 3 and 4 were the deployment of military nurses in preventive and supervisory activities, the solicitations of subsidies from NGOs, the relocation of health care facilities and the implementation of negotiation strategies with the belligerents.\n</p>", "<p><bold>Conclusion:</bold> Armed conflict results in traumatic events that disrupt the execution of the operational action plan of HZs. The HZs’ management team expertise, its strong leadership, and substantial financial support would enable this system to develop reliable and sustainable adaptive mechanisms.</p>", "<p>\n<bold>Citation:</bold> Makali LS, Karemere H, Banywesize R, et al. Adaptive mechanisms of health zones to chronic traumatic events in Eastern DRC: a multiple case study. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8001. doi:10.34172/ijhpm.2023.8001</p>" ]	[ "<title>Acknowledgements</title>", "<p> We sincerely thank the health provincial division of South Kivu for his contribution to this research.</p>", "<title>Ethical issues</title>", "<p> This study was approved by the ethics committee of the Catholic University of Bukavu (UCB/CIES/NC/017/022). Authorisation from the South Kivu provincial health division was obtained before data collection in the health zones. Verbal informed consent was systematically obtained from interviewees before the recording.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Disclaimer</title>", "<p> The views expressed in this article are author’s and not an official position of the institution or funder.</p>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nSelected Health Zones (source: performed by QIGS 3.30.1 based on Humaritarian Data Exchange shapefiles, provided by UNOCHA). Abbreviations: HZCO, health zone central office; GRH, General referral hospital; Tertiary hospilas, Hôpital Général de Référence de Bukavu and Ciriri hospital. Note: Some HZCO are located in the same place as the GRH (Fizi, Bunyakiri, and Idjwi health zones).</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nMain Traumatic Events in Case 3 (Unstable HZ) and Case 4 (Intermediate HZ) From 2013 to 2018. Abbreviations: HZ, health zone; IDPs, internally displaced persons.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nTrends in the Level of Achievement of Key Performance Indicators and NGO Subsidies in the 4 Cases From 2013 to 2018. Note: The black line on the trend’s charts indicates the norm for good performance in DRC for each indicator. Abbreviations: CSR, curative service utilisation rate; DR3, drop-out rate for the 3rd dose of pentavalent vaccine; ADR, assisted delivery rate; BOR, bed occupancy rate; IHR, in-hospital mortality ratio; NGO, non-governmental organisation; PAC, plan activities completed; ANC1, utilization rate of prenatal services 1; SUP, proportion of supervisions performed.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Main Comparative Characteristics of Selected Cases\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>HZ</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Location/Accessibility</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Administrative Territory/</bold>\n<break/>\n<bold>Number of Health areas</bold><sup>d</sup>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Population (2019)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>IDPs</bold><sup>a</sup>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>BRD</bold><sup>b</sup>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Conflict Score</bold><sup>c</sup>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Case Name</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Kadutu</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Urban/by road only</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Bukavu/13</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">380 501</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">0</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Case 1: Accessible and stable</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Idjwi</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Rural/by sea only</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Idjwi/21</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">294 209</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Case 2: Accessible and remote</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Fizi </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Rural/by road and sea</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Fizi/31</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">423 363</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Case 3: Unstable</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Bunyakiri</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Rural/by road only</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Kalehe/26</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">265 955</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Case 4: Intermediate</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Significance, Standard and Relationship With Armed Conflicts of Selected Health Indicators\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Health Indicator</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Level of Health System</bold><sup>a</sup>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Significance</bold><sup>b</sup>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Relationship With Armed Conflict </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Standard</bold><sup>b</sup>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Utilization rate of prenatal services 1 (ANC1)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1st </td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Reflects acceptance of the service and recruitment of pregnant women</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">During armed conflicts, preventive activities are often abandoned in favour of curative health emergencies</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">80%-100%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">CSR</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1st </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Measures the extent to which people use the service</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Accessibility to health services is often limited in areas affected by armed conflict</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">60%-100% </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> DR3<sup>c</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1st </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Appreciates the accessibility of the vaccination service by children</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">During armed conflicts, preventive activities are often abandoned in favour of curative health emergencies</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0%-10%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">ADR</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1st and 2nd</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Appreciates the management of deliveries by a trained person</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Delivery in appropriate conditions may be affected by armed conflict</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80%-100%</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">BOR</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2nd</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Evaluates the use of the hospital, assesses the quality of services</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Hospitals can sometimes be crowded with seriously injured or ill patients during armed conflicts</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80%-100%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">IHR</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2nd</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Capacity for adequate inpatient care</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Mortality is increased in hospital during armed conflicts, often related to serious bullet wounds</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><2%</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Proportion of action PAC</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3rd</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Appreciates the ability to monitor the level of achievement of the objectives set out in the action plan</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">The previously defined action plan is often forgotten in order to deal with health emergencies</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80%-100%</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Proportion of supervisions performed (SUP)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3rd</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Enables staff to be monitored, training needs to be identified, staff performance to be improved and service quality</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Supervision of health facilities in conflict affected areas may be compromised</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">80%-100%</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">ANGO</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2nd and 3rd</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Reflects the level of contribution of NGOs to the financial accessibility of care</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">In armed conflict settings, humanitarian aid is often extensive, managing health emergencies</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>-</bold>\n</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Health zones (HZs) remained effective in terms of providing healthcare during armed conflict periods thanks to certain adaptive mechanisms put in place by the central office of these HZ: (1) use of military nurses in preventive and supervisory activities, (2) solicitations of non-governmental organisations (NGOs) subsidies, (3) relocation of some health facilities or creation of community care sites, and (4) negotiations with belligerents. </p></list-item><list-item><p>Health system strengthening in armed conflicts-affected regions must focus on improving the leadership of the central office of the HZ and provide him with needful resources. </p></list-item><list-item><p>Assessing the performance of armed conflict-affected HZ must take account of the adaptations implemented by healthcare professionals during armed conflict periods. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> This research shows that health zones (HZs) affected by armed conflict in Eastern Democratic Republic of Congo (DRC) have managed to maintain good performance in terms of health outcome indicators. This was achieved through the adoption of a number of mechanisms by the HZ management team during periods of conflict, augmented by financial support from non-governmental organisations (NGOs). This suggests that in order to support the population affected by the atrocities of armed conflict in Eastern DRC, the Congolese government should allocate a substantial proportion of its financial and technical support to these HZs. This would enable to provide health workers with the resources they need to remain effective and committed to providing quality health services to the population.</p></sec></boxed-text>" ]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p> Abbreviations: HZ, health zone; IDPs, internally displaced persons; BRD, battle-related death.</p><p>\n<sup>a</sup>Number of Internal displacement people: <50 000 = 0 and ≥50 000 = 1.</p><p>\n<sup>b</sup>BRD: <5/1 000 000 inhabitants = 0 and ≥5/1 000 000 inhabitants = 1.</p><p>\n<sup>c</sup>Score obtained by the health zones concerning the two criteria: 0 = stable, 1 = Intermediate, and 2 = unstable.</p><p>\n<sup>d</sup>According to the “Pyramide sanitaire du Sud-Kivu, 2019.”</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: IHR, in-hospital mortality ratio; CSR, curative service utilisation rate; DR3, drop-out rate for the 3rd dose of pentavalent vaccine; ADR, assisted delivery rate; BOR, bed occupancy rate; NGOs, non-governmental organisations; PAC, plan activities completed; ANGO, Amount of funding received from NGOs; ANC1, utilization rate of prenatal services 1; SUP, proportion of supervisions performed.</p><p>\n<sup>a</sup>Level of health system in the health zone: 1st = health center, 2nd = general referral hospital, and 3rd = Health zone central office.</p><p>\n<sup>b</sup>Significances and standards are extracted from the DRC Ministry of Health catalogue of indicators (October 2004) and national health development plan (2019-2022).</p><p>\n<sup>c</sup>Pentavalent vaccine is a combination of 5 vaccines: diphtheria, pertussis, tetanus, hepatitis B, and Haemophilus influenzae type B.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-8001-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8001-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8001-g003\" position=\"float\"/>" ]	[]	[{"label": ["1"], "mixed-citation": [" Parens R. Conflict in Eastern Congo: A Spark Away from a Regional Conflagration. Foreign Policy Research Institute; 2022. "], "uri": ["https://www.fpri.org/article/2022/09/conflict-in-eastern-congo-a-spark-away-from-a-regional-conflagration/"]}, {"label": ["2"], "mixed-citation": [" Center for Preventive Action. Instability in the Democratic Republic of Congo. Global Conflict Tracker. "], "uri": ["https://www.cfr.org/global-conflict-tracker/conflict/violence-democratic-republic-congo"]}, {"label": ["3"], "mixed-citation": [" Kivu Security Tracker (KST). The Landscape of Armed Groups in Eastern Congo: Missed Opportunities, Protracted Insecurity and Self-Fulfilling Prophecies. KST; 2021. "], "uri": ["https://africacenter.org/security-article/the-landscape-of-armed-groups-in-eastern-congo-missed-opportunities-protracted-insecurity-and-self-fulfilling-prophecies/"]}, {"label": ["4"], "person-group": ["\n"], "surname": ["Lalji"], "given-names": ["N"], "article-title": ["The resource curse revised: conflict and coltan in the Congo"], "source": ["Harvard Int Rev"], "year": ["2007"], "volume": ["29"], "issue": ["3"], "fpage": ["34"], "lpage": ["38"]}, {"label": ["5"], "mixed-citation": [" Stearns J. North Kivu: The Background to Conflict in North Kivu Province of Eastern Congo. Rift Valley Institute (RVI); 2012. "], "uri": ["https://www.refworld.org/docid/51d3d5f04.html"]}, {"label": ["6"], "mixed-citation": [" Vlassenroot K. South Kivu: Identity, Territory, and Power in Eastern Congo. Rift Valley Institute (RVI); 2013. "], "uri": ["https://www.refworld.org/docid/5270e9fb4.html"]}, {"label": ["7"], "mixed-citation": [" Stearns J. From CNDP to M23: The Evolution of an Armed Movement in Eastern Congo. Rift Valley Institute (RVI); 2012. "], "uri": ["https://www.refworld.org/docid/51d2c87d4.html"]}, {"label": ["10"], "mixed-citation": [" European Commission\u2019s Directorate-General for European Civil Protection and Humanitarian Aid Operations (ECHO). Democratic Republic of the Congo - Conflict and Violence in The East. "], "uri": ["https://reliefweb.int/report/democratic-republic-congo/democratic-republic-congo-conflict-and-violence-east-dg-echo-un-ngos-echo-daily-flash-24-october-2022"]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Ghobarah", "Huth", "Russett"], "given-names": ["HA", "P", "B"], "article-title": ["Civil wars kill and maim people\u2014long after the shooting stops"], "source": ["Am Polit Sci Rev"], "year": ["2003"], "volume": ["97"], "issue": ["2"], "fpage": ["189"], "lpage": ["202"], "pub-id": ["10.1017/s0003055403000613"]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Gates", "Hegre", "Nyg\u00e5rd", "Strand"], "given-names": ["S", "H", "HM", "H"], "article-title": ["Development consequences of armed conflict"], "source": ["World Dev"], "year": ["2012"], "volume": ["40"], "issue": ["9"], "fpage": ["1713"], "lpage": ["1722"], "pub-id": ["10.1016/j.worlddev.2012.04.031"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Lai", "Thyne"], "given-names": ["B", "C"], "article-title": ["The effect of civil war on education, 1980-97"], "source": ["J Peace Res"], "year": ["2007"], "volume": ["44"], "issue": ["3"], "fpage": ["277"], "lpage": ["292"], "pub-id": ["10.1177/0022343307076631"]}, {"label": ["14"], "person-group": ["\n"], "surname": ["Kang", "Sawada", "Chung"], "given-names": ["SJ", "Y", "YW"], "article-title": ["Long-term consequences of armed conflicts on poverty: the case of Cambodia"], "source": ["Asia-Pac J Reg Sci"], "year": ["2017"], "volume": ["1"], "issue": ["2"], "fpage": ["519"], "lpage": ["535"], "pub-id": ["10.1007/s41685-017-0050-4"]}, {"label": ["16"], "person-group": ["\n"], "surname": ["Gesesew", "Berhane", "Siraj"], "given-names": ["H", "K", "ES"], "article-title": ["The impact of war on the health system of the Tigray region in Ethiopia: an assessment"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["11"], "fpage": ["e007328"], "pub-id": ["10.1136/bmjgh-2021-007328"]}, {"label": ["19"], "person-group": ["\n"], "surname": ["Ojeleke", "Groot", "Bonuedi", "Pavlova"], "given-names": ["O", "W", "I", "M"], "article-title": ["The impact of armed conflicts on health-care utilization in Northern Nigeria: a difference-in-differences analysis"], "source": ["World Med Health Policy"], "year": ["2022"], "volume": ["14"], "issue": ["4"], "fpage": ["624"], "lpage": ["664"], "pub-id": ["10.1002/wmh3.501"]}, {"label": ["21"], "person-group": ["\n"], "surname": ["Terry"], "given-names": ["F"], "article-title": ["Violence against health care: insights from Afghanistan, Somalia, and the Democratic Republic of the Congo"], "source": ["Int Rev Red Cross"], "year": ["2013"], "volume": ["95"], "issue": ["889"], "fpage": ["23"], "lpage": ["39"], "pub-id": ["10.1017/s1816383113000581"]}, {"label": ["22"], "mixed-citation": [" World Health Organization (WHO). Attacks on Health Care: Three-Year Analysis of SSA Data (2018-2020). WHO; 2020. "], "uri": ["https://www.who.int/data/stories/attacks-on-health-care-three-year-analysis-of-ssa-data-(2018-2020)"]}, {"label": ["23"], "mixed-citation": [" International Committee of the Red Cross (ICRC). Health Care in Danger (HCiD). "], "uri": ["https://healthcareindanger.org/fr/"]}, {"label": ["24"], "mixed-citation": [" UNICEF DRC. Building Schools Together with Communities. "], "uri": ["https://www.unicef.org/drcongo/en/recits/building-schools-together-with-communities"]}, {"label": ["25"], "mixed-citation": [" International Committee of the Red Cross (ICRC). Enhancing Protection: For Civilians in Armed Conflict and Other Situations of Violence. Geneva: ICRC; 2012. "], "uri": ["https://www.icrc.org/"]}, {"label": ["26"], "mixed-citation": [" Minist\u00e8re de la Sant\u00e9 Publique. Plan National de D\u00e9veloppement Sanitaire Recadr\u00e9 Pour La P\u00e9riode 2019-2022: Vers La Couverture Sanitaire Universelle. Democratic Republic of the Congo: Minist\u00e8re de la Sant\u00e9 Publique; 2018. "]}, {"label": ["27"], "mixed-citation": [" Makali LS, Malembaka EB, Lambert AS, et al. Comparative analysis of the health status of the population in six health zones in South Kivu: a cross-sectional population study using the WHODAS. Res Sq [Preprint]. December 16, 2020. "], "pub-id": ["10.21203/rs.3.rs-127388/v1"]}, {"label": ["28"], "mixed-citation": [" Centers for Disease Control and Prevention (CDC). Elevated mortality associated with armed conflict--Democratic Republic of Congo, 2002. JAMA. 2003;289(22):2932-2936. "], "pub-id": ["10.1001/jama.289.22.2932-b"]}, {"label": ["29"], "person-group": ["\n"], "surname": ["Dossa", "Hatem", "Zunzunegui", "Fraser"], "given-names": ["NI", "M", "MV", "W"], "article-title": ["Social consequences of conflict-related rape: the case of survivors in the Eastern Democratic Republic of Congo"], "source": ["Peace Confl"], "year": ["2014"], "volume": ["20"], "issue": ["3"], "fpage": ["241"], "lpage": ["255"], "pub-id": ["10.1037/pac0000044"]}, {"label": ["30"], "person-group": ["\n"], "surname": ["Bitenga Alexandre", "Moke Mutondo", "Bazilashe Balegamire", "Emile", "Mukwege"], "given-names": ["A", "K", "J", "A", "D"], "article-title": ["Motivations for sexual violence in armed conflicts: voices from combatants in eastern Democratic Republic of Congo"], "source": ["Med ConflSurviv"], "year": ["2021"], "volume": ["37"], "issue": ["1"], "fpage": ["15"], "lpage": ["33"], "pub-id": ["10.1080/13623699.2021.1882365"]}, {"label": ["32"], "mixed-citation": [" Insecurity Insight, Safeguarding Health in Conflict. Democratic Republic of the Congo: Violence Against Health Care in Conflict 2021. 2022. "], "uri": ["https://reliefweb.int/report/democratic-republic-congo/democratic-republic-congo-violence-against-health-care-conflict-2021"]}, {"label": ["35"], "person-group": ["\n"], "surname": ["Karemere", "Muhune", "Bigirimana", "Makali"], "given-names": ["H", "N", "R", "S"], "article-title": ["Vulnerability of the Katana health zone in the Democratic Republic of the Congo: a resilience strategy to malaria treatment in healthcare facilities from 2014 to 2018"], "source": ["Acta Sci Med Sci"], "year": ["2022"], "volume": ["6"], "issue": ["4"], "fpage": ["46"], "lpage": ["56"], "pub-id": ["10.31080/asms.2022.06.1212"]}, {"label": ["36"], "person-group": ["\n"], "surname": ["Kenanewabo", "Molima", "Karemere"], "given-names": ["N", "C", "H"], "article-title": ["Gestion adaptative des centres de sant\u00e9 dans un environnement changeant en R\u00e9publique d\u00e9mocratique du Congo"], "source": ["SantePublique"], "year": ["2020"], "volume": ["32"], "issue": ["4"], "fpage": ["359"], "lpage": ["370"], "pub-id": ["10.3917/spub.204.0359"]}, {"label": ["37"], "mixed-citation": [" Stake RE. Multiple Case Study Analysis. Guilford Press; 2006. "], "uri": ["https://books.google.com/books/about/Multiple_Case_Study_Analysis.html?hl=fr&id=rQWT5aDHiZYC"]}, {"label": ["38"], "mixed-citation": [" Institut National de la Statistique. Annuairestatistique RDC 2020. 2021. "], "uri": ["https://www.undp.org/fr/drcongo/publications/annuaire-statistique-rdc-2020"]}, {"label": ["39"], "mixed-citation": [" Minist\u00e8re de la Sant\u00e9 Publique. RDC. Recueil des NormesD\u2019organisation et de Fonctionnement des Structures Sanitaires de La Zone de Sant\u00e9enR\u00e9publiqueD\u00e9mocratique du Congo. Minist\u00e8re de la Sant\u00e9 Publique; 2012. "]}, {"label": ["40"], "mixed-citation": [" Minsit\u00e8re de la sant\u00e9 R. Catalogue Des Indicateurs Du SNIS; 2014. "]}, {"label": ["41"], "mixed-citation": [" R\u00e9publique D\u00e9mocratique du Congo, Minist\u00e8re de la Sant\u00e9 Publique. Syst\u00e8me National d\u2019Information Sanitaire (SNIS-RDC). "], "uri": ["https://snisrdc.com/dhis-web-commons/security/login.action"]}, {"label": ["42"], "mixed-citation": [" Clarke V, Braun V. Thematic Analysis: A Practical Guide (Upcoming Book). Vol 376. SAGE Publications Ltd; 2021. "], "uri": ["https://uk.sagepub.com/en-gb/eur/thematic-analysis/book248481#description"]}, {"label": ["43"], "mixed-citation": [" Tazoacha F, Kibu O. Implications of Armed Conflict on Healthcare Interventions in Cameroon. "], "uri": ["https://onpolicy.org/implications-of-armed-conflict-on-healthcare-interventions-in-cameroon/"]}, {"label": ["45"], "mixed-citation": [" African Union. Abuja Declaration on HIV/AIDS, Tuberculosis, and Other Related Infectious Diseases. 2001. "], "uri": ["https://au.int/en/file/32894-file-2001-abuja-declarationpdf"]}, {"label": ["46"], "mixed-citation": [" Perrin P. The Impact of Humanitarian Aid on Conflict Development. International Review of the Red Cross; 1998. "], "uri": ["https://www.icrc.org/en/doc/resources/documents/article/other/57jpcj.htm"]}, {"label": ["47"], "person-group": ["\n"], "surname": ["Wood", "Sullivan"], "given-names": ["RM", "C"], "article-title": ["Doing harm by doing good? The negative externalities of humanitarian aid provision during civil conflict"], "source": ["J Polit"], "year": ["2015"], "volume": ["77"], "issue": ["3"], "fpage": ["736"], "lpage": ["748"], "pub-id": ["10.1086/681239"]}, {"label": ["48"], "mixed-citation": [" M\u00e9decins Sans Fronti\u00e8res. DRC: Violent Attacks Against Staff Force MSF to End Projects in Fizi Territory, South Kivu. "], "uri": ["https://www.msf.org/msf-forced-pull-out-eastern-drc-territory-following-violent-attacks"]}, {"label": ["50"], "person-group": ["\n"], "surname": ["Bayumbasire", "Bakulikira", "Nduwimana", "Mubalama", "Wand\u2019arhasima", "Bagalwa"], "given-names": ["C", "JP", "A", "L", "L", "L"], "article-title": ["The urbanization of the city of Bukavu and its involvement in the socio-economic situation of the urban population, South Kivu, Democratic Republic of Congo"], "source": ["Int J Progress Sci Technol"], "year": ["2021"], "volume": ["27"], "issue": ["2"], "fpage": ["203"], "lpage": ["216"], "pub-id": ["10.52155/ijpsat.v27.2.3298"]}, {"label": ["51"], "mixed-citation": [" World Health Organization (WHO). Increasing Access to Health Workers in Remote and Rural Areas Through Improved Retention. WHO; 2010. "]}, {"label": ["52"], "mixed-citation": [" Australian Institute of Health and Welfare. Rural and Remote Health. "], "uri": ["https://www.aihw.gov.au/reports/rural-remote-australians/rural-and-remote-health"]}]	{ "acronym": [], "definition": [] }	52	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 17; 12:8001	oa_package/09/54/PMC10699820.tar.gz
PMC10699821	0	[ "<title>Background</title>", "<p> The COVID-19 pandemic, which pushed millions of people into extreme poverty, is described by the United Nations Development Programme (UNDP) as “the worst setback in a generation.”<sup>##UREF##0##1##</sup> The pandemic has renewed recognition of the need to better address the drivers protecting and producing health.<sup>##UREF##1##2##</sup> The United Nations (UN) has called for “ambitious plans that reimagine and rebuild health, social and economic systems.”<sup>##UREF##2##3##</sup> This is echoed by the World Health Organization (WHO) in its calls for “a healthy recovery from COVID-19.”<sup>##UREF##1##2##</sup></p>", "<p> The question however, is whether we want a recovery returning to our previous unhealthy and unsustainable state? Arguably, the world was primed for the pandemic and its inequitable impacts precisely because of a lack of meaningful action on the systemic and institutional drivers of health inequities. Until recently, improvements in economic progress have been accompanied with widening inequality, increased migration, growing urbanisation, decreased social mobility, expanding labour vulnerabilities, fraying social safety nets — in short, social conditions are worsening.<sup>##UREF##3##4##,##UREF##4##5##</sup> The idea that we can “treat our way out” of the existing situation is increasingly untenable.</p>", "<p> Experiences within and beyond the health system provide insights into the kind of recovery possible – including what has been termed “healthy societies.”<sup>##UREF##5##6##</sup> The idea of healthy societies builds on the Declaration of Alma Ata,<sup>##UREF##6##7##</sup> the Ottawa Charter,<sup>##UREF##7##8##</sup> and the WHO Commission on the Social Determinants of Health.<sup>##UREF##8##9##</sup> It has also been advanced by other initiatives.<sup>##REF##32505243##10##</sup> While general statements are made and whole-of-society models have been endorsed in select geographies, there is limited clarity or agreement on the needed action and research agendas.</p>", "<p> We explore these themes and ideas as part of a larger narrative synthesis of the healthy societies literature reported in a companion paper.<sup>##UREF##5##6##</sup> As mentioned in that paper, our aim was <italic toggle=\"yes\">to understand how several linked concepts inform healthy societies approaches, with the intention to inform political engagement for action, eventual policy interventions, and research in support of both. </italic>Our analysis did not seek to develop a unifying theory, but focus on both the “what” and the “how” of healthy societies. In this second paper, we focus on the policy actions and research priorities (the “how”).</p>", "<p> Based on our prior work, we began with the premise that societal efforts for health are driven by policy levers, broadly defined as instruments used by governments to elicit system-wide and societal change to meet objectives and/or respond to key stakeholders.<sup>##UREF##9##11##</sup> Governments can use and adjust policy levers to achieve such change.<sup>##UREF##9##11##, ####UREF##10##12##, ##UREF##11##13####11##13##</sup> In the health sector, a policy lever can represent a discrete area of the system’s function.<sup>##UREF##10##12##</sup> Levers operate across broader contexts; their implementation and effectiveness are conditioned by the presence of what are termed “enablers.” We defined enablers as broader conditions to be established or created alongside levers.</p>" ]	[ "<title>Methods</title>", "<p> This study was initiated following a series of meetings and conversations that senior authors were involved with on defining the scope of healthy societies. These meetings and interactions relate to articulating what the WHO’s third Triple Billion target would encompass – it states that 1 billion more people should enjoy better health and well-being.<sup>##UREF##12##14##</sup> Alongside this, some co-authors were involved with an institutional strategy-building on societal determinants of health and on articulating a research vision for “healthier societies.”</p>", "<p> These discussions and considerations were the starting point of our document selection which itself issued from two reviews, Maani et al<sup>##REF##31953933##15##</sup> (a review of how commercial determinants of health are represented in social determinants frameworks) and van Olmen et al<sup>##REF##22971107##16##</sup> (a review of health systems frameworks). Using these reviews as a base, we determined inclusion criteria and developed a sample of documents in the English literature starting from the 1974 Lalonde Commission Report.<sup>##UREF##13##17##</sup> Our database included political declarations, commission and UN reports, peer-reviewed papers, commissioned academic evidence reviews and non-government organisation<sup>##UREF##7##8##</sup> guidance notes. Additional documents were identified through Google Scholar searches, snowball sampling and author suggestions based on meetings and emerging literature in the course of the analysis, that at least two co-authors also determined to be relevant to defining and understanding the concept of ‘healthy societies.’<sup>[<xref rid=\"fn1\" ref-type=\"fn\">1</xref>]</sup> (See ##SUPPL##0##Supplementary file 1##).</p>", "<p> Ultimately, 68 documents were used as the database for extraction (See ##SUPPL##1##Supplementary file 2##). Given the wide variation of type of documents and the aim to examine the ‘how,’ this analysis did not include a quality appraisal of texts used. Rather, we sought to explore the operationalization of frameworks, seeking to build the “how” from the “what” extracted in an earlier paper.<sup>##UREF##5##6##</sup></p>", "<p> Three researchers independently extracted data from the included documents into a coding template. The initial analysis focused on basic details (date published, authors, affiliations, type of document, funder) and analytical information (aim, broad topics, policy approaches, recommendations, and action and research agendas advocated). Coding was discussed and revised and the framework revised and reapplied. Additional documents used to contextualise the findings were identified through citation chaining and iterative examination.</p>", "<p> Following this initial coding and indexing, a thematic, inductive approach to analysis was used, and the findings focused on key themes and implications, rather than the number of documents that refer to specific themes. The framework presented here, on levers and enablers, was developed iteratively through a focused extraction of ‘action agendas.’ These were defined as calls or recommendations made in the documents to any range of stakeholders to raise the salience of, take steps toward (including investments) or place renewed emphasis on an issue, value, way of doing things, and/or an idea. In addition to extracting text on specific policy levers and agendas, researchers noted text pertaining to accountability, and processes that would have to be in place for levers to function. These are categorized as “enablers.” Through several iterative drafts and discussions, the analysis identified that levers and enablers operate across multiple levels and interact. These have been indexed in relation to a ‘cube’ and finally presented in a narrative structure.</p>" ]	[ "<title>Results</title>", "<p> This analysis found that levers and enablers play a range of critical roles to engender healthy societies through their interactions at local, national and global levels (See Figure). All sides of the cube are interlinked, in the way Gaventa’s power cube also conceives of the interlinkages of various dimensions of power.<sup>##UREF##14##18##</sup> Our conceptualisation departs somewhat from Gaventa’s exegesis, however, in that the “power cube” specifies forms and spaces, while this “action cube” emphasizes levers and enablers. In presenting the results, policy levers are outlined first and then the enablers. We also mention challenges and barriers to enacting the enablers and pulling the policy levers as identified in the literature. There is no hierarchy implied in the order of presentation.</p>", "<title> Levers</title>", "<title> Lever 1 – Regulatory and Fiscal Measures</title>", "<p> Regulatory measures enforced by the state are described as key “mechanisms for change.” For example, Dahlgren and Whitehead argue that robust governmental social protection programmes are needed to address social and health inequities.<sup>##UREF##15##19##</sup> Regulatory measures include reducing income inequality, promoting full and fair employment, providing social protection, and supporting equitable health financing.<sup>##UREF##2##3##,##UREF##8##9##,##UREF##15##19##, ####UREF##16##20##, ##UREF##17##21##, ##UREF##18##22##, ##UREF##19##23####19##23##</sup> Many documents focus on governmental regulation, while others focus on hybrid models as well as the drawbacks of industry self-regulation. Legislation and other expressions of state-led regulation are critical to the four components of healthy societies described in our first paper (People, Places, Products, and Planet). For example, the predominant domestic regulatory measures discussed in the literature were taxes on tobacco and alcohol products and marketing regulations, as well as regulation of marketing aimed at children, including digital media, where it was suggested that government efforts to protect health are at present insufficient.<sup>##UREF##20##24##,##REF##32085821##25##</sup> Some argue that for non-communicable disease (NCD) prevention, inadequate state intervention, self-regulation by industry and weak accountability mechanisms all limit action on upstream drivers.<sup>##REF##28619031##26##</sup></p>", "<p> Many documents call for supportive trans- or inter-national regulation through regional and global agreements and treaties (such as in the trade sector),<sup>##REF##26188744##27##,##REF##28110222##28##</sup> that reduce inequalities between and across nations.<sup>##UREF##21##29##</sup> Some call for examination of new and binding framework conventions similar to the WHO Framework Convention on Tobacco Control.<sup>##REF##28619031##26##,##UREF##22##30##</sup> This includes, for example, global agreements on childhood obesity, on alcohol and health-harming products/industries<sup>##UREF##22##30##</sup> and on food systems.<sup>##REF##30700377##31##</sup> A number of the documents draw attention to the need to protect regulatory processes from undue industry interference.<sup>##REF##30700377##31##, ####REF##30660336##32##, ##REF##31217191##33####31217191##33##</sup> Others argue that the existing human rights machinery must be used to support and hold countries (and corporations) accountable to established standards in existing agreements.<sup>##REF##28619031##26##</sup></p>", "<p> Documents also refer to industry self-regulation and hybrid forms of public-private regulation. Many analysts are concerned that the profit motive tends to make these approaches to regulation less effective that state-led regulation.<sup>##REF##28619031##26##</sup> Weaknesses of self-regulation include shallow commitments (or low standards), inadequate monitoring mechanisms (including those that lack independence), and a lack of enforcement. Where hybrid and self-regulation prevail, there is a need for “robust and independent accountability mechanisms” and capacity building to “negotiate with the private sector” on government-determined and -led activities.<sup>##UREF##22##30##</sup> Regulation requires a combination of long-term and dynamic capabilities in the public sector.<sup>##UREF##23##34##</sup></p>", "<p> The frameworks and literature we found support an interventionist and redistributive state.<sup>##UREF##2##3##,##UREF##8##9##,##UREF##13##17##,##UREF##15##19##,##UREF##18##22##,##UREF##19##23##</sup> Calls relating to fiscal measures include investing more in interventions that control the determinants of health.<sup>##UREF##8##9##,##UREF##20##24##,##UREF##22##30##,##REF##30700377##31##,##UREF##24##35##,##REF##32386579##36##</sup> There are also exhortations to remove health harming subsidies,<sup>##UREF##0##1##,##REF##26188744##27##</sup> including those propping up and/or incentivising the fossil fuel industry,<sup>##REF##30700377##31##</sup> or agricultural ones that prevent nature-based solutions and trap farmers on degraded lands. Fiscal incentives may increase the efficiency of carbon pricing and help channel private sector investment into long-lived, low-carbon technologies.<sup>##UREF##0##1##</sup> Some documents called for “double duty” and “triple duty actions.”<sup>##REF##30700377##31##</sup> For example, in response to COVID-19, some economic stimulus programmes supported transitions to greener sustainable economies, leading to greater equity, resilience and sustainability.<sup>##UREF##2##3##</sup> Stimulus programs are described as double duty benefits in that they reduce NCDs and protect the planet.<sup>##UREF##22##30##</sup></p>", "<p> There are calls for greater research on more impactful and equitable fiscal measures. This includes assessing cross-sectoral policies, new technologies, and products. There is a particular focus in many research agendas on health co-benefits (and co-harms), including the distribution of co-impacts and their equity considerations.<sup>##REF##26188744##27##</sup> Research themes identified include how best to: (<italic toggle=\"yes\">i</italic>) reduce and repurpose harmful subsidies; (<italic toggle=\"yes\">ii</italic>) develop and implement appropriate taxes that promote sustainability, improve health, and reduce inequities; (<italic toggle=\"yes\">iii</italic>) support local sustainable development initiatives that foster health; and (<italic toggle=\"yes\">iv</italic>) regulate harmful activities.<sup>##REF##26188744##27##</sup></p>", "<title> Lever 2 – Intersectoral Action</title>", "<p> The need for purposeful and coordinated engagement of sectors beyond the health ministry or department of health features prominently in early documents<sup>##UREF##7##8##,##UREF##13##17##</sup> and is reiterated in subsequent frameworks.<sup>##UREF##19##23##,##UREF##25##37##, ####REF##17152313##38##, ##REF##27814893##39##, ##UREF##26##40####26##40##</sup> This is referred to as “intersectoral action” in a number of documents, defined as “a recognized relationship between part or parts of the health sector and part or parts of another sector, that has been formed to take action on an issue or to achieve health outcomes (or intermediate health outcomes) in a way which is more effective, efficient or sustainable than could be achieved by the health sector working alone.”<sup>##UREF##27##41##</sup> Variants of such initiatives include multi- and trans-sectoral action (and policy and governance). In 1978, the Alma-Ata Declaration called for “national health policies and plans [to] take full account of the inputs of other sectors bearing on health.”<sup>##UREF##6##7##</sup> There are also calls for greater integration and policy coherence between policy efforts.<sup>##UREF##26##40##</sup> Among the most prominent frameworks is that of “healthy public policy” – which is achieved through a Health-in-All-Policies (HiAP) approach.<sup>##UREF##19##23##</sup> This literature includes calls for strengthened legal obligations to embed health into policy making across sectors.<sup>##UREF##19##23##,##UREF##28##42##</sup> The WHO European Regional office has published a number of strategies to enhance governance to facilitate multisectoral action.<sup>##UREF##15##19##,##UREF##20##24##</sup> These and other documents advocate for more widespread use of health impact assessments of relevant policies across all ministries.</p>", "<p> Yet efforts to realize inter- or multi-sectoral action have had limited impact as health actors have struggled to link with other sectors and develop compelling messaging which resonates beyond public health and academic communities.<sup>##REF##30249506##43##</sup> These challenges reflect the complexity and challenges of intersectoral work.<sup>##REF##33564855##44##</sup> For example, a summary of intersectoral action in the field of women, child and adolescent health found limited evidence on the effectiveness of the health sector,<sup>##REF##30530519##45##</sup> with some calls for indicators to measure collaborative relationships.<sup>##UREF##15##19##,##UREF##20##24##</sup></p>", "<p> The literature considers whether health or other sectors ought to lead on intersectoral action for health – and most of the literature suggests that the health sector holds this obligation. At the global level, some documents called for multilateral organizations (such as WHO) to support countries to coordinate HiAPs approaches across other sectors. Many of the documents consider various challenges of integrating health concerns into public policy beyond the health sector. In a more recent paper, a typology of roles of the health sector vis-à-vis other actors has been proposed; the health sector could lead, be in bi- or tri-lateral collaboration, support or otherwise have a minimal role. More recent papers explore the role of theory in informing multi-sectoral action and the mechanisms that enable effective intersectoral policy-making. These recent contributions advance the field and aim to pivot conversations from descriptive to strategic analysis. This includes evidence on the “political economy” of intersectoral action, including how ideas, institutions and interests influence intersectoral action outcomes (particularly in low- or middle-income country [LMIC] contexts) and the need for distinction between inter-, multi-, and trans-sectoral action, policy and governance.<sup>##REF##34706927##46##</sup></p>", "<title> Lever 3 - Redefining Measures of Progress</title>", "<p> The final lever reflects calls for a recalibration of definitions of societal progress–reconsidering ultimate goals in public policy making. Several frameworks question the reliance on gross domestic product or gross national income type measures, and instead propose new approaches for societal well-being and sustainable development, like the Human Development Index. Some argue that COVID-19 provided an opportunity for such recalibration, and that rather than returning to “normal” we should ask what sort of societies we want. This includes calibrating progress in terms of how solutions address the challenges faced by people experiencing marginalisation, and the taking a longer-term view of impacts on and relationship of people and planet.</p>", "<p> Suggestions for redefining progress include placing greater emphasis on human welfare values (and indicators) that prioritise justice, inclusion and transparency.<sup>##UREF##13##17##,##REF##26188744##27##,##REF##16533108##47##, ####UREF##29##48##, ##UREF##30##49####30##49##</sup> An obvious approach is to focus on equity metrics rather than metrics that look at averages or only outcomes in the poor.<sup>##UREF##15##19##</sup> Multiple authors propose research on and integration of equity indicators and/or disaggregation of data and targets.<sup>##UREF##17##21##,##UREF##31##50##, ####REF##30426875##51##, ##UREF##32##52##, ##UREF##33##53####33##53##</sup> Part of the process of establishing alternative goals and metrics involves acknowledging the relationship between health and economic well-being and the role of “institutionalised prejudices and administrative inefficiencies.”<sup>##UREF##17##21##</sup></p>", "<p> Calls are made for indicators that move beyond measures of illness to measures of well-being. One suggestion is to assess all public policy against their impact on life satisfaction, availability of social support, percentage of the population with improved sanitation facilities, income distribution, unemployment rates and the proportion of primary school aged children not enrolled.<sup>##REF##28830297##54##</sup> However, some noted that well-being is not a clearly defined concept, calling for more research on indicators based on eudaimonic areas (realising one’s fullest potential) as metrics of progress and success. Similarly, others call for focusing research on mental well-being. Here, too, health must be seen in broader context: well-being is determined by our ability to obtain quality education, food and housing, among other factors.<sup>##UREF##34##55##</sup></p>", "<p> A few models and ways to measure well-being have been advanced,<sup>##UREF##35##56##, ####UREF##36##57##, ##UREF##37##58##, ##UREF##38##59####38##59##</sup> including that by the Wellbeing Economy Alliance.<sup>##UREF##39##60##</sup> Bhutan’s The Gross National Happiness Index (GNHI) suggests centering a population’s happiness and well-being with four principles: sustainable and equitable economic development; conservation of the environment (related to people’s relationship with a healthy and sustainable natural environment); preservation and promotion of culture; as well as good governance.<sup>##UREF##40##61##</sup> However, the GNHI faces some criticism for not addressing human rights principles essential for health.<sup>##REF##27781010##62##</sup> In the same way that the New Zealand well-being budget<sup>##UREF##41##63##</sup> demands that all governmental work is assessed by how it contributes to well-being, Bhutan’s GNHI creates a policy lever based on an alternative conception of the end points of development.<sup>##UREF##42##64##</sup></p>", "<title> Enablers</title>", "<p> Policy levers do not operate in a vacuum. The literature we analysed lays out the features of these contexts – the conditions within which policies emerge, or the conditions under which they are more likely to emerge, which are referred to as enablers.</p>", "<title> Enabler 1 - Political Will and Accountability</title>", "<p> The mobilization of ‘political will’ as well as the use of targets and mechanisms for accountability surface continually in the literature.<sup>##UREF##28##42##</sup> Documents refer to the need for public and political support to enable regulatory reforms.<sup>##UREF##7##8##,##UREF##8##9##,##UREF##26##40##</sup> Less consideration is given to what would lead to such will or why such will, has not been forthcoming in health or other sectors. Corporate interference is mentioned as a significant barrier.<sup>##UREF##34##55##</sup> Calls are, however, made for research to address barriers to the translation of knowledge into action, such as research addressing lack of political will<sup>##REF##21091195##65##</sup> or decision-making under uncertainty, such as in cases of non-linear, complex interacting forces.<sup>##REF##26188744##27##</sup> The centrality of political will to enable the right policy levers to be pulled to enhance regulation, and that such will is often needed simultaneously at all or different levels illustrates the interactive dynamics of the cube as per Figure.</p>", "<p> The literature highlights the adoption of transparent accountability mechanisms to cultivate trust across government and between governments and communities, for example, through parliamentary health committees for intersectoral governance.<sup>##UREF##20##24##</sup> A key barrier identified is the asymmetry of power, with a vicious cycle whereby certain political and economic institutions (like unions of informal sector workers or indigenous political formations) face disadvantage and have less often been able to shape the economic rules of the game globally, which could, in turn, reduce their disadvantage.<sup>##REF##19531164##66##</sup> This applies within countries to populations facing historical disadvantage, which may be less represented in decision-making or accountability processes.<sup>##UREF##17##21##</sup></p>", "<p> The literature also proposes accountability mechanisms based on human rights principles with independent monitoring bodies reporting, for example, to global platforms and/or greater use of national commissions on health including specifically for intersectoral action.<sup>##UREF##6##7##,##UREF##22##30##,##UREF##25##37##,##UREF##30##49##,##UREF##43##67##</sup> Yet, despite repeated calls for enhanced and independent monitoring to facilitate accountability, such mechanisms remain rare and underdeveloped. Some call for disaggregated data and continued monitoring of health inequalities to facilitate accountability (eg, to leave no one behind), seeing this as a necessary, but not sufficient step to tracking and ensuring political will and accountability.</p>", "<title> Enabler 2 - Social Mobilization and Community Action</title>", "<p> Many authors point to the power of civil society and social movements, and the power of collective action and alliances,<sup>##UREF##7##8##,##UREF##16##20##,##REF##26188744##27##,##UREF##44##68##</sup> where the legacy of popular protest, women’s movements, sexual and reproductive rights movements and the HIV movements loom large. In the context of global NCD targets, more recently, civil society organisations have played a key role in “accelerat(ing) political action” and ensuring accountability.<sup>##UREF##22##30##</sup> Others call for citizens to directly lobby politicians for action by promoting or protesting actions by government,<sup>##UREF##34##55##</sup> and for citizen involvement to challenge government decisions (eg, through mechanisms such as public protest or appointment of ombudspersons).<sup>##REF##28125390##69##</sup></p>", "<p> The literature repeatedly emphasizes the need for governments to encourage community engagement and the empowerment of community members.<sup>##UREF##6##7##,##UREF##7##8##,##UREF##16##20##,##UREF##19##23##,##UREF##43##67##</sup> Some documents place emphasis on needed mechanisms to enable community mobilisation, and genuine and meaningful participation of communities<sup>##UREF##8##9##,##UREF##34##55##,##UREF##45##70##</sup> and the resources that would enable it<sup>##REF##30700377##31##,##UREF##46##71##</sup> (eg, the Lancet Syndemic Commission called for US$ 1 billion over 10 years to support civil society).<sup>##REF##30700377##31##</sup> Additionally, these mechanisms should seek to shift norms and structural drivers to address health inequity.<sup>##REF##33327689##72##,##REF##34192622##73##</sup> One barrier mentioned with respect to inclusion, recommended ensuring that “the least well off [were] included and the interests of powerful groups [were] contained.”<sup>##REF##16533108##47##</sup></p>", "<p> Frameworks consider questions of representation and diversity in relevant decision-making processes.<sup>##UREF##2##3##,##UREF##20##24##,##REF##28619031##26##,##UREF##31##50##</sup> The involvement of people living with specific conditions is encouraged through global cooperation and mobilisation.<sup>##UREF##22##30##</sup> The literature focuses on the need for people-centred social action<sup>##UREF##6##7##,##UREF##18##22##</sup> and for increased stakeholder engagement, research co-production and capacity including working with health and other sectors.<sup>##REF##26188744##27##,##UREF##30##49##,##UREF##45##70##,##UREF##47##74##</sup> It is argued that people-centred programme design and implementation could help reduce hierarchies of knowledge.<sup>##UREF##48##75##</sup></p>", "<p> Public education<sup>##UREF##19##23##,##REF##30426875##51##</sup> is also identified in multiple documents as a critical enabler, in some cases promulgated under the term health literacy.<sup>##UREF##28##42##,##UREF##44##68##,##UREF##49##76##</sup> As the 1974 Lalonde report on social determinants lays out, informing the public of structural drivers would not merely help protect their own health through individual level behaviour modifications but more importantly enable people to come together, through local organisations to demand action on the social determinants.<sup>##UREF##13##17##</sup></p>", "<title> Enabler 3 - Generation and Use of Knowledge</title>", "<p> Many documents make the case that to drive progress, there is a need for more, and better quality, evidence.<sup>##REF##30426875##51##</sup> The literature on the social determinants of health underscores the need to use different evidence types, explore research methodologies to understand structural determinants across settings and from different perspectives, and to link research to integrated action strategies.<sup>##REF##32386579##36##</sup> Methods advocated include ethnographic,<sup>##UREF##15##19##</sup> life course and longitudinal,<sup>##REF##21091195##65##</sup> systems,<sup>##REF##30700377##31##</sup> complexity, collaborative research approaches (using ‘process innovations’),<sup>##UREF##48##75##</sup> as well as policy and programme evaluations.<sup>##UREF##18##22##,##REF##30700377##31##,##UREF##49##76##</sup> Additionally, proposals are made for integrating gender and socio-economic status.<sup>##UREF##45##70##,##UREF##50##77##</sup> There are also calls for the inclusion of perspectives of those (disproportionately and negatively) affected,<sup>##REF##28110222##28##,##UREF##51##78##,##REF##29510520##79##</sup> and in particular, to include indigenous and traditional approaches in the knowledge ecosystem.<sup>##REF##30700377##31##</sup> Calls have been made, and methodologies developed, to share and co-produce knowledge through citizen science methodologies,<sup>##REF##30426875##51##</sup> and to close the gap between research and practice.</p>", "<p> Given the necessary blurring of boundaries between research, policy, and practice, the importance of individual or organisational agents that explicitly and transparently straddle boundaries, political entrepreneurs and change agents were also found to be crucial for progress.<sup>##REF##28125390##69##</sup> There are also outstanding methodological challenges; we are at early stages of developing appropriate methods and mechanisms to obtain sufficient evidence on the exact relationship between social determinants and health in specific, actionable contexts,<sup>##REF##24560252##80##</sup> and much more thought needs to be given to process evaluation associated multisectoral action, policy and governance – for example in relation to civic engagement strategies, prioritised joint action plans and divisions of labour among ministries.</p>", "<p> The reviewed literature stresses the importance of (researchers) carrying out policy research – to understand and address the policy inertia preventing adoption or implementation of progressive, equity-oriented measures.<sup>##REF##30700377##31##</sup> Whitehead and Dahlgren<sup>##UREF##45##70##</sup> for example, argue that a deeper analysis of the “ways in which health systems can confront them [structural determinants] in different contexts” would aid policy-makers. More recently Gilson et al refer to similar processes as “collective sensemaking for action.”<sup>##REF##33593963##81##</sup> Such approaches are especially critical given the many barriers that exist to leveraging available evidence – particularly that which challenges the status quo. An analysis of the use of evidence during the COVID-19 pandemic calls for attention to governance of evidence itself, by way of scientific advisory systems in government decision-making.<sup>##UREF##2##3##</sup> The EAT Forum for global food system transformation was designed as a platform for collaboration to co-create policy-relevant empirical evidence and corresponding solutions,<sup>##REF##30660336##32##</sup> with some success, but also some important critiques, including its purported endorsement of a “one-size-fits-all” approach.<sup>##REF##32061173##82##</sup></p>", "<p> The gap between the knowledge of disease and knowledge for implementation, is described as “unacceptable,” especially in LMICs – and the same is true of the creation of health.<sup>##REF##26188744##27##</sup> The need to fill the gap between scientific evidence and policy making is repeatedly made.<sup>##REF##30660336##32##</sup> There is some discussion in the literature on building partnerships outside the ministry of health, for example to conduct health impact assessments.<sup>##REF##15296629##83##</sup> One approach to building partnerships involves learning-by-doing,<sup>##UREF##0##1##</sup> where competencies are acquired in a context, directly confronting complexity through application rather than abstract or conceptually focused training. The literature further emphasizes the importance of methodologies relevant to action or the more contextually nuanced approach of realist synthesis.<sup>##REF##27814893##39##,##REF##17496254##84##</sup> Other documents advocate for “prospective action-oriented applied research.”<sup>##REF##26188744##27##,##UREF##49##76##</sup></p>", "<p> Multiple calls are made to generate evidence around “why” and “how” questions and for a shift from focus on individual behaviour to systems: for instance why individuals and communities adopt risky “lifestyle” behaviours and/or consume unhealthy commodities, including tobacco,<sup>##UREF##26##40##</sup> alcohol<sup>##UREF##31##50##</sup> and unhealthy foods.<sup>##UREF##49##76##</sup> The literature also calls for inquiry into “how” structural or upstream drivers of “lifestyle” and “unhealthy” behaviours may be addressed.<sup>##REF##30700377##31##,##REF##34615652##85##</sup> A political economy lens could identify interests and actors and their power include to frame and normalise the focus on the individual; it could also explore to what extent most individuals have the agency and opportunities to pursue healthy lifestyles. This kind of knowledge is not prominent in this literature, nor is it mainstreamed across health sector thinking and action.</p>", "<p> In some cases, enablers and barriers are shared across multiple health challenges and may drive a synergistic action agenda.<sup>##UREF##2##3##</sup> For example, linking obesity with undernutrition and climate change into a single syndemic framework focuses attention on the scale and urgency of addressing these combined challenges and emphasises the need for and benefits of common solutions.<sup>##REF##30700377##31##</sup></p>" ]	[ "<title>Discussion</title>", "<p> The selection of texts was made on the basis of frameworks identified in previous reviews; we extended our sample beyond those reviews both qualitatively and quantitatively—several points emerge as discussed below.</p>", "<title> Where Is the Consideration of Politics and Power?</title>", "<p> The literature has tended to focus on technical, individual-oriented solutions rather than political reform or political-economy informed upstream change. It neglects engagement with civic groups and social movements in political processes.<sup>##UREF##7##8##</sup> Of the 27 frameworks looking at the drivers of health equity reviewed by Givens et al, only five consider political or institutional power.<sup>##REF##33111031##86##</sup> As a result, with a few exceptions,<sup>##UREF##52##87##</sup> questions of how to motivate decision makers, how to rally movements, how to engage communities, and how to counteract vested interests are under-articulated and/or unanswered.</p>", "<p> The literature typically does not engage in analysis of power and political-economy; it fails to consider how agendas are advanced and implemented. There were exceptions with some authors arguing that efforts “must be driven by politics.”<sup>##REF##28125390##69##</sup> The lack of prominence given to politics reflects a positivist, often reductionist and technocratic emphasis of the prevailing and dominant biomedical approach. Useful questions would be around how to disrupt the power of those interests who set the agenda and keep the kind of levers and enablers off such agendas, how to get the public and public health communities to focus on what really matters, how better to frame problems and solutions that mobilize the kind of action called for across frameworks. One example of this could be to establish frameworks focused on societal equity – where health would be one among many sectors where we would seek to remove inequalities and redress the underlying power imbalances that perpetuate them.</p>", "<p> Indeed, one assumption with a lot of intersectoral action models is that decision makers outside the health sector are looking for the health sector to lead action on the social determinants of health. While this may have major implications for action on the structural drivers of health, the health ministry is often unable or unwilling to convene or coordinate other ministries. Moreover, there is a need to question the feasibility of this by policy-makers who tend to privilege bio-medical, technocratic interventions. The type of broad based — equity focused — platform that operates well beyond the paradigms of (only) the health sector, as aforementioned, may offer more strategic and impactful avenues for healthy societies.</p>", "<p> From the perspective of Lukes’ three faces of power heuristic,<sup>##UREF##53##88##</sup> the literature does engage with the politics of agenda setting (Lukes’ first face) and to some extent, albeit more limited, on keeping regulatory and fiscal measures off the health agenda (second face). But there is little engagement with the third face of power; the one that perpetuates the status quo in hidden and often unconscious ways – perpetuating power asymmetries or getting people to want things inimical to their interests (such as the over consumption of ultra-processed foods or lower corporate taxes). With an ever-increased concentration of power and wealth in health harming industries, the tools of such power exercised through marketing, promotions and control of print and social media create and shape societal preferences. There is inadequate exploration of the ways in which vested interests and institutions ‘naturalise’ the focus on disease and sickness, diverting attention from a focus on well-being, let alone the development of pro-health, counter-narratives.<sup>##REF##35508319##89##</sup></p>", "<p> The healthy societies agenda requires an activist or at least progressive interventionist and redistributive government. Yet few of the documents in the sample reflect on the likely or real impact of the structural, institutional and systemic factors introduced or reinforced by neo-liberalism. Few engaged in thinking about how to challenge the prevailing paradigm, where the state has retrenched and the influence of corporate players is substantial.<sup>##REF##28619031##26##,##UREF##52##87##,##REF##30301457##90##,##UREF##54##91##</sup> The period reflected in this paper, when one might have hoped to see the vision and measures outlined in Alma Ata Declaration implemented, was marked at least from the 1980s by a swing away from the state. It was a period during which the post-war social contract in Europe and North America gave way to neo-liberalism. This doctrine was firmly at odds with a large and social-welfare oriented state pulling the above-mentioned levers and investing in the enablers. Trends in many parts of the world represents a move towards authoritarianism and populism, the implications of which are inadequately explored, or ignored altogether.<sup>##REF##32780437##92##,##REF##28575491##93##</sup></p>", "<p> Community-based partnerships and collaborations between professionals and communities are seen to start to redress imbalances of power, and calls have been made to evaluate such efforts.<sup>##REF##30426875##51##, ####UREF##32##52##, ##UREF##33##53####33##53##,##UREF##43##67##</sup> Documents focus on the need for people-centred social action<sup>##UREF##30##49##,##UREF##45##70##</sup> and the need for wider stakeholder engagement including working with health and other sectors.<sup>##REF##26188744##27##,##UREF##47##74##</sup> Yet it is only recently that guidelines to support such efforts are emerging.<sup>##UREF##55##94##</sup></p>", "<title> Documentation and Evaluation of What Works</title>", "<p> The literature expands considerably on the nature of the challenges facing healthy societies (the problem space), and yet is thin on assessment of what has worked or not worked to build or move towards them. Evaluations or documentation of successful or failed examples of action are limited. For example, the calls for multi-sector coordination are plentiful, but there is little guidance on what works under what circumstances. There are exceptions, for example, a UNDP report draws on examples of financial and monetary policies to manage climate risks.The WHO Health 2020 framework provides assessments and detailed suggestions, for example, on how to make multi-sectoral action happen — and there are some examples beyond our sample (for example on HiAPs<sup>##REF##28125390##69##</sup>). The extent to which, and importantly why or why not — and for whom, under what circumstances — the levers and enablers described have worked to bring about transformative change would be something to be encouraged to advance the agenda.</p>", "<p> Just as co-benefits can occur from taking integrated approaches to improving health, unintended negative or inequitable impacts can result from well-meaning interventions — both need to be carefully documented.<sup>##UREF##26##40##,##UREF##56##95##</sup> Indeed, particularly if we use a broader societal frame, understanding shared drivers and arriving at co-benefit type approaches will require complexity-based approaches and systems thinking. The methodological challenges in describing and theorizing co-benefits and intersectoral, whole-of-society type approaches, may require a fundamental shift away from or significant adaptations to the dominant modes of measurement and computation that privilege individual level quantitative data.</p>", "<title> Paradigm Shifts, Mindsets for Change</title>", "<p> Efforts to cast societal well-being in a broader context have been made for the past few decades. The 1990 Human Development Report sought to create an alternative to the gross domestic product, instead “ranking all countries by whether people had the freedom and opportunity to live a life they valued. In so doing, we [UNDP] gave voice to a new conversation on the meaning of a good life and the ways we could achieve it.” Overall, we found that while some of the literature raised this notion of what a good life could be, there was less agreement or even articulation about how this could be achieved.</p>", "<p> While a stream of thinking calls for a redefinition of what constitutes societal progress, our documents did not reflect literature advocating for alternative models of progress to stay within “planetary boundaries.”<sup>##UREF##57##96##</sup> Raworth,<sup>##UREF##58##97##</sup> O’Neill et al,<sup>##UREF##59##98##</sup> Hickel,<sup>##UREF##60##99##</sup> and others have laid out social and biophysical threshold levels whereby nations may stay within planetary boundaries — something that is by default achieved in several “poorer” nations and achievable by other global South economies.<sup>##UREF##61##100##,##UREF##62##101##</sup> Concern has been raised that rather than a framing of high-income country or LMIC as monolithic, we must consider the impact of elite population subgroups within high-income country and LMIC contexts, whose negative contribution to planetary health far outstrips that of populations facing disadvantage in either setting.<sup>##UREF##61##100##,##UREF##62##101##</sup></p>", "<p> There was some limited discussion that societal drivers are supra-territorial, needing to be governed at regional and global levels. For example, the Lancet Commission on Planetary Health (2015) looked at the role of regional trade treaties “to further incorporate the protection of health in the near and long term.” It is hard to envision sustained progress on ideas like a circular or well-being economies without broader, paradigmatic shifts. Relatedly, some authors highlight how most planetary health studies were conducted in the global North, and how action and research agendas shaped by such experiences are too narrow.</p>", "<p> There is a need to understand how individual and social power can be organized to advance knowledge, and how this power can be used. In harnessing that power, it will be important that gender, class, disability and other inequities are not further entrenched. This means positively framing healthy and sustainable options for decision-makers and holding governments accountable for the collective right to health and to healthy environments to live, grow, move, work and play.<sup>##UREF##63##102##</sup></p>", "<p> The field may, however, need to reconsider accountability. What we found in the literature were general principles on the one hand (eg, calls for transparency) and, on the other, relatively narrow measures. The latter included, for example, undertaking reviews of the practice of intersectoral action for health, establishing independent monitoring boards for specific issues/initiatives or ensuring a forum for monitoring progress on HiAP.<sup>##UREF##64##103##,##UREF##65##104##</sup> Smaller measures, such as investment in the social determinants of health,<sup>##UREF##63##102##</sup> could be more effective as part of a wider and systematic effort to hold societies to account for the structural and systemic factors.</p>", "<p> Such reframing has at least three further implications.First, that efforts must be made to identify leadership for this agenda beyond ministries of health. Second, given that the agenda is already large and distributed, there is a need for local priority setting. Third, there is a need for more agile and appropriate methodological approaches, such as systems thinking and political-economy analysis, to guide action.</p>", "<title> Limitations</title>", "<p> The aims of this work required an expansive literature search; apart from the 68 documents in our sample, we draw upon additional analyses. This zooming in and out of the literature further expanded the literature, and therefore did not meet the criteria of a systematic, close-ended search. As a team of researchers from countries in the Global North and South, our process was iterative and recursive, but constrained by our own positionality. All authors are social scientists with strong orientations towards equity, human rights and social justice. In addition, we were not appraising the validity, reliability or quality of concepts proposed in frameworks or literature we analysed, which would perhaps calibrate or change the emphasis on the various policy levers proposed as well as enablers that emerged. Relatedly, we have crafted our policy levers and enablers to encompass common themes across the literature. Unique themes or other themes with nuances outside of our cube could also emerge from another round of analysis of our data (See ##SUPPL##1##Supplementary file 2##), but was not included here. Indeed, there may be regional, geographic or other variations that could be looked at in further research on healthy societies, following from Loewenson et al.<sup>##UREF##66##105##</sup></p>", "<p> Our focus, on the “how” was not informed by a detailed analysis of barriers to policy action, though we concede that this could have revealed as much as our identification of enablers did. This is a critical area going forward, as indeed, barriers could forestall action on policy levers or otherwise create contexts where even enablers may be vitiated. The analysis was limited to English-language documents, which may be part of why we have a preponderance of documents from high-income, anglophone countries, which creates a bias in terms of perspectives represented in our analysis. Further, our thematic approach has resulted in high-level descriptions with limited quantitative analysis. Finally, it was beyond our purview to map gaps in the research agendas identified as our narrower focus was on the policy and action elements, eg, the “how” of healthy societies. There is a clear role of research in this and of identifying gaps in how research for healthy societies has been framed. Identifying and then filling these research gaps is another area of future work in this space.</p>" ]	[ "<title>Conclusion</title>", "<p> This paper has explored the “how” of healthy societies, finding some recurring themes, ideas and approaches promoted in the literature to achieve them. The literature identifies policy levers and enablers, but does not provide a closer diagnosis of why such levers have not been leveraged. Despite continuous advocacy around generating political will, many documents continued to view levers as technical instruments. Yet levers are connected to political-economic arrangements associated with the prevailing socio-economic paradigms as are decisions to invest (or not) in enablers. Apolitical approaches do not create healthy societies. This represents a failure of our collective imagination and a major missed opportunity to those who seek Health for All. By ceding space for more progressive sources of power to emerge, the paralyzing limits of the healthcare system may be transcended, and our minds and societies opened to more radical possibilities for a future focused on systems for health and the ensuing health and well-being.<sup>##UREF##67##106##</sup></p>" ]	[ "<p>\n<bold>Background:</bold> As the Sustainable Development Goals deadline of 2030 draws near, greater attention is being given to health beyond the health sector, in other words, to the creation of healthy societies. However, action and reform in this area has not kept pace, in part due to a focus on narrower interventions and the lack of upstream action on health inequity. With an aim to guide action and political engagement for reform, we conducted a thematic analysis of concepts seeking to arrive at healthy societies.\n</p>", "<p><bold>Methods:</bold> This paper drew on a qualitative thematic analysis of a purposive sample of 68 documents including political declarations, reports, peer reviewed literature and guidance published since 1974. Three independent reviewers extracted data to identify, discuss and critique public policy levers and ‘enablers’ of healthy societies, the \"how.\"\n</p>", "<p><bold>Results:</bold> The first lever concerned regulatory and fiscal measures. The second was intersectoral action. The final lever a shift in the global consensus around what signifies societal transformation and outcomes. The three enablers covered political leadership and accountability, popular mobilization and the generation and use of knowledge.\n</p>", "<p><bold>Conclusion:</bold> Documents focused largely on technical rather than political solutions. Even as the importance of political leadership was recognized, analysis of power was limited. Rights-based approaches were generally neglected as was assessing what worked or did not work to pull the levers or invest in the enablers. Frameworks typically failed to acknowledge or challenge prevailing ideologies, and did not seek to identify ways to hold or governments or corporations accountable for failures. Finally, ideas and approaches seem to recur again over the decades, without adding further nuance or analysis. This suggests a need for more upstream, critical and radical approaches to achieve healthy societies.</p>", "<p>\n<bold>Citation:</bold> Nambiar D, Bestman A, Srivastava S, Marten R, Yangchen S, Buse K. How to build healthy societies: a thematic analysis of relevant conceptual frameworks.<italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7451. doi:10.34172/ijhpm.2023.7451</p>" ]	[ "<title>Acknowledgements</title>", "<p> The authors would like to acknowledge Sreejini Jaya for initial data extraction and coding.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Robert Marten and Sonam Yangchen are staff members of the Alliance for Health Policy and Systems Research, a WHO-hosted partnership.</p>", "<title>Funding</title>", "<p> This research received funding from The Alliance for Health Policy and Systems Research.</p>", "<title>Endnotes</title>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nThe Healthy Societies Action Cube, Adapted From the Power Cube by Gaventa.<sup>##UREF##14##18##</sup></p></statement></fig>" ]	[]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) Flow Diagram.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 2. Documents Included in the Review.\n</p></caption></supplementary-material>" ]	[ "<fn-group><fn id=\"fn1\"><p> [1] As described in our companion paper, we carried out Google Scholar searches (using terms ‘Healthy Societies + Framework,’ ‘Health + Framework,’ ‘Health + Societies,’ ‘Healthy Societies + approach,’ ‘Health Systems + Framework’ covering period 1974 to 2022), yielding 31 included documents. Another 25 documents were included proposed by the senior authors as relevant to the study aims or through snowballing.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"ijhpm-12-7451-g001\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7451-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7451-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" United Nations Development Programme (UNDP). Human Development Report 2020: The Next Frontier Human Development and the Anthropocene. New York: UNDP; 2020. "]}, {"label": ["2"], "mixed-citation": [" World Health Organization (WHO). WHO Manifesto for a Health Recovery from COVID-19: Prescriptions and Actionables for a Healthy and Green Recovery. Geneva: WHO; 2021. "]}, {"label": ["3"], "mixed-citation": [" United Nations. UN Research Roadmap for the COVID-19 Recovery: Leveraging the Power of Science for a More Equitable, Resilient and Sustainable Future. Geneva: United Nations; 2020. "]}, {"label": ["4"], "mixed-citation": [" Oxfam. Survival of the Richest: How We Must Tax the Super-Rich Now to Fight Inequality. Oxfam; 2023. "]}, {"label": ["5"], "mixed-citation": [" Chancel L, Piketty T, Saez E, Zucman G. World Inequality Report 2022. World Inequality Lab; 2022. "]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Buse", "Bestman", "Srivastava", "Marten", "Yangchen", "Nambiar"], "given-names": ["K", "A", "S", "R", "S", "D"], "article-title": ["What are healthy societies? A thematic analysis of relevant conceptual frameworks"], "source": ["Int J Health Policy Manag"], "year": ["2023"], "volume": ["12"], "fpage": ["7450"], "pub-id": ["10.34172/ijhpm.2023.7450"]}, {"label": ["7"], "mixed-citation": [" World Health Organization (WHO). Primary Health Care: Report of the International Conference on Primary Health Care, Alma-Ata, USSR, 6-12 September 1978. WHO; 1978. "]}, {"label": ["8"], "mixed-citation": [" WHO Euro. Ottawa Charter for Health Promotion. WHO Euro; 1986. "]}, {"label": ["9"], "mixed-citation": [" Commission on Social Determinants of Health. Closing the Gap in a Generation: Health Equity Through Action on the Social Determinants of Health: Final Report of the Commission on Social Determinants of Health. World Health Organization; 2008. "]}, {"label": ["11"], "mixed-citation": [" Vedung E, Rist RC, Bemelmans-Videc ML. Carrots, Sticks, and Sermons: Policy Instruments and Their Evaluation. New Brunswick: Transaction Publishers; 1998. "]}, {"label": ["12"], "mixed-citation": [" Roberts MJ, Hsiao W, Berman P, Reich MR. Getting Health Reform Right: A Guide to Improving Performance and Equity. New York: Oxford University Press; 2008. "]}, {"label": ["13"], "mixed-citation": [" Althaus C. The Australian Policy Handbook. 5th ed. Crows Nest, NSW: Allen & Unwin; 2013. "]}, {"label": ["14"], "mixed-citation": [" World Health Organization (WHO). Thirteenth General Programme of Work 2019-2023. Geneva: WHO; 2019. "]}, {"label": ["17"], "mixed-citation": [" Lalonde M. A New Perspective on the Health of Canadians: A Working Document. Ottawa: Minister of Supply and Services Canada; 1974. "]}, {"label": ["18"], "person-group": ["\n"], "surname": ["Gaventa"], "given-names": ["J"], "article-title": ["Finding the Spaces for Change: A Power Analysis"], "source": ["IDS Bull"], "year": ["2006"], "volume": ["37"], "issue": ["6"], "fpage": ["23"], "lpage": ["33"], "pub-id": ["10.1111/j.1759-5436.2006.tb00320.x"]}, {"label": ["19"], "mixed-citation": [" Dahlgren G, Whitehead M. European Strategies for Tackling Social Inequities in Health: Levelling up Part 2. Copenhagen: WHO Regional Office for Europe; 2006. "]}, {"label": ["20"], "mixed-citation": [" Solar O, Irwin A. A Conceptual Framework for Action on the Social Determinants of Health. Geneva: WHO; 2010. "]}, {"label": ["21"], "mixed-citation": [" US House of Representatives. A Bold Vision for a Legislative Path Toward Health and Economic Equity. House of Representatives (USA), Chair Richard E. Neal; 2021. "]}, {"label": ["22"], "mixed-citation": [" Siddiqi A, Irwin L, Hertzman C. Total Environment Assessment Model for Early Child Development: Evidence Report for the World Health Organization\u2019s Commission on the Social Determinants of Health. Vancouver, BC: Human Early Learning Partnership (HELP); 2007. "]}, {"label": ["23"], "mixed-citation": [" St\u00e5hl T, Wismar M, Ollila E, Lahtinen E, Leppo K. Health in All Policies: Prospects and Potentials. The European Observatory on Health Systems and Policies; 2006. "]}, {"label": ["24"], "mixed-citation": [" WHO Regional Committee for Europe. Health 2020: A European Policy Framework and Strategy for the 21st Century. WHO Regional Office for Europe; 2013. "]}, {"label": ["29"], "mixed-citation": [" People\u2019s Health Movement. The People\u2019s Charter for Health. Dhaka, Bangladesh: First People\u2019s Health Assembly; 2000. "]}, {"label": ["30"], "mixed-citation": [" WHO Independent High-level Commission on NCDs. Time to Deliver: Report of the WHO Independent High-Level Commission on Noncommunicable Diseases. Geneva, Switzerland: WHO; 2018. "]}, {"label": ["34"], "mixed-citation": [" Mazzucato M, Kattel R, Quaggiotto G, Begovic M. COVID-19 and the Need for Dynamic State Capabilities: An International Comparison. New York: United Nations Development Programme; 2021. "]}, {"label": ["35"], "mixed-citation": [" Newman L, Javanparast S, Baum F, Hutchinson C. Evidence Review: Settings for Addressing the Social Determinants of Health Inequities. Melbourne: VicHealth; 2015. "]}, {"label": ["37"], "mixed-citation": [" Participants of the Conference on \u201cHealth Care for All.\u201d Declaration on \u2018Health Care for All.\u2019 Antwerp: Health Care for All; 2001. "]}, {"label": ["40"], "mixed-citation": [" Purcell K. Evidence Review: Addressing the Social Determinants of Inequities in Tobacco Use. Victoria: Victorian Health Promotion Foundation; 2015. "]}, {"label": ["41"], "mixed-citation": [" de Leeuw E. Intersectoral Action. New York: Oxford University Press; 2021. "], "pub-id": ["10.1093/OBO/9780199756797-0203"]}, {"label": ["42"], "mixed-citation": [" World Health Organization (WHO). Health in All Policies: Helsinki Statement. Framework for Country Action. WHO; 2014. "]}, {"label": ["48"], "mixed-citation": [" Hamilton N, Bhatti T. Population Health Promotion: An Integrated Model of Population Health and Health Promotion. Ottawa: Health Promotion Development Division; 1996. "]}, {"label": ["49"], "person-group": ["\n"], "surname": ["Chen", "Narasimhan"], "given-names": ["L", "V"], "article-title": ["Human security and global health"], "source": ["J Hum Dev"], "year": ["2003"], "volume": ["4"], "issue": ["2"], "fpage": ["181"], "lpage": ["190"], "pub-id": ["10.1080/1464988032000087532"]}, {"label": ["50"], "mixed-citation": [" Roche A, Kostadinov V, Fischer J, Nicholas R. Evidence Review: The Social Determinants of Inequities in Alcohol Consumption and Alcohol-Related Health Outcomes. Victoria: VicHealth; 2015. "]}, {"label": ["52"], "mixed-citation": [" Board on Population Health Public Health Practice, Division of Behavioral Social Sciences Education IoM, National Research Council, Committee on Population, Panel on Understanding Cross-National Health Differences Among High-Income Countries. U.S. Health in International Perspective: Shorter Lives, Poorer Health. Washington, DC: National Academies Press; 2013. "]}, {"label": ["53"], "mixed-citation": [" Welsh J, Ford L, Strazdins L, Friel S. Evidence Review: Addressing the Social Determinants of Inequities in Mental Wellbeing of Children and Adolescents. VicHealth; 2014. "]}, {"label": ["55"], "mixed-citation": [" Raphael D, Bryant T, Mikkonen J, Raphael A. Social Determinants of Health: The Canadian Facts. 2nd ed. Oshawa, ON: Ontario Tech University Faculty of Health Sciences and Toronto, York University School of Health Policy and Management; 2020. "]}, {"label": ["56"], "person-group": ["\n"], "surname": ["Alexandrova"], "given-names": ["A"], "article-title": ["Well-being and philosophy of science"], "source": ["Philos Compass"], "year": ["2015"], "volume": ["10"], "issue": ["3"], "fpage": ["219"], "lpage": ["231"], "pub-id": ["10.1111/phc3.12203"]}, {"label": ["57"], "person-group": ["\n"], "surname": ["Diener", "Chan"], "given-names": ["E", "MY"], "article-title": ["Happy people live longer: subjective well-being contributes to health and longevity"], "source": ["Appl Psychol Health Well Being"], "year": ["2011"], "volume": ["3"], "issue": ["1"], "fpage": ["1"], "lpage": ["43"], "pub-id": ["10.1111/j.1758-0854.2010.01045.x"]}, {"label": ["58"], "person-group": ["\n"], "surname": ["Durayappah"], "given-names": ["A"], "article-title": ["The 3P model: a general theory of subjective well-being"], "source": ["J Happiness Stud"], "year": ["2011"], "volume": ["12"], "issue": ["4"], "fpage": ["681"], "lpage": ["716"], "pub-id": ["10.1007/s10902-010-9223-9"]}, {"label": ["59"], "person-group": ["\n"], "surname": ["Verma"], "given-names": ["R"], "article-title": ["The eight manifestations of GNH: multiple meanings of a development alternative"], "source": ["J Bhutan Stud"], "year": ["2019"], "volume": ["41"], "fpage": ["1"], "lpage": ["33"]}, {"label": ["60"], "mixed-citation": [" The Wellbeing Economy Alliance. About. 2022. "], "uri": ["https://weall.org/about"]}, {"label": ["61"], "mixed-citation": [" Choden T, Kusago T, Shirai K. Gross National Happiness and Material Welfare in Bhutan and Japan. Bhutan: Centre for Bhutan Studies; 2007. "]}, {"label": ["63"], "mixed-citation": [" Government of New Zealand. The Wellbeing Budget 2019. New Zealand Treasury; 2019. "]}, {"label": ["64"], "mixed-citation": [" Ura K, Alkire S, Zangmo T, Wangdi K. An Extensive Analysis of GNH Index. Bhutan: Centre for Bhutan Studies; 2012. "]}, {"label": ["67"], "mixed-citation": [" VicHealth. Promoting Equity in Early Childhood Development for Health Equity Through the Life Course. Victorian Health Promotion Foundation; 2015. "]}, {"label": ["68"], "mixed-citation": [" Attendees of the 9th Global Conference on Health Promotion. Shanghai Declaration on promoting health in the 2030 Agenda for Sustainable Development. 2016. "]}, {"label": ["70"], "mixed-citation": [" Whitehead M, Dahlgren G. Concepts and Principles for Tackling Social Inequities in Health: Levelling up Part 1. Copenhagen: WHO Regional Office for Europe; 2006. "]}, {"label": ["71"], "mixed-citation": [" Kawachi I, Subramanian SV, Kim D. Social capital and health: a decade of progress and beyond. In: Kawachi I, Subramanian SV, Kim D, eds. Social Capital and Health. New York, NY: Springer New York; 2008:1-26. "], "pub-id": ["10.1007/978-0-387-71311-3_1"]}, {"label": ["74"], "mixed-citation": [" Boswell K, Joy I, Lamb C. Keeping Us Well: How Non-Health Charities Address the Social Determinants of Health. The Health Foundation and the Institute of Health Equity, 2017. "]}, {"label": ["75"], "mixed-citation": [" VicHealth. Promoting Equity Through Social Innovation. Victorian Health Promotion Foundation; 2015. "]}, {"label": ["76"], "mixed-citation": [" Friel S, Hattersley L, Ford L, O\u2019Rourke K. Evidence Review: Addressing the Social Determinants of Inequities in Healthy Eating. The National Centre for Epidemiology and Population Health. Canberra: The Australian National University; 2015. "]}, {"label": ["77"], "person-group": ["\n"], "surname": ["Herrick", "Bell"], "given-names": ["C", "K"], "article-title": ["Concepts, disciplines and politics: on \u2018structural violence\u2019 and the \u2018social determinants of health"], "source": ["\u2019 Crit Public Health"], "year": ["2022"], "volume": ["32"], "issue": ["3"], "fpage": ["295"], "lpage": ["308"], "pub-id": ["10.1080/09581596.2020.1810637"]}, {"label": ["78"], "mixed-citation": [" Dyck M. Social Determinants of M\u00e9tis Health. Canada: M\u00e9tis Centre, National Aboriginal Health Organization; 2008. "]}, {"label": ["87"], "person-group": ["\n"], "surname": ["Lacy-Nichols", "Marten"], "given-names": ["J", "R"], "article-title": ["Power and the commercial determinants of health: ideas for a research agenda"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["2"], "fpage": ["e003850"], "pub-id": ["10.1136/bmjgh-2020-003850"]}, {"label": ["88"], "mixed-citation": [" Lukes S. Power: A Radical View. 2nd ed. New York: Palgrave Macmillan; 2005. "]}, {"label": ["91"], "mixed-citation": [" Birn AE, Pillay Y, Holtz TH. Textbook of International Health: Global Health in a Dynamic World. USA: Oxford University Press; 2009. "]}, {"label": ["94"], "mixed-citation": [" Pan American Health Organization (PAHO). Road Map for the Plan of Action on Health in All Policies. Washington, DC: PAHO; 2016. "]}, {"label": ["95"], "mixed-citation": [" Ball K, Carver A, Jackson M, Downing K. Evidence Review: Addressing the Social Determinants of Inequities in Physical Activity and Related Health Outcomes. Carlton South, Victoria: Victorian Health Promotion Foundation; 2015. "]}, {"label": ["96"], "person-group": ["\n"], "surname": ["Alier"], "given-names": ["JM"], "article-title": ["Socially sustainable economic de-growth"], "source": ["Dev Change"], "year": ["2009"], "volume": ["40"], "issue": ["6"], "fpage": ["1099"], "lpage": ["1119"], "pub-id": ["10.1111/j.1467-7660.2009.01618.x"]}, {"label": ["97"], "mixed-citation": [" Raworth K. Doughnut Economics: Seven Ways to Think Like a 21st-Century Economist. White River Junction, Vermont: Chelsea Green Publishing; 2017. "]}, {"label": ["98"], "person-group": ["\n"], "surname": ["O\u2019Neill", "Fanning", "Lamb", "Steinberger"], "given-names": ["DW", "AL", "WF", "JK"], "article-title": ["A good life for all within planetary boundaries"], "source": ["Nat Sustain"], "year": ["2018"], "volume": ["1"], "issue": ["2"], "fpage": ["88"], "lpage": ["95"], "pub-id": ["10.1038/s41893-018-0021-4"]}, {"label": ["99"], "person-group": ["\n"], "surname": ["Hickel"], "given-names": ["J"], "article-title": ["Is it possible to achieve a good life for all within planetary boundaries?"], "source": ["Third World Q"], "year": ["2019"], "volume": ["40"], "issue": ["1"], "fpage": ["18"], "lpage": ["35"], "pub-id": ["10.1080/01436597.2018.1535895"]}, {"label": ["100"], "person-group": ["\n"], "surname": ["Gill", "Benatar"], "given-names": ["SR", "SR"], "article-title": ["Reflections on the political economy of planetary health"], "source": ["Rev Int Polit Econ"], "year": ["2020"], "volume": ["27"], "issue": ["1"], "fpage": ["167"], "lpage": ["190"], "pub-id": ["10.1080/09692290.2019.1607769"]}, {"label": ["101"], "mixed-citation": [" Harvey F. Emissions Divide Now Greater Within Countries Than Between Them \u2013 Study. The Guardian; 2023. "], "uri": ["https://www.theguardian.com/environment/2023/jan/31/emissions-divide-now-greater-within-countries-than-between-them-study?CMP=Share_iOSApp_Other"]}, {"label": ["102"], "mixed-citation": [" United Nations Human Rights Council. The Human Right to a Clean, Healthy and Sustainable Environment (A/HRC/48/L.23/Rev.1). 48th session of the Human Rights Council: Resolutions, decisions and President\u2019s statements 2021. "], "uri": ["https://www.ohchr.org/EN/HRBodies/HRC/RegularSessions/Session48/Pages/ResDecStat.aspx"]}, {"label": ["103"], "mixed-citation": [" World Health Organization (WHO). Report of a Conference on Intersectoral Action for Health: A Cornerstone for Health-for-All in the Twenty-First Century, 20-23 April 1997, Halifax, Nova Scotia, Canada. WHO; 1997. "]}, {"label": ["104"], "mixed-citation": [" Abdalla S, Mutaz M. Road Map for Implementing Health in All Policies in Sudan. Sudan: Public Health Institute, Federal Ministry of Health; 2014. "]}, {"label": ["105"], "person-group": ["\n"], "surname": ["Loewenson", "Villar", "Baru", "Marten"], "given-names": ["R", "E", "R", "R"], "article-title": ["Engaging globally with how to achieve healthy societies: insights from India, Latin America and East and Southern Africa"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["4"], "fpage": ["e005257"], "pub-id": ["10.1136/bmjgh-2021-005257"]}, {"label": ["106"], "mixed-citation": [" Alliance for Health Policy and Systems Research SCI. Systems for Health: Everyone Has a Role. World Health Organization; 2022. "]}]	{ "acronym": [], "definition": [] }	106	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Nov 7; 12:7451	oa_package/64/99/PMC10699821.tar.gz
PMC10699822	0	[ "<title>Background</title>", "<p> Benchmarking, a common systematic practice that allows organizations to measure and compare key practice metrics to understand what, how and where changes are needed to improve performance, has been increasing employed on drug regulatory systems to achieve pharmaceutical system strengthening and universal health coverage.<sup>##REF##32974367##1##</sup> Drug regulatory systems operated by national regulatory authorities (NRAs) play an integral role in the pharmaceutical system destined to ensure equitable access to essential medical products, vaccines and technologies of assured quality, safety, efficacy and cost-effectiveness, and their scientifically sound and cost-effective use.<sup>##UREF##0##2##</sup> The quest to excel the regulatory practice is further heightened amid the challenges brought about by, among other forces, the innovation and technology advancement, and major public health incidents.</p>", "<p> By comparing their performance and capacities against a reference point, NRAs can determine how they perform, their weaknesses and strengths, and how to prioritise actions to continuously improve quality use of pharmaceutical products with respect to the local context.<sup>##UREF##1##3##</sup> It is envisioned that benchmarking NRAs would also benefit the development of strategies for promoting regulatory practice standardization for transnational harmonization, reliance and recognition, as well as system resilience at country level in response to globalization of pharmaceutical products.<sup>##REF##28025324##4##,##REF##34002090##5##</sup></p>", "<p> Drawing on the integrated approach of benchmarking and the experiences of public sector benchmarking,<sup>##UREF##2##6##, ####UREF##3##7##, ##UREF##4##8##, ##UREF##5##9####5##9##</sup> the practices of benchmarking drug regulatory capacities are complicated. First, to achieve a meaningful outcome of benchmarking, it is imperative to have a realistic decision-making about the development endpoint of the NRA (whether it be a “gatekeeper” mitigating drug-related risks to the public health and/or as an “enabler” supporting research and innovation that weights on the different functionalities of the system).<sup>##UREF##6##10##</sup> The complexity in operating benchmarking NRAs is further compounded by the different choices of reference points and tools for measuring functionalities, the means to collect data according to the predefined parameters, and the process of analysis in order to draw reliable comparison against the reference point. More importantly, it is the efforts put into learning and changes implementation based on evaluation results that matter in the quest for better capacities through benchmarking.</p>", "<p> Given the growing interests in benchmarking drug regulatory systems, it becomes highly relevant to see what research and country experiences has had to say about this phenomenon. Previous literature mainly focused on a number of aspects of regulatory benchmarking including: the introduction of the practice of benchmarking NRA<sup>##UREF##7##11##</sup>; the application of benchmarking NRAs for different purposes such as public health emergencies<sup>##REF##35725614##12##,##REF##34485350##13##</sup> and pharmacovigilance<sup>##REF##35723862##14##,##REF##31919794##15##</sup>; various benchmarking tools or programmes such as the Global Benchmarking Tool (GBT) developed by the World Health Organization (WHO),<sup>##UREF##8##16##</sup> and Optimizing Efficiencies in Regulatory Agencies (OpERA)<sup>##UREF##9##17##</sup>; and the country experiences of assessing and comparing regulatory capacities using benchmarking.<sup>##REF##31919794##15##,##REF##36434730##18##, ####REF##32865804##19##, ##REF##34434109##20####34434109##20##</sup> However, such literature is yet to be systematically analyzed and reviewed to depict an overall research landscape about how regulatory capacities can be approved through benchmarking NRAs. This is especially concerning when considering that, according to the WHO, 70% of its member states are not able to effectively and efficiently regulate medical products in their nations, especially in many low- and middle-income countries.<sup>##UREF##10##21##,##UREF##11##22##</sup></p>", "<p> As such, this study aimed to answer the following questions: What are the scopes of regulatory capacities covered by benchmarking NRAs? What tools are available for benchmarking regulatory capacities? What benefits have the NRAs seen from benchmarking regulatory capacities? And what is the most recent development in the benchmarking practices? For the purpose of this study, in consultation with the resolution WHA 67.20 by the WHO, benchmarking of regulatory systems implies “<italic toggle=\"yes\">a structured and documented process by which national drug regulatory authorities can identify and address gaps with the goal of reaching a level of regulatory oversight commensurate with a stable, well-functioning and integrated regulatory system.</italic>”<sup>##UREF##12##23##</sup></p>" ]	[ "<title>Methods and Materials</title>", "<p> This study employed an integrative and critical review of the research on benchmarking drug regulatory capacities in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.<sup>##REF##15649667##24##</sup> An integrative literature review was considered appropriate for the purpose of the study because it focused on combining, critiquing, and studying literature on the topic of benchmarking regulatory capacities in an integrated way in order to generate new frameworks and perspectives on this topic.<sup>##UREF##13##25##</sup></p>", "<title> Search Strategy</title>", "<p> Identification of the journal articles eligible for this review study consisted of the following steps. The primary concepts in this review included “benchmarking” and “regulatory capacity.” Based on preliminary research, the potential synonyms of “benchmarking” may include “benchmark,” “ranking,” “index,” “performance,” “indicator,” “evaluation,” and “assessment.” A pilot search for each term was conducted in PubMed and Web of Science to determine the frequency and relevance of each term. The four most frequent and relevant terms (“benchmark,” “ranking,” “index,” and “indicator”) were chosen to be included in the search strategy. Similarly, the terms “drug regulation,” “medicine regulation,” “regulatory authority,” “regulatory agency,” and “regulatory capacity” were used in the search strategy to reflect the concept of “regulatory capacity.” The search terms used in Chinese databases were: ((监管能力 OR 监管体系 OR 监管措施) AND (框架 OR 指标 OR 工具 OR 模型) AND (药品)).</p>", "<p> Six databases (PubMed, Scopus, Medline, Web of Science, Science Direct, and China National Knowledge Infrastructure) were searched for eligible literature since the database inception till 30 November 2022. To ensure an effective search, Medical Subject Headings terms, synonyms and keywords related to the two concepts were used to develop a comprehensive search strategy. Terms of each concept were combined using OR, then the two concepts were combined using AND. In addition, reference lists and citations of included literature were screened to identify possibly eligible studies for inclusion.</p>", "<p> Furthermore, international organizations and government agencies which had previously issued formal regulatory benchmarking tools or programmes were identified from the eligible studies and searched for eligible documents to be included in this study. The search covered the websites of such entities including the WHO (<uri xlink:href=\"https://www.who.int/\">https://www.who.int/</uri>), the Organization for Economic Co-operation and Development (OECD) (<uri xlink:href=\"https://www.oecd.org/\">https://www.oecd.org/</uri>), the Heads of Medicine Agencies (HMA) (<uri xlink:href=\"https://www.hma.eu/\">https://www.hma.eu/</uri>), the Centre for Innovation in Regulatory Science (CIRS) (<uri xlink:href=\"https://www.cirsci.org/\">https://www.cirsci.org/</uri>), the US Government Accountability Office (GAO) (<uri xlink:href=\"https://www.gao.gov/\">https://www.gao.gov/</uri>).</p>", "<title> Inclusion and Exclusion Criteria</title>", "<p> Literature, published in either English or Chinese, was included if it directly discussed about benchmarking drug regulatory capacities, or employed benchmarking approach to compare different regulatory systems for the purpose of identifying gaps and making improvement. Literature which investigated, evaluated or compared drug regulatory systems without employing benchmarking approach or posing any direct or indirect implications for benchmarking practice were excluded.</p>", "<title> Screening Process</title>", "<p> Literature was screened in compliance with the PRISMA statement. After removing the duplication, two authors (JS and XC) independently screened the titles and abstracts to identify literature that met the inclusion criteria. Full texts of potentially relevant articles were retrieved for detailed assessment. Discrepancies were discussed and resolved by agreement in consultation with 2 others authors (HH and COLU).</p>", "<title> Data Extraction and Analysis</title>", "<p> The following data was extracted from the included articles into an Excel table: title, authors, year of publication, paper type/study design, purpose, underlying evaluation tools or frameworks, key indicators, current problems, major findings, and major implications/comments. For eligible studies, 2 authors (JS and XC) independently extracted data and any disagreements were resolved by seeking confirmation from another author (COLU). Different tools or programmes collected were verified and presented into seven criteria categories of the NRAs for capacity building, including: the name of tool/programme, issuing organization and time, scope of application, purpose, focus areas, compositions and quality assessment methods (if applicable). Such information was then used for in-depth and comparative analyses.</p>" ]	[ "<title>Results</title>", "<title> Literature Selection</title>", "<p> Nine hundred and fifty-six records were identified from different databases, including 838 English initial records and 118 Chinese initial records. Upon removal of 468 duplicate articles, 488 records were proceeded to further screening by title and abstract, and, as a result, another 386 records were excluded. After full-text screening of the remaining 102 records, 59 records that did not related to benchmarking drug regulatory capacities were excluded. Ultimately, 43 eligible studies were included in this review (##FIG##0##Figure 1##). Furthermore, 6 documents about regulatory benchmarking tools or programmes retrieved from the websites of international organizations and government agencies were also included in this review for further analysis.</p>", "<title> Literature Characteristics</title>", "<p> The 43 articles and 6 additional records included in this review were published between 2005 and 2022. The description of 43 articles is presented in ##TAB##0##Table 1##.<sup>##UREF##7##11##, ####REF##35725614##12##, ##REF##34485350##13##, ##REF##35723862##14##, ##REF##31919794##15####31919794##15##,##REF##36434730##18##, ####REF##32865804##19##, ##REF##34434109##20####34434109##20##,##REF##32610811##26##, ####UREF##14##27##, ##REF##35657484##28##, ##REF##33300773##29##, ##REF##34814672##30##, ##REF##34645359##31##, ##UREF##15##32##, ##UREF##16##33##, ##UREF##17##34##, ##REF##32617911##35##, ##REF##34472048##36##, ##REF##33387356##37##, ##REF##32591289##38##, ##REF##32865802##39##, ##REF##32939288##40##, ##REF##32519282##41##, ##UREF##18##42##, ##UREF##19##43##, ##REF##30923501##44##, ##UREF##20##45##, ##REF##29422861##46##, ##UREF##21##47##, ##REF##28721199##48##, ##UREF##22##49##, ##UREF##23##50##, ##UREF##24##51##, ##UREF##25##52##, ##UREF##26##53##, ##UREF##27##54##, ##UREF##28##55##, ##REF##30235555##56##, ##UREF##29##57##, ##UREF##30##58##, ##UREF##31##59##, ##REF##16253133##60####16253133##60##</sup> The research design included literature review (n = 3),<sup>##REF##35657484##28##,##UREF##15##32##,##UREF##22##49##</sup> expert interview (n = 1),<sup>##REF##28721199##48##</sup> empirical analysis (n = 2),<sup>##UREF##19##43##,##UREF##25##52##</sup> comparative analysis (n = 7),<sup>##REF##35725614##12##,##REF##31919794##15##,##REF##32617911##35##,##UREF##18##42##,##UREF##21##47##,##UREF##30##58##,##UREF##31##59##</sup> retrospective analysis (n = 2),<sup>##REF##32865804##19##,##REF##32519282##41##</sup> questionnaire (n = 10),<sup>##REF##35723862##14##,##REF##34434109##20##,##REF##32610811##26##,##UREF##14##27##,##REF##33387356##37##, ####REF##32591289##38##, ##REF##32865802##39##, ##REF##32939288##40####32939288##40##,##UREF##28##55##,##REF##30235555##56##</sup> description analysis (n = 6),<sup>##UREF##7##11##,##REF##34485350##13##,##UREF##16##33##,##REF##34472048##36##,##UREF##20##45##,##REF##16253133##60##</sup> and mixed methods (n = 12).<sup>##REF##36434730##18##,##REF##33300773##29##, ####REF##34814672##30##, ##REF##34645359##31####34645359##31##,##UREF##17##34##,##REF##30923501##44##,##REF##29422861##46##,##UREF##23##50##,##UREF##24##51##,##UREF##26##53##,##UREF##27##54##,##UREF##29##57##</sup></p>", "<p> As reported in 22 of the 43 included studies, benchmarking had been employed to assess the drug regulatory system in a specific country including developed countries — including UK (n = 1), Canada (n = 1), and Finland (n = 1) — and developing countries — including China (n = 11), Eritrea (n = 1), Myanmar (n = 1), Rwanda (n = 1), Turkish (n = 1), Zimbabwe (n = 1), Malaysia (n = 1), Iran (n = 1), and Brazil (n = 1). Comparing drug regulatory systems using benchmarking at regional level had also been reported for the Caribbean Community (CARICOM) region (n = 1), East Africa (n = 1), South Africa (n = 3), and West Africa (n = 1). Furthermore, cross-country benchmarking based on international organizations, such as Asia-Pacific Economic Cooperation (APEC) (n = 2) and CIRS (n = 1), were also reported in 15 studies.</p>", "<p> In terms of benchmarking tools, 11 of the 43 included studies assessed the drug regulatory systems based on the GBT, of which 1 study combined indicators from the GBT and the Benchmarking of European Medicines Agencies (BEMA) (n = 1), 2 studies combined GBT indicators and OpERA tool (n = 2) and 2 studies combined GBT indicators and other indicators tool (n = 2). Four studies employed the OpERA tool to evaluated the NRAs’ regulatory capabilities and 14 studies employed other organizations evaluation indicators or methods. The remaining 16 studies used self-developed indicators or methods when conducting benchmarking.</p>", "<title> The Main Themes of the Included Literature </title>", "<p> After review and analysis of the included literature, 3 main themes related to benchmarking regulatory capabilities were identified: introduction of the concepts or methods of benchmarking; the application of benchmarking for internal assessment; and the application of benchmarking for external evaluation.</p>", "<title> Introduction of the Concepts or Methods of Benchmarking</title>", "<p> Four studies introduced benchmarking and highlighted the advantages and benefits of applying benchmarking methods or tools in the assessment of regulatory capability. For instance, among these 4 studies, 2 of them focused on explaining the GBT,<sup>##REF##31919794##15##,##UREF##14##27##</sup> 1 study emphasised on the utilization of three-party evaluation systems,<sup>##UREF##16##33##</sup> and 1 study explored the relationship between drug regulatory capabilities and regulatory performance.<sup>##UREF##26##53##</sup></p>", "<title> The application of Benchmarking for Internal Assessment </title>", "<p> A total of 19 studies were conducted to internally assess the regulatory capabilities of NRAs. Of these, 6 studies were dedicated to observing the establishment of the national-level regulatory system.<sup>##REF##36434730##18##,##REF##34814672##30##,##REF##32617911##35##,##UREF##23##50##,##UREF##27##54##,##UREF##29##57##</sup> Additionally, 5 studies were designed to analyse the drug review process.<sup>##REF##32865804##19##,##REF##34645359##31##,##UREF##17##34##,##REF##32939288##40##,##UREF##21##47##</sup> Two studies focused on measuring the effectiveness of capability building in healthcare,<sup>##UREF##19##43##,##REF##16253133##60##</sup> while 3 studies concentrated on post-marketing surveillance,<sup>##UREF##24##51##,##UREF##25##52##,##UREF##28##55##</sup> particularly regarding the circulation and safety of drugs. One study aimed to enhance the vaccine regulatory system in China,<sup>##UREF##15##32##</sup> another aimed to evaluate the level of adherence to good review practices (GRevP),<sup>##REF##29422861##46##</sup> and 1 study aimed to identify the allocation of resources for capability building.<sup>##UREF##22##49##</sup></p>", "<title> The Application of Benchmarking for External Evaluation</title>", "<p> Drug regulatory capability of various countries or regions were investigated in 20 studies. At the national level, 4 studies aimed to evaluation the implementation of regulatory standards, including the Caribbean Regulatory System,<sup>##REF##32865802##39##</sup> GRevP,<sup>##REF##30235555##56##</sup> Certificate of pharmaceutical product,<sup>##UREF##18##42##</sup> Pharmacovigilance (PV) system master file.<sup>##REF##35723862##14##</sup> Three studies aimed to evaluate the current regulatory situation evaluation and analyse the main challenge or problems faced by NRAs.<sup>##REF##34814672##30##,##REF##32519282##41##,##UREF##20##45##</sup> Additionally, the capacity required for effective regulatory decision-making process was also a topic of interest in 2 studies.<sup>##REF##32610811##26##,##REF##28721199##48##</sup> At the operation level, 7 studies were designed to identify the problems of the drug review process in the target area,<sup>##REF##34434109##20##,##REF##33300773##29##,##REF##34645359##31##,##REF##32591289##38##,##REF##30923501##44##,##UREF##30##58##,##UREF##31##59##</sup> of which four studies focused on the new drug registration process.<sup>##UREF##13##25##,##UREF##19##43##,##UREF##29##57##,##UREF##30##58##</sup> The remaining 4 studies aimed to assess the regulatory functionalities related to pharmacovigilance,<sup>##REF##35657484##28##,##REF##33387356##37##</sup> vaccines<sup>##UREF##7##11##</sup> and clinical trials.<sup>##REF##35725614##12##</sup></p>", "<title> Tools Used for Benchmarking</title>", "<p> According to the 6 additional records retrieved from WHO (n = 1),<sup>##UREF##8##16##</sup> OECD (n = 1),<sup>##UREF##32##61##</sup> HMA (n = 1),<sup>##UREF##33##62##</sup> CIRS (n = 1),<sup>##UREF##9##17##</sup> GAO (n = 2),<sup>##UREF##34##63##,##UREF##35##64##</sup> a total of 5 benchmarking tools were identified (##TAB##1##Table 2##). These included the Global GBT Revision VI,<sup>##UREF##8##16##</sup> the indicators of Regulatory Policy and Governance (iREG),<sup>##UREF##32##61##</sup> the BEMA,<sup>##UREF##33##62##</sup> OpERA programme,<sup>##UREF##9##17##</sup> and the report evaluated the Workforce planning and Scientific-integrity-related procedures and training.<sup>##UREF##34##63##,##UREF##35##64##</sup> The 5 tools or programs were issued from 2013 to 2022. The number of indicators included in these tools or programs range from 3 to 288.</p>", "<p> The benchmarking tools or programmes identified in this study were developed or recognised by a variety of international organizations, third-party professional organizations, and independent government departments, each with different purposes and focuses. Particularly, the GBT was developed to assess the national regulatory frameworks in terms of regulatory functions, while iREG was applicable to the investigation of the processes in relation to national regulatory policy. The tools issued by OpERA and GAO focused more specifically on the review processes and procedures. In addition, HMA was operated to liaise the regulatory frameworks of pharmaceutical product under the European Union (EU) and European Medicines Agency (EMA), while BEMA aimed to advance the standards of regulatory practices for individual member state bodies focusing on benchmarking management systems, drug authorization, pharmacovigilance, and inspection services. Further description of the assessment tools or programmes is presented in ##TAB##1##Table 2##.</p>", "<title> Functions, Indicators, and Sub-indicators Covered by the Benchmarking Tools </title>", "<p> The GBT measured 9 functions across an overarching national regulatory system framework and regulatory functions (including national regulatory system; registration and marketing authorization; pharmacovigilance; market surveillance and control; licensing of establishments; regulatory inspections; laboratory testing; clinical trials oversight; and lot release of vaccines) by using 9 indicator categories (legal provisions, regulations and guidelines; organization and governance; policy and strategic planning; leadership and crisis management; quality and risk management system; resources; regulatory process; transparency, accountability and commination; and monitoring progress and assessing outcomes and impact) outlining 268 sub-indicators.</p>", "<p> The iREG indicators measured three key principles (including stakeholder engagement, regulatory impact analysis and ex post evaluation) using a total of 61 sub indicators. With BEMA, the key performance indicators and specific performance indicators were not separately listed but embedded in 14 sub-indicators of GBT and iREG. In the OpERA programme, the five indicators for evaluating the regulatory process of drug review and approval aligned with the GBT M06 (Mechanism in place to monitor regulatory performance and output), while the indicators for the workforce planning and scientific-integrity-related procedures and training were derived from the GBT RS06 (Human resources to perform regulatory activities) and RS10 (Mechanism in place to monitor regulatory performance and output).</p>", "<p> An integrative analysis of the above-mentioned 5 benchmarking tools and programmes provided an overall landscape of the benchmarking scope. As shown in ##FIG##1##Figure 2##, an integrated benchmarking framework comprised of a total of 12 functions (including 4 at system level and 8 at operation level), 9 indicator categories and 382 sub-indicators.</p>", "<p> The commonalities across the regulatory benchmarking tools and programmes in terms of the functions and indicators covered are depicted in ##FIG##1##Figure 2##. As shown, benchmarking “<italic toggle=\"yes\">1. Regulatory system</italic>” at the system level and “<italic toggle=\"yes\">5. Marketing authorization</italic>” at the operation level were of common interests to at least 3 benchmarking tools or programmes. Other functions such as “<italic toggle=\"yes\">2. Stakeholder engagement</italic>,” “<italic toggle=\"yes\">3. Regulatory impact assessment,</italic>” and “<italic toggle=\"yes\">4. Ex post evaluation</italic>” at the system level and “<italic toggle=\"yes\">11. Clinical trials</italic>” at the operation level were also of common interests to at least 2 benchmarking tools or programmes. Comparatively, the GBT was the most comprehensive benchmarking tool covering 9 out of the 12 functions.</p>", "<p> With regards to the indicators, it is also worth noting that all the indicators identified from the selected benchmarking tools or programmes corresponded to the 9 indicator categories in the GBT. This is demonstrated by the lines connecting the functions and the GBT indicator categories as shown in ##FIG##1##Figure 2##. When considering the number of connecting lines of each of the GBT indicator category, it is also noted that the GBT indicator categories “<italic toggle=\"yes\">1. Legal provisions, regulations and guidelines</italic>,” “<italic toggle=\"yes\">2. Organization and governance</italic>,” “<italic toggle=\"yes\">6. Resources</italic>,” “<italic toggle=\"yes\">7. Regulatory process</italic>,” “<italic toggle=\"yes\">8. Monitor process and access outcomes </italic>&<italic toggle=\"yes\"> impact</italic>,” and “<italic toggle=\"yes\">9. Transparency, accountability and communication</italic>” were used most often to measure different functions of a regulatory system. More detailed information about the indicator categories used to measure the 12 functions of is provided in Table S1 of ##SUPPL##0##Supplementary file 1##. Importantly, it can be seen that the assessment of any function in a drug regulatory system is a complex evaluation approach involving not one but multiple dimensions of indicators. More detailed description of the functions, indicators and sub-indicators is provided in Table S2.</p>", "<title> Key Functions and Indicators Employed in the Benchmarking Studies </title>", "<p> Among the 43 included studies, 15 studies covered multiple regulatory functions<sup>##UREF##7##11##,##REF##34485350##13##,##REF##31919794##15##,##REF##36434730##18##,##REF##34434109##20##,##UREF##14##27##,##UREF##15##32##, ####UREF##16##33##, ##UREF##17##34####17##34##,##UREF##18##42##,##REF##30923501##44##,##UREF##20##45##,##UREF##23##50##,##UREF##27##54##,##UREF##29##57##</sup> while the remaining 28 studies focused on only 1 function when evaluating the regulatory capacities of NRAs.<sup>##REF##35725614##12##,##REF##35723862##14##,##REF##32865804##19##,##REF##32610811##26##,##REF##35657484##28##, ####REF##33300773##29##, ##REF##34814672##30##, ##REF##34645359##31####34645359##31##,##REF##32617911##35##, ####REF##34472048##36##, ##REF##33387356##37##, ##REF##32591289##38##, ##REF##32865802##39##, ##REF##32939288##40##, ##REF##32519282##41####32519282##41##,##UREF##19##43##,##REF##29422861##46##, ####UREF##21##47##, ##REF##28721199##48##, ##UREF##22##49####22##49##,##UREF##24##51##, ####UREF##25##52##, ##UREF##26##53####26##53##,##UREF##28##55##,##REF##30235555##56##,##UREF##30##58##, ####UREF##31##59##, ##REF##16253133##60####16253133##60##</sup> Apart from 6 of the studies<sup>##UREF##7##11##,##REF##34485350##13##,##REF##36434730##18##,##UREF##14##27##,##UREF##15##32##,##UREF##18##42##</sup> which fully adopted the 9 GBT indicator categories when evaluating the functions of interest, the remaining studies adopted only some of the GBT indicator categories and sub-indicators whenever deemed relevant by the researchers. In 5 studies,<sup>##REF##35725614##12##,##REF##31919794##15##,##REF##33300773##29##,##UREF##16##33##,##UREF##17##34##</sup> a combination of indicators from different benchmarking tools or programmes were used as measurements of the regulatory capacities. More detailed description about the key functions and indicators employed in the benchmarking studies is provided Table S3.</p>", "<title> Most Common Problems and Recommended Actions Based on Benchmarking Results</title>", "<p> Among the 43 studies, some common problems or challenges in drug regulation had been repeatedly reported and, in some occasions, recommended actions based on the benchmarking results had been proposed accordingly. As shown in ##TAB##2##Table 3##, there were 6 key aspects identified as the major areas of concern which included: legal provision; regulatory process; resources; cooperation and communication; and stakeholder engagement.</p>", "<p> With respect to legal prevision, 6 studies identified four main types of regulatory issues including the lack of flexible regulatory policies or guidelines (n = 2),<sup>##UREF##23##50##,##UREF##24##51##</sup> pharmacovigilance systems (n = 2),<sup>##REF##35657484##28##,##REF##34472048##36##</sup> the framework of emergence preparedness (n = 1),<sup>##REF##35725614##12##</sup> and a lack of quality management systems (n = 1).<sup>##REF##36434730##18##</sup> Correspondingly, 1 study recommended advancing the establishment of policy and legal framework,<sup>##REF##32939288##40##</sup> while 10 studies focused on the promotion of practical strategies and guideline.<sup>##REF##35725614##12##,##REF##34485350##13##,##UREF##14##27##,##REF##33300773##29##,##REF##34645359##31##,##UREF##15##32##,##REF##32591289##38##,##UREF##23##50##,##UREF##26##53##,##REF##30235555##56##</sup></p>", "<p> Regarding the regulatory processes, 17 studies identified 10 common problems, with a significant emphasis on the prolonged product review time (n = 6),<sup>##REF##32865804##19##,##REF##34645359##31##,##REF##32939288##40##,##REF##32519282##41##,##REF##30923501##44##,##REF##29422861##46##</sup> and 8 studies also pointed to setting milestone for review time.<sup>##REF##32865804##19##,##REF##33300773##29##,##REF##34645359##31##,##REF##32617911##35##,##REF##33387356##37##,##REF##32519282##41##,##REF##30923501##44##,##REF##29422861##46##</sup> Twenty-two studies sought to optimise the regulatory processes and practice,<sup>##REF##34002090##5##,##REF##36434730##18##, ####REF##32865804##19##, ##REF##34434109##20####34434109##20##,##REF##33300773##29##,##REF##34645359##31##, ####UREF##15##32##, ##UREF##16##33####16##33##,##REF##32617911##35##,##REF##33387356##37##,##REF##32865802##39##, ####REF##32939288##40##, ##REF##32519282##41####32519282##41##,##REF##30923501##44##,##REF##29422861##46##,##UREF##21##47##,##UREF##24##51##,##UREF##25##52##,##REF##30235555##56##, ####UREF##29##57##, ##UREF##30##58##, ##UREF##31##59####31##59##</sup> but did not provide specific implementation details.</p>", "<p> The shortage of human resources,<sup>##REF##36434730##18##,##UREF##14##27##,##REF##32865802##39##,##REF##32939288##40##,##UREF##18##42##</sup> training or education<sup>##REF##36434730##18##,##REF##33300773##29##,##REF##32865802##39##,##UREF##21##47##,##REF##28721199##48##,##UREF##26##53##,##UREF##29##57##</sup> financial resources<sup>##UREF##18##42##,##UREF##22##49##</sup> and equipment or technique resources<sup>##REF##36434730##18##,##REF##33300773##29##</sup> were reported to exert a negative impact on regulation. In addition, the lack of transparency and communication,<sup>##REF##35723862##14##,##REF##33300773##29##,##REF##34645359##31##</sup> as well as the lack of involvement of key stakeholders,<sup>##REF##33387356##37##</sup> were identified as common problems upon benchmarking. Nineteen studies proposed enhancing communication and cooperation at all levels<sup>##REF##35725614##12##,##REF##35723862##14##,##REF##32610811##26##,##REF##35657484##28##,##REF##33300773##29##,##REF##34645359##31##,##UREF##15##32##,##REF##32617911##35##,##REF##32591289##38##,##REF##32865802##39##,##UREF##18##42##, ####UREF##19##43##, ##REF##30923501##44##, ##UREF##20##45##, ##REF##29422861##46####29422861##46##,##REF##28721199##48##,##UREF##25##52##,##REF##30235555##56##,##REF##16253133##60##</sup> while 5 studies encouraged stakeholder participation to drive regulatory decision-making.<sup>##REF##35723862##14##,##REF##31919794##15##,##REF##35657484##28##,##REF##32591289##38##,##REF##28721199##48##</sup></p>", "<p> Moreover, 1 study mentioned the gaps between the academic outcomes of publications in peer reviewed journals or successful grant applications and the resolution of regulatory practices.<sup>##REF##16253133##60##</sup> Nevertheless, it is worth noting that not every common problem was addressed with specific recommended action.</p>", "<title> Anticipated Outcomes of Benchmarking Reported in the Included Studies</title>", "<p> Eighteen studies assessed the outcomes when applying benchmarking for regulatory improvement, including the promotion of regulatory reliance and harmonization (n = 7),<sup>##UREF##7##11##,##REF##34485350##13##,##REF##35723862##14##,##REF##35657484##28##,##REF##32617911##35##,##REF##32865802##39##,##UREF##20##45##</sup> the enhancement of regulatory transparency (n = 4),<sup>##UREF##14##27##,##REF##33300773##29##,##REF##34645359##31##,##REF##30923501##44##</sup> the reducing of timelines and improving patients’ access to new medicines (n = 3),<sup>##UREF##7##11##,##REF##33300773##29##,##UREF##15##32##</sup> the optimization of publicly available information (n = 3),<sup>##UREF##14##27##,##REF##30923501##44##,##UREF##25##52##</sup> and the improvement of pharmaceutical trade (n = 1).<sup>##UREF##7##11##</sup></p>" ]	[ "<title>Discussion</title>", "<p> This literature review reaffirms that benchmarking has been employed by many NRAs as an important strategy in quality monitoring and management in pursuit of improvement in regulatory capacities. Further analysis of the included literature has depicted an overall research landscape on this phenomenon covering the main purposes of benchmarking, different benchmarking tools and comparison of the corresponding indicators, key indicators selected for benchmarking, major areas of improvement based on benchmarking results, most common recommended actions following up benchmarking practices, and anticipated of benchmarking outcomes. An integrative analysis of such findings gave rise to a framework for decision-makers in NRAs when deciding why and how benchmarking should be undertaken (##FIG##2##Figure 3##) which will be further discussed in the following. Nevertheless, the literature included in this review did not provide any empirical findings showing that NRAs had benefited from benchmarking regulatory capacities.</p>", "<title> The Decision-Making Framework of Benchmarking </title>", "<p> Using benchmarking to guide the advancement of pharmaceutical regulatory system echoed with the increasing emphasis of policy-makers on “evidence-informed health policy-making” (EIHP) to inform the decision-making in the contemporary healthcare.<sup>##REF##15913387##65##,##REF##20018099##66##</sup> The EIHP approach aims to fully inform the best available research evidence as an input to the healthcare policy-making process. As shown in the current review, more and more NRAs currently include the benchmarking results as one of evidence in their regulatory capacity monitoring and management.</p>", "<p> As shown in ##FIG##2##Figure 3##, the decision-making about benchmarking regulatory capacities involved multifaceted considerations of the benchmarking scope in terms of functionalities, the choice of benchmarking tools and reference points which would collectively determine the benchmarking outcome. At the functionality level, the benchmarking scope may encompass “strategy” (focus on the strategic goals and leadership of advancing NRAs such as the vaccine regulatory system<sup>##UREF##15##32##</sup>), “operation” (focus on the key processes to eliminate the weaknesses of regulation such as the PV system,<sup>##REF##35723862##14##,##REF##35657484##28##,##REF##34472048##36##,##REF##32591289##38##</sup> “performance” (focus on the key performance indicators such as the delays in assessing applications owing to the staff manpower<sup>##REF##32939288##40##</sup>) and “training” (focus on priority areas of capacity building such as workforce planning and training<sup>##UREF##9##17##,##REF##33300773##29##</sup>). Another perspective when deciding on the scope might refer to pre-marketing and post-marketing functionalities of an NRA.</p>", "<p> The next important consideration when conducting benchmarking in drug regulation practice is the choice of reference points. When benchmarking was conducted internally, previous benchmarking results could be used as a baseline for continuous monitoring of performance to identify any changes in regulatory practice over time. Cross-country benchmarking, on the other hand, could be used to inform actions for regulatory practice standardization that promotes collaboration and harmonization across a region or a consortium. Coordinated efforts across NRAs in improving regulatory practice in common areas have been recognised as an important measure to facilitate regulatory reliance and harmonization at regional level.<sup>##UREF##7##11##,##REF##34485350##13##,##REF##32865802##39##,##UREF##20##45##</sup></p>", "<p> It was also found that benchmarking was conducted with different tools and indicators which were selected based on the functionalities of interests. A range of benchmarking tools have been made available and it remained at decision-maker’s discretion about the choice of tools and the combination of indicators from readily available benchmarking tools or self-developed initiative as they were deemed fit the purpose of benchmarking.</p>", "<p> Comprehensive benchmarking against an international benchmarking framework would further benefit the credibility and international recognition of the NRAs. For instance, following Singapore which reached Maturity Level 4 in medicines in February 2022 which is the highest level achievable for regulatory system evaluation against the WHO’s GBT, the Ministry of Food and Drug Safety of the Republic of Korea also announced in November 2022 that it had reached Maturity Level 4, in both medicines and vaccines regulations.<sup>##UREF##36##67##</sup> Countries with Maturity Level 3 or Maturity Level 4 according to the GBT are eligible to become a WHO listed authority so that they may be considered as a reference point by other regulatory authorities for reaching own decisions in approving medical products.<sup>##UREF##37##68##</sup> For NRAs to be evaluated and recognised as operating at an advanced level of performance with continuous improvement is pertained to profound both practical and signifying implications at an international level.<sup>##UREF##36##67##</sup> Benchmarking against best practices would further help NRAs to achieve regulatory excellence.</p>", "<title> Benchmarking as a Process From Bench-Learning to Bench-Action</title>", "<p> It is worth noting that while benchmarking is important in identifying gaps and weakness, it is the “bench-learning” and “bench-action” that are key to making changes.<sup>##REF##10351394##69##,##UREF##38##70##</sup> However, little has been reported about communicating the aftermaths of benchmarking exercises and how to divert the findings and knowledge between and among researchers and NRAs to advance performance and address the gaps. All the included studies rested on the monologues about the relevance of benchmarking.</p>", "<p> Decisions about employing benchmarking requires systematic planning and multifaceted perspectives (including but not limited to the political environment, the latest advances in pharmaceutical research and development, the unmet needs of the patients, the availability of high-level engagement and resources, etc) to formulate effective implementation approaches. Addressing the gaps in regulatory performance is part of a highly complex undertaking involving not just NRAs but also other counterparts in the pharmaceutical system, as well as other counterparts in the larger environment of health system, both locally and beyond.<sup>##REF##25160707##71##</sup> However, it appeared in this review that benchmarking often took place in silos with no significant engagement of researchers or other government agencies with the NRAs on following up the findings and solving critical gaps.</p>", "<p> Indeed, as revealed in this review, barriers to implementing changes might be multifaceted encompassing, just to name a few, the political environment, the deficit in the information systems, the scarcity of related research to form the scientific foundation, and the lack of continuous engagement of leadership. Decisions about interventions that bring changes to drug regulatory practices often warrants the guidance from high-level governance to identify effective approaches and thus systematic planning.</p>", "<p> To move this facet of practice forward, a systems thinking approach guided by implementation science might offer a roadmap that help translate the benchmarking findings into formulation of actions for facilitating changes. Systems thinking is an approach that advocates for the involvement of key stakeholders to map the drug regulatory system, identify where the key impediments lie, and design synergistic and system-ready pathway towards benchmarking practice.<sup>##REF##19276332##72##</sup> This approach calls for transdisciplinary and translational approaches and encourages relationship-building across various functionalities of the NRAs so as to achieve a common set of relevant goals and objectives on drug regulation.</p>", "<p> Identifying the strengths and weaknesses in drug regulatory capacities through benchmarking using “systems thinking” approach then leads to the need for a coordinated and collaborative effort to implement and sustain changes in regulatory measure. Nevertheless, major challenges for bench-actions to be translated into sustained routine practice are foreseeable. There needs to be a scientific approach to identify the range of factors that are likely to facilitate the uptake of recommended actions and changes in regulatory practice, and to plan and act accordingly. More importantly, regulatory management systems to measure changes and demonstrate any outcomes associated with changes in regulatory capacities related to benchmarking is essential to support the sustainable development of the intervention or service. For this, implementation science knowledge and strategies must be employed and incorporate into the regulatory management systems to promote intervention validity, while collecting the data necessary for establishing evidence-based improvement to bargain for continuous resources input for benchmarking exercises.<sup>##REF##28600197##73##</sup></p>", "<title> Limitations of the Study Findings </title>", "<p> This study provides a comprehensive view of benchmarking the NRAs for capacity building in term of the existing tools, practices, and recommendations based on literature retrieval, analysis and data synthesis. Nevertheless, our review has some limitations. The first limitation is that we were not able to define a uniform system to determine the “maturity level” for all indicators due to the heterogenicity of the assessment methods employed in each benchmarking tool or programme included in this study. For each indicator of regulatory capacity, the maturity level is important not only for reflecting the status but also for measuring progress. Drawing on the successful experiences of the work on the GBT by the WHO, future research is warranted to yield specific criteria of quality assessment methods for each indicator. Another limitation of this review may be contributed by publication bias. The risks of negative outcomes about benchmarking regulatory capacity being rarely or unlikely to be fully reported in the literature cannot be ruled out possibly compromising the comprehensiveness of the overall research landscape about regulatory benchmarking presented in this review. Furthermore, considering that not all benchmarking tools or programs, and the related regulatory performance data are publicly available, the limitation in full access to all regulatory benchmarking information may inevitably affect the completeness of the findings reported in this review.</p>" ]	[ "<title>Conclusion</title>", "<p> Benchmarking drug regulatory capacities is a complex process that has been increasingly adopted by NRAs for measuring the regulatory performance and monitoring the progress. This review has analysed in detail the “why” and “how” to employ benchmarking to improve regulatory practice. For effective benchmarking that leads to bench-learning and bench-action, well-informed decisions about the goals, the scope, the choice of reference points and benchmarking tools are essential to guide the implementation strategies, coordination of resources, and stakeholders’ participation and cooperation. Nevertheless, the evidence for the possible benefits of benchmarking remains scarce. There is a need for more empirical studies to develop evidence about how benchmarking can improve drug regulatory capacities.</p>" ]	[ "<p>\n<bold>Background:</bold> Benchmarking has been increasingly used on drug regulatory systems to achieve sustainable pharmaceutical system strengthening. This study aimed to identify the scope, tools and benefits of benchmarking regulatory capacities and the most recent development in such phenomenon.\n</p>", "<p><bold>Methods:</bold> This study employed an integrative and critical review of the literature and documents on benchmarking drug regulatory capacities identified from 6 databases and 5 websites of related organizations and government agencies in compliance with the Preferred Reporting Items for Systematic Review (PRISMA) guidelines.\n</p>", "<p><bold>Results:</bold> Forty-three studies and 6 documents about regulatory benchmarking published between 2005 and 2022 were included in this review. Five benchmarking assessment tools or programmes recommended or adopted by international organizations or government agencies had been identified, which collectively covered 12 major regulatory functions (4 at system level and 8 at operational level) involving 9 indicator categories and 382 sub-indicators. Benchmarking drug regulatory systems was reportedly employed at national, regional and international levels for either internal assessment (mostly on regulatory system establishment, drug review process and post marketing surveillance) or external evaluation (mostly on regulatory standards, drug review process and pharmacovigilance systems) to assess current status, monitor performance, determine major challenges and inform actions for capacity building. Priority of actions in areas such as regulatory process, resources allocation, cooperation and communication, and stakeholder engagement have been suggested for strengthening drug regulatory systems. Nevertheless, the evidence about benchmarking in optimizing regulatory capacities remained underreported.\n</p>", "<p><bold>Conclusion:</bold> This integrative review depicted a framework for decision-makers about why and how benchmarking drug regulatory systems should be undertaken. For effective benchmarking, well-informed decisions about the goals, the scope, the choice of reference points and benchmarking tools are essential to guide the implementation strategies. Further studies about the positive effects of regulatory benchmarking are warranted to engage continuous commitment to the practice.</p>", "<p>\n<bold>Citation:</bold> Shi J, Chen X, Hu H, Ung COL. Benchmarking drug regulatory systems for capacity building: an integrative review of tools, practice, and recommendations. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8100. doi:10.34172/ijhpm.2023.8100</p>" ]	[ "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This work was supported by a grant from University of Macau (reference numbers: SRG2021-00007- ICMS and MYRG2022-00229-ICMS).</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nPRISMA Flowchart of Study Selection. Abbreviation: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nThe Commonalities Across the Regulatory Benchmarking Tools and Programmes. The indicator categories are connected to the corresponding functions by lines of the same colors. Indicator categories with more connecting lines are those used more often to measure the regulatory functions. Abbreviations: GBT, Global Benchmarking Tool; iREG, Indicators of Regulatory Policy and Governance; BEMA, Benchmarking of European Medicines Agencies; OpERA, Optimising Efficiencies in Regulatory Agencies; GAO, Government Accountability Office.</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nDecision-Making Framework for Benchmarking Drug Regulatory Capacities. Abbreviations: WHO, World Health Organization; GBT, Global Benchmarking Tool; HMA, Heads of Medicine Agencies; BEMA, Benchmarking of European Medicines Agencies; OECD, Organization for Economic Co-operation and Development; iREG, Indicators of Regulatory Policy and Governance; CIRS, Centre for Innovation in Regulatory Science; OpERA, Optimizing Efficiencies in Regulatory Agencies; FDA, Food and Drug Administration; GAO, Government Accountability Office.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Description of Individual Studies Related to the Regulatory Capacity Building for National Regulatory Authorities\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Year, Authors</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Country/Region</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Study Design</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Main Purpose</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Underlying Tools or Frameworks</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">2022, Bujar et al<sup>##REF##32610811##26##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">CIRS members</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Questionnaire</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Ensure quality, transparent, and consistent decision-making processes</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Others: QoDoS</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Chaw et al<sup>##UREF##14##27##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Myanmar</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To assess the national regulatory system and regulatory activities with WHO-GBT indicators</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Garashi et al<sup>##REF##35657484##28##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Developing countries</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Literature review</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To synthesise current research evaluating developing countries’ PV systems’ performance</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Others: WHO-PV indicator</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Keyter et al<sup>##REF##33300773##29##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">South African</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Comparative analysis, questionnaire </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Develop a new regulatory review model for enhanced regulatory performance</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT, OpERA, UMBRA</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Lavery et al<sup>##REF##35723862##14##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Global</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Structured benchmarking survey</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To gain a better understanding of the impact of the pharmacovigilance system master file for MAHs</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Mahdavi et al<sup>##REF##34814672##30##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Iran</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Literature review and experts validating</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To draw a roadmap for strengthening EIHP in Iran</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Others: SAHSHA<sup>a</sup> project: EIHP</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Owusu Sekyere et al<sup>##REF##35725614##12##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Liberia, Sierra Leone, and the Gambia</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Comparative analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Probed the outputs of capacity-strengthening activities for clinical trials oversight to take stock of progress made and examine remaining priorities</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT; Others: GHPP RegTrain-VaccTrain</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Shabani et al<sup>##REF##36434730##18##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Rwanda</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Descriptive cross-sectional design with both quantitative and qualitative approaches</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To assess the capacity of the Rwanda FDA </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Sithole et al<sup>##REF##34645359##31##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Zimbabwe with Australia, Canada, Singapore, and Switzerland</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire, comparative analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To compare the medicines registration process of the Medicines Control Authority</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Xing et al<sup>##UREF##15##32##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Policy review</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To improve the vaccine regulatory system in China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2022, Zhang et al<sup>##UREF##16##33##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Descriptive analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To introduce the third-party evaluation systems</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT, OpERA</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2021, Khadem Broojerdi et al<sup>##REF##34485350##13##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">WHO</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Descriptive analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To analyse and document the current regulatory preparedness status, highlight the related gaps and challenges</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2021, Li<sup>##UREF##17##34##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Dual organization theory, Delphi experts interview</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To construct the drug emulation ability model</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT, BEMA</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2021, Rahalkar et al<sup>##REF##34434109##20##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">BRICS-TM with Australia, Canada, and Switzerland</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Semi-quantitative questionnaire</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To identify, compare, and evaluate regulatory requirements for the biosimilar development and review processes</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2021, Rodier et al<sup>##REF##32617911##35##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">18 Maturing pharmaceutical markets</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Comparative analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To determine current certificate of pharmaceutical product practices versus national regulatory guidelines </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2021, Russom et al<sup>##REF##34472048##36##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Eritrea</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Descriptive analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To describe Eritrea’s success stories, key strategies for success, challenges encountered, and lessons learned</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2021, Sithole et al<sup>##REF##33387356##37##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Zimbabwe</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To assess the current regulatory review process of the Medicines Control Authority of Zimbabwe </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">OpERA</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Barry et al<sup>##REF##31919794##15##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">East Africa</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Comparative assessment</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To assess the functionality and identify the strengths and limitations of the national pharmacovigilance systems</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">The East African Community Harmonized Pharmacovigilance Indicators tool, GBT</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Guzman et al<sup>##UREF##7##11##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Descriptive analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To analyse the GBT key benefits for countries</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT </td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Hartmann et al<sup>##REF##32591289##38##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Emerging countries</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To scale up global immunization, improve access to vaccines, and enhance scientific knowledge and operational efficiency in PV</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">ICH, EMA-GVP</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Keyter et al<sup>##REF##32865802##39##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">South Africa</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To identify criteria and current practices for implementing an abridged review process</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Good reliance practices </td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Liberti et al<sup>##REF##32939288##40##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">CARICOM region</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To understand the effectiveness and efficiency of the processes implemented by the Caribbean Regulatory System for the regulatory assessment of medicines for the region</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">OpERA</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Patel et al<sup>##REF##32519282##41##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Brazil</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Retrospective analysis </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Analysis the timelines associated with important components of the ANVISA regulatory review process</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">OpERA</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Preston et al<sup>##UREF##18##42##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Small states</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Assessment analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To strengthen the regulatory system </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GBT </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Saaristo et al<sup>##UREF##19##43##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Finland</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Empirical analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To analyse and test a theoretical generic health promotion capacity-building framework with empirical data on primary healthcare</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Others: Health promotion capacity-building framework</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2020, Sani et al<sup>##REF##32865804##19##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Malaysia</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Retrospective analysis </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To provide NPRA with a breakdown of where the time is spent in their approval process </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">OpERA</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2019, Keyter et al<sup>##REF##30923501##44##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">South African</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire, comparative analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To compare the registration process and the regulatory review model </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2018, Chong et al<sup>##UREF##20##45##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">APEC</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Policy review</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To identify appropriate regulatory practice and explores the feasible processes of regulatory convergence of APEC</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2018, Mashaki Ceyhan et al<sup>##REF##29422861##46##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Turkish</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire, comparative analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To assess the level of adherence to GRevP</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2018, Tang et al<sup>##UREF##21##47##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Assessment analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To explore a method of construction of knowledge management system for drug evaluation and inspection</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Knowledge management system</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2017, Li et al<sup>##REF##28721199##48##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Low- and middle-income countries</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Stakeholder interview</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Analysis the kinds of capacity needed to support decision makers when setting health priorities</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Others: INNE Model</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2017, Mery et al<sup>##UREF##22##49##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Canada</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Systematic review</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To identify key steps and elements considered for system-level evaluations of investment in quality improvement capacity building</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2016, Liu et al<sup>##UREF##23##50##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Literature analysis, empirical studies</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To establish regulatory capacity indicator system for social regulatory agencies to measure their regulatory capacity</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Others: OECD 1995</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2016, Zhang et al<sup>##UREF##24##51##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Literature survey, expert brainstorming, maximum difference scaling and internet questionnaire survey</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To establish drug safety performance indicator system in Beijing </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2015, Chen et al<sup>##UREF##25##52##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Empirical analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To establish an evaluation index system for the level of supervision of the circulation and safety of essential drugs in rural areas </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2015, Yang et al<sup>##UREF##26##53##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Literature review, expert interview, content analysis and case study</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To explore the definition, dimensions, and building mechanisms of drug regulatory capabilities and their relationship with regulatory performance</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2014, Yao et al<sup>##UREF##27##54##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Literature and individual work experience</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To explore the construction of drug regulatory core indicators in China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2014, Zhang et al<sup>##UREF##28##55##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Key stakeholder survey</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To explore the model of evaluation on the ability of drug safety supervision in Beijing</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Government performance theory</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2013, Liu et al<sup>##REF##30235555##56##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">APEC member economies</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Questionnaire</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To assess the current use of GRevP</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">GRevP</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2012, Yang et al<sup>##UREF##29##57##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Literature review, expert interview</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To establish the indicator system for evaluating drug regulatory capacity in China</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2009, McAuslane et al<sup>##UREF##30##58##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13 Countries in Asia, Latin America, the Middle East, and Africa</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Comparative analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To record and analyse the regulatory procedures for the authorization of new medicines </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2007, Hirako et al<sup>##UREF##31##59##</sup></td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">United States, Europe, Canada, Switzerland, and Australia</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Comparative analysis</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">To identify and quantitate the stages of submission, review and regulatory action for NDA</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2005, Cooke et al<sup>##REF##16253133##60##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">UK</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Literature analysis</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Measure the effectiveness of research capacity building in healthcare</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Others: Research capacity building framework</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Description of Included Tools/Programmes Related to the Capacity Building\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Tool/Programme</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Organization & Start Time</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Scope of Application</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Purpose</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Focus Areas</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Composition</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Quality Assessment Methods</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">GBT<sup>##UREF##8##16##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">WHO, 2018</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">National regulatory systems </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Identify strengths and areas for improvement; facilitate the formulation of an IDP to build upon strengths and address the identified gaps; prioritise IDP interventions; and monitor progress and achievements.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A variety of product types, including medicines, vaccines, blood products and medical devices.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">9 Indicator categories, 9 regulatory functions, 268 (sub)indicators.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Maturity level, ranging from 1 to 4- no formal approach (level 1); reactive approach (level 2); stable, well-functioning system (level 3) and continual improvement emphasised (level 4).</td></tr><tr><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">iREG<sup>##UREF##32##61##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">OECD, 2015</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">National policy areas in OECD member countries, not include practices at the sub-national level</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Up-to-date evidence of OECD member countries’ regulatory policy and governance practices.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The processes of developing regulations that are carried out by the executive branch of the national Government. </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3 Core areas, four sub-dimensions, 61 (sub)indicators.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Composite indicators are calculated as weighted averages of sub-indexes and vary between 0 and 6. </td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">BEMA<sup>##UREF##33##62##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">HMA, 2019</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Systems and processes in individual agencies in EU/EEA</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">To contribute to the development of a world-class medicines regulatory system based on a network of agencies operating to best practice standards.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Management systems;<break/>Assessment of marketing authorisation applications;<break/>PV (drug safety) activities; and<break/>Inspection services.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">12 Key performance indicator, 41 specific performance indicators. </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Self-assessment and peer review assessment, and broadly based on ISO 9004 guidelines.</td></tr><tr><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">OpERA<sup>##UREF##9##17##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">CIRS, 2013</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">National regulatory agencies</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Help regulators integrate best practices that are fit-for-purpose for their remit, while ensuring the safety, efficacy and quality of their products.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review performance goals and optimise review processes.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">5 Performance metrics.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Country report and specific metrics collections, summary of review process timelines.</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">GAO analysis (Workforce planning & Scientific-integrity-related procedures and training)<sup>##UREF##34##63##,##UREF##35##64##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">GAO, 2022</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FDA</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Help the government save money and work more efficiently and provide scientific advice on specific issues in the FDA's decision-making process.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Project-specific analysis.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">3 Leading practice and 4 elements.</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Data collection and analysis, Stakeholders interviews, etc.</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Most Common Regulatory Problems and Recommended Actions Identified From Benchmarking Results\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Key Areas of Benchmarking Regulatory Capacity</bold></td><td style=\"vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Common Regulatory Problems</bold>\n</td><td style=\"vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Specific Recommended Actions to the Problem</bold></td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"4\" style=\"vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Legal prevision</td><td style=\"vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Inflexible regulatory policies or guidelines (n = 2)<sup>##UREF##23##50##,##UREF##24##51##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Policy and legal framework (n = 1)<sup>##REF##32939288##40##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of pharmacovigilance system (n = 2)<sup>##REF##35657484##28##,##REF##34472048##36##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of framework of emergency preparedness (n = 1)<sup>##REF##35725614##12##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Application strategies/guideline/framework (n = 10)<sup>##REF##35725614##12##,##REF##34485350##13##,##UREF##14##27##,##REF##33300773##29##,##REF##34645359##31##,##UREF##15##32##,##REF##32591289##38##,##UREF##23##50##,##UREF##26##53##,##REF##30235555##56##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of the quality management system (n = 1)<sup>##REF##36434730##18##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td rowspan=\"10\" style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Regulatory process</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review time exceed the agency’s overall target time or the international average time (n = 6)<sup>##REF##32865804##19##,##REF##34645359##31##,##REF##32939288##40##,##REF##32519282##41##,##REF##30923501##44##,##REF##29422861##46##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Review time milestone(n = 8)<sup>##REF##32865804##19##,##REF##33300773##29##,##REF##34645359##31##,##REF##32617911##35##,##REF##33387356##37##,##REF##32519282##41##,##REF##30923501##44##,##REF##29422861##46##</sup></td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Inefficient drug safety supervision (n = 4)<sup>##UREF##24##51##,##UREF##25##52##,##UREF##27##54##,##UREF##28##55##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Need for improvement of decision-making practices (n = 2)<sup>##REF##32610811##26##,##REF##33387356##37##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Evidence-based decision-making practices (n = 5)<sup>##REF##32610811##26##,##REF##33300773##29##,##REF##34814672##30##,##REF##34645359##31##,##REF##33387356##37##</sup></td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of quality measure or risk-based evaluation (n = 2)<sup>##REF##35657484##28##,##REF##33300773##29##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Regulatory process and practice (n = 22)<sup>##REF##31919794##15##,##REF##36434730##18##, ####REF##32865804##19##, ##REF##34434109##20####34434109##20##,##REF##33300773##29##,##REF##34645359##31##, ####UREF##15##32##, ##UREF##16##33####16##33##,##REF##32617911##35##,##REF##33387356##37##,##REF##32865802##39##, ####REF##32939288##40##, ##REF##32519282##41####32519282##41##,##REF##30923501##44##,##REF##29422861##46##,##UREF##21##47##,##UREF##24##51##,##UREF##25##52##,##REF##30235555##56##, ####UREF##29##57##, ##UREF##30##58##, ##UREF##31##59####31##59##</sup></td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Insufficient independence of regulators (n = 1)<sup>##UREF##23##50##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of centralised functions and powers (n = 1)<sup>##UREF##23##50##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Single regulatory tools (n = 1)<sup>##UREF##23##50##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Unclear level of performance appraisals (n = 1)<sup>##UREF##25##52##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance appraisal (n = 7)<sup>##UREF##15##32##,##REF##32591289##38##,##UREF##20##45##,##UREF##25##52##,##UREF##26##53##,##UREF##28##55##,##UREF##29##57##</sup></td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Challenge of setting the priority areas (n = 1)<sup>##REF##28721199##48##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Fast-track/accelerated reviews (n = 1)<sup>##UREF##18##42##</sup></td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Informal implementation of GRevP (n = 2)<sup>##REF##29422861##46##,##REF##30235555##56##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Good review practice (n = 2)<sup>##REF##30923501##44##,##REF##29422861##46##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"6\" style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Resources</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of training and education (n = 7)<sup>##REF##36434730##18##,##REF##33300773##29##,##REF##32865802##39##,##UREF##21##47##,##REF##28721199##48##,##UREF##26##53##,##UREF##29##57##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Research and training (n = 7)<sup>##REF##36434730##18##,##UREF##14##27##,##REF##32591289##38##,##REF##28721199##48##,##UREF##22##49##,##REF##30235555##56##,##REF##16253133##60##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Insufficient human resources (n = 5)<sup>##REF##36434730##18##,##UREF##14##27##,##REF##32865802##39##,##REF##32939288##40##,##UREF##18##42##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Human resources staffing (n = 5)<sup>##REF##36434730##18##,##REF##35657484##28##,##REF##34814672##30##,##REF##28721199##48##,##REF##16253133##60##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Insufficient financial resources (n = 2)<sup>##UREF##18##42##,##UREF##22##49##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of regulatory inspection tools/equipments (n = 1)<sup>##REF##36434730##18##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Equipment and tools, automation systems (n = 5)<sup>##REF##36434730##18##,##REF##35657484##28##,##REF##34814672##30##,##UREF##25##52##,##REF##16253133##60##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lack of enough capacity of the quality control laboratory (n = 1)<sup>##REF##36434730##18##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Insufficient innovation technologies (n = 2)<sup>##REF##36434730##18##,##REF##33300773##29##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Digitization (online submission/database/Develop algorithms) (n = 6)<sup>##REF##35657484##28##,##REF##34434109##20##,##REF##34645359##31##,##REF##32591289##38##,##UREF##18##42##,##UREF##25##52##</sup></td></tr><tr><td rowspan=\"2\" style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" colspan=\"1\">Cooperation and communication</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Lagging transparency and communication (n = 3)<sup>##REF##35723862##14##,##REF##33300773##29##,##REF##34645359##31##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Collaboration/networks (n = 19)<sup>##REF##35725614##12##,##REF##35723862##14##,##REF##32610811##26##,##REF##35657484##28##,##REF##33300773##29##,##REF##34645359##31##,##UREF##15##32##,##REF##32617911##35##,##REF##32591289##38##,##REF##32865802##39##,##UREF##18##42##, ####UREF##19##43##, ##REF##30923501##44##, ##UREF##20##45##, ##REF##29422861##46####29422861##46##,##REF##28721199##48##,##UREF##25##52##,##REF##30235555##56##,##REF##16253133##60##</sup></td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Absence of reliance approach and participation in harmonization activities (n = 2)<sup>##REF##34434109##20##,##REF##32591289##38##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Stakeholder engagement</td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Limited stakeholder involvement and engagement (n = 1)<sup>##REF##33387356##37##</sup></td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.25pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Relevant stakeholders’ participation (n = 5)<sup>##REF##35723862##14##,##REF##31919794##15##,##REF##35657484##28##,##REF##32591289##38##,##REF##28721199##48##</sup></td></tr><tr><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Others</td><td style=\"vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Gaps between the academic outcomes of publications in peer reviewed journals or successful grant applications and the resolution of the regulatory practices (n = 1)<sup>##REF##16253133##60##</sup></td><td style=\"text-align:left;vertical-align:middle;border-width:0.25pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1 contains Tables S1-S3.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: CIRS, Centre for Innovation in Regulatory Science; QoDoS, Quality of Decision-Making Orientation Scheme; GBT, Global Benchmarking Tool; WHO, World Health Organization; PV, Pharmacovigilance; UMBRA, Universal Methodology for Benefit-Risk Assessment; OpERA, Optimizing Efficiencies in Regulatory Agencies; EIHP, evidence-informed health policy-making; GHPP, Global Health Protection Programme; BEMA, Benchmarking of European Medicines Agencies; EMA, European Medicines Agency; CARICOM, Caribbean Community; ANVISA, Agência Nacional de Vigilância Sanitária; APEC, Asia-Pacific Economic Cooperation; GRevP, good review practices; OECD, Organization for Economic Co-operation and Development; FDA, Food and Drug Administration; BRICS-TM, Brazil, Russia, India, China, South Africa, Turkey, Mexico; MAHs, marketing authorization holders; N/A, not applicable; ICH, The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; GVP, Good Pharmacovigilance Practices; NPRA, National Pharmaceutical Regulatory Agency; NDA, New Drug Application.</p><p>\n<sup>a</sup>SASHA stands for evidence-informed health policy-making in Persian; INNE, Identification, Notification, and Evaluation of New Events.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: GBT, Global Benchmarking Tool; WHO, World Health Organization; IDP, institutional development plan; iREG, Indicators of Regulatory Policy and Governance; OECD, Organization for Economic Co-operation and Development; HMA, Heads of Medicine Agencies; BEMA, Benchmarking of European Medicines Agencies; EEA, European Economic Area; EU, European Union; PV, pharmacovigilance; OpERA, Optimising Efficiencies in Regulatory Agencies; CIRS, Centre for Innovation in Regulatory Science; GAO, Government Accountability Office; FDA, Food and Drug Administration.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviation: GRevP, good review practices.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-8100-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8100-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-8100-g003\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-8100-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["2"], "mixed-citation": [" World Health Organization (WHO). Everybody\u2019s Business--Strengthening Health Systems to Improve Health Outcomes: WHO\u2019s Framework for Action. WHO; 2007. "]}, {"label": ["3"], "mixed-citation": [" Lodge M. Regulatory capacity. In: Lodge M, Wegrich K, eds. The Problem-Solving Capacity of the Modern State: Governance Challenges and Administrative Capacities. Oxford University Press; 2014;63-85. "]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Zairi"], "given-names": ["M"], "article-title": ["Benchmarking: the best tool for measuring competitiveness"], "source": ["Benchmarking for Quality Management & Technology"], "year": ["1994"], "volume": ["1"], "issue": ["1"], "fpage": ["11"], "lpage": ["24"], "pub-id": ["10.1108/14635779410056859"]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Ahmed", "Rafiq"], "given-names": ["PK", "M"], "article-title": ["Integrated benchmarking: a holistic examination of select techniques for benchmarking analysis"], "source": ["Benchmarking for Quality Management & Technology"], "year": ["1998"], "volume": ["5"], "issue": ["3"], "fpage": ["225"], "lpage": ["242"], "pub-id": ["10.1108/14635779810234802"]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Tillema"], "given-names": ["S"], "article-title": ["Public sector benchmarking and performance improvement: what is the link and can it be improved?"], "source": ["Public Money Manag"], "year": ["2010"], "volume": ["30"], "issue": ["1"], "fpage": ["69"], "lpage": ["75"], "pub-id": ["10.1080/09540960903492414"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Triantafillou"], "given-names": ["P"], "article-title": ["Benchmarking in the public sector: a critical conceptual framework"], "source": ["Public Adm"], "year": ["2007"], "volume": ["85"], "issue": ["3"], "fpage": ["829"], "lpage": ["846"], "pub-id": ["10.1111/j.1467-9299.2007.00669.x"]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Dorsch", "Yasin"], "given-names": ["JJ", "MM"], "article-title": ["A framework for benchmarking in the public sector"], "source": ["Int J Public Sect Manag"], "year": ["1998"], "volume": ["11"], "issue": ["2/3"], "fpage": ["91"], "lpage": ["115"], "pub-id": ["10.1108/09513559810216410"]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Guzman", "O\u2019Connell", "Kikule", "Hafner"], "given-names": ["J", "E", "K", "T"], "article-title": ["The WHO Global Benchmarking Tool: a game changer for strengthening national regulatory capacity"], "source": ["BMJ Glob Health"], "year": ["2020"], "volume": ["5"], "issue": ["8"], "fpage": ["e003181"], "pub-id": ["10.1136/bmjgh-2020-003181"]}, {"label": ["16"], "mixed-citation": [" World Health Organization (WHO). WHO Global Benchmarking Tool (GBT) for Evaluation of National Regulatory Systems of Medical Products: Revision VI. WHO; 2021. "]}, {"label": ["17"], "mixed-citation": [" Centre for Innovation in Regulatory Science (CIRS). Measuring Process and Performance in Regulatory Agencies: The OpERA Programme. CIRS; 2020. "], "uri": ["https://www.cirsci.org/wp-content/uploads/2020/02/CIRS-RD-Briefing-74-OpERA-programme.pdf"]}, {"label": ["21"], "mixed-citation": [" World Health Organization (WHO). WHO Benchmarks for International Health Regulations (\u200eIHR)\u200e Capacities. WHO; 2019. "], "uri": ["https://apps.who.int/iris/handle/10665/311158"]}, {"label": ["22"], "mixed-citation": [" World Health Organization (WHO). WHO Essential Medicines and Health Products: Annual Report 2017: Towards Access 2030. WHO; 2018. "], "uri": ["https://apps.who.int/iris/handle/10665/272972"]}, {"label": ["23"], "mixed-citation": [" World Health Organization (WHO). Regulatory System Strengthening for Medical Products. Proceedings of the 67th World Health Assembly.2014:28. "]}, {"label": ["25"], "person-group": ["\n"], "surname": ["Torraco"], "given-names": ["RJ"], "article-title": ["Writing integrative literature reviews: guidelines and examples"], "source": ["Hum Resour Dev Rev"], "year": ["2005"], "volume": ["4"], "fpage": ["356"], "lpage": ["367"], "pub-id": ["10.1177/1534484305278283"]}, {"label": ["27"], "person-group": ["\n"], "surname": ["Chaw", "Suntornsuk"], "given-names": ["EE", "L"], "article-title": ["Regulatory landscape analysis of Myanmar Food and Drug Administration based on the World Health Organization Global Benchmarking Tool"], "source": ["Pharm Sci Asia"], "year": ["2022"], "volume": ["49"], "issue": ["5"], "fpage": ["498"], "lpage": ["505"], "pub-id": ["10.29090/psa.2022.05.22.174"]}, {"label": ["32"], "mixed-citation": [" Xing LY, Lin XN, Zhou HX, Mo JL, Chen M. Research on the construction of vaccine supervision quality management of drug regulatory authorities in compliance with WHO Global Benchmarking Tool (GBT). Chin Pharm 2022;36(4):391-398. [Chinese]. "]}, {"label": ["33"], "mixed-citation": [" Zhang Q, Xie Y, Sheng LL, et al. Third-party evaluation methods and systems for drug regulatory measures. Chin food & Drug Administration Magazine. 2022;4:20-29. [Chinese]. "]}, {"label": ["34"], "mixed-citation": [" Li F. Study on ability evaluation model for drug review authority. Chin J New Drugs 2021;30(24):2242-2248. [Chinese]. "]}, {"label": ["42"], "person-group": ["\n"], "surname": ["Preston", "Freitas Dias", "Pe\u00f1a", "Pombo", "Porr\u00e1s"], "given-names": ["C", "M", "J", "ML", "A"], "article-title": ["Addressing the challenges of regulatory systems strengthening in small states"], "source": ["BMJ Glob Health"], "year": ["2020"], "volume": ["5"], "issue": ["2"], "fpage": ["e001912"], "pub-id": ["10.1136/bmjgh-2019-001912"]}, {"label": ["43"], "person-group": ["\n"], "surname": ["Saaristo", "Hakam\u00e4ki", "Koskinen", "Wiss", "St\u00e5hl"], "given-names": ["V", "P", "H", "K", "T"], "article-title": ["The comparative and objective measurement of health promotion capacity-building: from conceptual framework to operationalization"], "source": ["Glob Health Promot"], "year": ["2020"], "volume": ["27"], "issue": ["1"], "fpage": ["24"], "lpage": ["32"], "pub-id": ["10.1177/1757975918769608"]}, {"label": ["45"], "person-group": ["\n"], "surname": ["Chong", "Lim", "Tominaga"], "given-names": ["SSF", "JCW", "T"], "article-title": ["Developing key performance indicators to measure the progress of regional regulatory convergence and cooperation in Asia-Pacific Economic Cooperation (APEC)"], "source": ["AAPS Open"], "year": ["2018"], "volume": ["4"], "issue": ["1"], "fpage": ["4"], "pub-id": ["10.1186/s41120-018-0024-2"]}, {"label": ["47"], "mixed-citation": [" Tang WY, Zhang H, Jin DZ. Study on construction of knowledge management system for drug evaluation and inspection. Shanghai Med Pharm J 2018;39(13):56-57. [Chinese]. "]}, {"label": ["49"], "person-group": ["\n"], "surname": ["Mery", "Dobrow", "Baker", "Im", "Brown"], "given-names": ["G", "MJ", "GR", "J", "A"], "article-title": ["Evaluating investment in quality improvement capacity building: a systematic review"], "source": ["BMJ Open"], "year": ["2017"], "volume": ["7"], "issue": ["2"], "fpage": ["e012431"], "pub-id": ["10.1136/bmjopen-2016-012431"]}, {"label": ["50"], "mixed-citation": [" Liu P, Liu ZP. Measurement and Assessment of Regulatory Capability of Social Regulatory Agencies -Based on a comparative analysis of three regulatory authorities. Wuhan Univer J 2016;69(4):32-40. [Chinese]. "]}, {"label": ["51"], "mixed-citation": [" Zhang M, Guan X, Li J, Gao H, Liu D, Shi L. Establishment of drug safety performance evaluation indicator system for work quality evaluation of drug administration department. Chin Pharm 2016;27(1):1-4. [Chinese]. "]}, {"label": ["52"], "mixed-citation": [" Chen YC, Wang SZ, Jiang JF. Research on evaluation system of regulatory standards of circulation safety about essential medicines in rural in Jiangxi province. Chin Health Service Management 2015;5:373-377. [Chinese]. "]}, {"label": ["53"], "mixed-citation": [" Yang S, Yang DS, Zheng XY, Huang G, Cong LL, Jiang B. Introduction to drug regulatory capabilities: a theory and framework. J Chin Pharm Sci 2015;24(4):257-262. [Chinese]. "]}, {"label": ["54"], "mixed-citation": [" Yao JC, Zeng LG, Li YB, Hu L, Du J, Rao J. Research on the key indicators of drug regulation. Chin Pharmaceut. 2014,23(12):3-5. [Chinese]. "]}, {"label": ["55"], "mixed-citation": [" Zhang X, Lin ZJ, Dong L. Questionaire designing of evaluation on drug safety supervision capacities based upon a 360 degree performance model. Chin Pharmaceut 2014;28(7):700-705. [Chinese]. "]}, {"label": ["57"], "mixed-citation": [" Yang S, Wang GP, Huang G, Jiang B. Research on evaluation index system of China\u2019s drug regulatory capability. Chin Pharmceut J 2012;47(14):1175-1178. [Chinese]. "]}, {"label": ["58"], "person-group": ["\n"], "surname": ["McAuslane", "Cone", "Collins", "Walker"], "given-names": ["N", "M", "J", "S"], "article-title": ["Emerging markets and emerging agencies: a comparative study of how key regulatory agencies in Asia, Latin America, the Middle East, and Africa are developing regulatory processes and review models for new medicinal products"], "source": ["Drug Inf J"], "year": ["2009"], "volume": ["43"], "issue": ["3"], "fpage": ["349"], "lpage": ["359"], "pub-id": ["10.1177/009286150904300314"]}, {"label": ["59"], "person-group": ["\n"], "surname": ["Hirako", "McAuslane", "Salek", "Anderson", "Walker"], "given-names": ["M", "N", "S", "C", "S"], "article-title": ["A comparison of the drug review process at five international regulatory agencies"], "source": ["Ther Innov Regul Sci"], "year": ["2007"], "volume": ["41"], "issue": ["3"], "fpage": ["291"], "lpage": ["308"], "pub-id": ["10.1177/009286150704100302"]}, {"label": ["61"], "mixed-citation": [" Arndt C, Baker AC, Querbach T, Schultz R. 2015 Indicators of Regulatory Policy and Governance: Design, Methodology and Key Results. In: OECD Regulatory Policy Working Papers. Paris: OECD Publishing; 2015. "], "pub-id": ["10.1787/5jrnwqm3zp43-en"]}, {"label": ["62"], "mixed-citation": [" Heads of Medicines Agencies (HMA). Benchmarking of European Medicines Agencies (BEMA). Final Report on the Fourth BEMA Cycle. HMA; 2019. "], "uri": ["https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/BEMA/2019_10_BEMA_IV_Final_Report.pdf"]}, {"label": ["63"], "mixed-citation": [" Government Accountability Office (GAO). FDA Workforce: Agency-Wide Workforce Planning Needed to Ensure Medical Product Staff Meet Current and Future Needs. GAO; 2022. "], "uri": ["https://www.gao.gov/products/gao-22-104791"]}, {"label": ["64"], "mixed-citation": [" Government Accountability Office (GAO). Scientific Integrity: HHS Agencies Need to Develop Procedures and Train Staff on Reporting and Addressing Political Interference. GAO; 2022. "], "uri": ["https://www.gao.gov/assets/gao-22-104613.pdf"]}, {"label": ["67"], "mixed-citation": [" World Health Organization (WHO). Republic of Korea Achieves the Highest Who Level for Regulation of Medicines and Vaccines. WHO; 2022.\u2005"], "uri": ["https://www.who.int/news/item/29-11-2022-republic-of-korea-achieves-the-highest-who-level--for-regulation-of-medicines-and-vaccines"]}, {"label": ["68"], "mixed-citation": [" World Health Organization (WHO). Manual for Benchmarking of the National Regulatory System of Medical Products and Formulation of Institutional Development Plans. WHO; 2021. "]}, {"label": ["70"], "person-group": ["\n"], "surname": ["Zairi", "Ahmed"], "given-names": ["M", "PK"], "article-title": ["Benchmarking maturity as we approach the millennium?"], "source": ["Total Qual Manag"], "year": ["1999"], "volume": ["10"], "issue": ["4-5"], "fpage": ["810"], "lpage": ["816"], "pub-id": ["10.1080/0954412997848"]}]	{ "acronym": [], "definition": [] }	73	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 16; 12:8100	oa_package/91/fe/PMC10699822.tar.gz
PMC10699823	0	[ "<title>Background</title>", "<p> Childhood pneumonia, the leading infectious cause of death among children under 5 years of age globally, contributed to 740 000 deaths in children in 2019.<sup>##REF##34800370##1##</sup> In low- and middle-income countries (LMICs), childhood pneumonia diagnosis, classification and case management are guided by measuring respiratory rates (RRs) (ie, manually counting thoracic movements and breaths for 60 seconds) in children with cough and/or difficult breathing or chest indrawing. This approach identifies fast-breathing and determines whether children are treated with antibiotics, referred for specialized care and/or oxygen therapy.<sup>##UREF##0##2##</sup> Manually counting RR has limited accuracy, high variability, and incorrectly measuring and recording RR can lead to misdiagnosis, inappropriate antibiotic use and delayed referrals.<sup>##REF##31388660##3##, ####REF##29163934##4##, ##UREF##1##5##, ##REF##31982627##6##, ##REF##23600592##7####23600592##7##</sup> Innovations such as automated RR counters could potentially improve the quality of care for childhood pneumonia at the primary healthcare level.<sup>##REF##28485694##8##,##REF##32224491##9##</sup></p>", "<p> At the time of the study, two automated RR counters were commercially available: Children’s Automated Respiration Monitor (ChARM) by Phillips<sup>®</sup> (measures RR only) and Rad-G by Masimo<sup>®</sup> (a multimodal device that measures RR and pulse oximetry).<sup>##REF##32224491##9##</sup> ChARM, which is no longer in production, has shown moderate RR count agreement when compared to RR measurements from a video panel of experts.<sup>##REF##32238340##10##</sup> It was feasible and easy to use within Integrated Management of Newborn and Childhood Illness (IMNCI) and integrated Community Case Management (iCCM) platforms, with field trials demonstrating that facility and community health workers correctly adhered to assessment steps.<sup>##REF##31769406##11##, ####REF##31762072##12##, ##REF##31638714##13####31638714##13##</sup> Strong agreement has been shown between automated RR measurements from Rad-G and paediatrician’s manual RR counting in India<sup>##REF##32518740##14##</sup> but lower agreement has been observed in the Democratic Republic of Congo, especially for fast breathing.<sup>##REF##34829427##15##</sup> Multimodal devices such as Rad-G, which include pulse oximetry in addition to RR measurement, could potentially improve rates of correct management of severe childhood pneumonia cases by 44% within IMNCI.<sup>##REF##26633766##16##</sup> The addition of temperature and oxygen saturation to RR measurement has also been shown to improve the specificity of diagnosing childhood pneumonia.<sup>##UREF##2##17##</sup></p>", "<p> While innovations like automated RR counters address a key bottleneck related to childhood pneumonia diagnosis, other bottlenecks along the pneumonia care pathway still remain (eg, delayed care seeking, lack of access to quality healthcare with skilled providers and uninterrupted stock of essential commodities) and increase children’s risk of severe illness and death from pneumonia and other childhood illnesses.<sup>##REF##24990815##18##, ####REF##30195398##19##, ##REF##27070913##20####27070913##20##</sup></p>", "<title> The Acute Respiratory Infection Diagnostic Aids Initiative in Ethiopia</title>", "<p> Between 2015-2019 a multipronged approach was launched in Ethiopia to increase oxygen in public hospitals via policy development, procurement and maintenance of oxygen equipment, and training healthcare workers. A study of 32 national hospitals indicated that during this time, the functional availability of pulse oximetry increased from 45%-86%.<sup>##REF##34649554##21##</sup> In addition, the Ethiopian government implemented the Acute Respiratory Infection Diagnostic Aids (ARIDA) initiative supported by United Nations Children’s Emergency Fund (UNICEF). The aim of the ARIDA initiative was to identify and test innovative diagnostic tools to improve the identification, classification and management of children with pneumonia. Under ARIDA, the use of two automated RR counters, the ChARM (RR only) and the RadG (RR and pulse oximetry) were evaluated within the context of iCCM/IMNCI at primary-level health facilities (eg, hospitals, health centres and health posts) and in communities in Ethiopia.<sup>##UREF##3##22##</sup></p>", "<p> The ARIDA initiative was implemented in 5 regions of Ethiopia (from November 2018 to April 2019). Health extension workers (HEWs) who diagnose children with pneumonia at community-based health posts as well as at patient homes, and Front-line health workers (FLHWs) based in facilities were trained. Trainings and refresher trainings covered pneumonia diagnosis and management and the correct application of the devices. Trainings lasted one to one and a half days using the Training of Trainers model and included training guides along with job aids that were provided to each trainee. Training was given to 5291 health workers (3911 HEWs from 1973 health posts were trained on ChARM; 1380 FLHWs in over 445 health centres and primary hospitals were trained on Rad-G).</p>", "<p> This initiative resulted in an estimated 279 750 direct child beneficiaries. Detailed methods of the ARIDA initiative have been described previously.<sup>##REF##32224491##9##</sup> iCCM and IMNCI guidelines were updated to include use of the ARIDA devices.<sup>##UREF##4##23##</sup> Regional health bureaus allocated devices. District Health Office supervisors who completed the training provided monthly supportive supervision to the districts and the facilities. UNICEF field and central offices performed at least two site visits during the project. The first visit occurred within a month of the training and receipt of the devices and the second occurred during the middle of the project implementation.</p>", "<p> The results of the usability and acceptability of the ARIDA initiative have been published elsewhere.<sup>##REF##31762072##12##,##REF##31638714##13##,##REF##33220086##24##,##REF##31762072##25##</sup></p>", "<p> This study aimed to identify practical health system-level lessons from the implementation of the ARIDA initiative. Objectives included understanding successes, challenges and recommendations for implementation from multiple perspectives within the health system and to identify further evidence needed for scale-up.</p>" ]	[ "<title>Methods</title>", "<p> This study’s approach builds upon the World Health Organization (WHO) health system building blocks and the conceptual implementation research framework by Peters et al.<sup>##UREF##5##26##,##UREF##6##27##</sup> We applied a modified Tanahashi Bottleneck Framework for the evaluation.<sup>##REF##96953##28##</sup> We utilized semi-structured key informant interviews (KIIs) to meet the research objectives. KIIs were conducted using interview guides tailored to participants’ expertise and informed by current literature in consultation with the UNICEF Ethiopia country office and the Federal Ministry of Health of Ethiopia (FMoH). The guides included themes related to use of devices for RR counting, health workforce perceptions, training and supportive supervision, referral pathways, availability of supplies and commodities for pneumonia (eg, amoxicillin, gentamicin and oxygen), community uptake of the ARIDA initiative (including community engagement and perceived caregivers’ responses) and scaling up within the health system. The guides were not pilot tested. Recruitment, data collection and data quality monitoring were completed by trained researchers in coordination with UNICEF. Members of the research team were male, with Masters degrees or undergraduate degrees, trained in data collection, qualitative research methods, and the objectives of the study. Interviewer requirements included being male or female, having university level education related to health sciences, had no prior relationship with or knowledge about the interviewees and no reported biases. Participants had no prior knowledge of the researcher, other than knowing the objectives of the research. No interviewer biases were identified.</p>", "<p> Criterion purposive sampling was used to identify participants in each region from HEWs in communities, facilities (eg, FLHWs, clinic managers), trainers of the health workers, and district management/decision-makers (eg, <italic toggle=\"yes\">woreda</italic>- and zonal-level management, regional key decision-makers and policy influencers) until a pre-determined number was reached. Participants were approached face-to-face, provided with information (verbally and in writing) on the objectives of the research and the voluntary nature of participation. All participants provided written, informed consent, and their identities were kept confidential. Interviews lasted between 15 to 78 minutes. Interviews were conducted at the interviewees’ offices in their preferred language (Amharic, Tigrigna or Afan Oromo), with no other people present. KIIs were audio recorded and field notes were taken. Audio files were transcribed and translated into English. Data quality and translation consistency were checked across the study process by the research team. Due to time limitations, the transcripts were not returned to participants for confirmation. No repeat interviews were done and no one refused to participate. The aim of the study was to reach saturation within participant groups across diverse perspectives in the health system and geographic areas within the timeframe and budget of the study.</p>", "<p> The study was designed and coordinated in partnership with the FMoH and adhered to ethical standards of embedded implementation research.<sup>##UREF##7##29##</sup> Institutional review board approval was not sought as the study was part of routine program evaluation. All regional health bureaus provided letters of support endorsing the qualitative data collection. FMoH partners and regional bureau heads reviewed and approved the consent forms and study. Written, informed consent was collected from all participants and no identifying, personal information was reported. All data were kept secure in password protected files.</p>", "<title> Participants</title>", "<p> Participants (n = 57) were interviewed between June 10, 2019 and July 4, 2019 across five regions, seven zones and 14 <italic toggle=\"yes\">woredas</italic> where the ARIDA initiative was implemented. The regions included Benishangul-Gumuz, Oromia, Southern Nations, Nationalities, and Peoples’ Region (SNNPR), Tigray, and Afar. The regions with the largest numbers of participants were SNNPR (30%, n = 17) and Oromia (26%, n = 15), coinciding with the areas where the largest scale of activities occurred (##TAB##0##Table 1##). Participants were interviewed an average of 4 months after ARIDA implementation (range: 3-5 months).</p>", "<p> The majority of participants were health workers, including HEWs (n = 14) and FLHWs (n = 14), health centre managers (n = 7) and trainers of the health workers (n = 7). Participants also included Zonal or regional health system managers (n = 5) and policy influencers and decision-makers (n = 10), which included senior management from the FMoH (##TAB##1##Table 2##). The HEWs interviewed covered an average of 1600 households (range: 144 to 7754).</p>", "<title> Data Handling and Analysis</title>", "<p> English transcripts were analyzed by a trained researcher (AR) utilizing ATLAS.ti version 8 software (Scientific Software Development GmbH). Open, first-level coding was done based on the <italic toggle=\"yes\">a priori</italic> sub-categories of the KII guides using a deductive approach. No new emergent themes were identified. This resulted in 1271 unique open codes which were applied to a modified Tanahashi bottleneck analysis framework,<sup>##REF##96953##28##</sup> resulting in 58 codes. The Tanahashi framework focuses on the interactions between service provision and the end service users. We modified the framework with an emphasis on ascertaining health system successes and challenges related to the implementation of the ARIDA initiative, within the following domains: (1) Supply; (2) Demand; (3) Enabling environment; and (4) Quality (see ##SUPPL##0##Supplementary file 1##).</p>", "<p> Co-authors (JK and AA) confirmed the correct application of the framework. For codes in the ‘supply’ category, data were disaggregated by pastoralist/semi-pastoralist regions (eg, Afar and Benishangul-Gumuz) and non-pastoralist regions in order to identify geographical differences in the supply chains or access to commodities across these parameters. Additionally, health-seeking behaviour was disaggregated by participant category. Differences that were identified in these sub-analyses are described in the results section. Data were synthesized by participant categories, and themes related to the specific objectives of the research were identified utilizing the grounded theory approach.<sup>##REF##14725778##30##</sup></p>" ]	[ "<title>Results</title>", "<title> Devices-ChARM (Supply and Quality)</title>", "<p> The majority of participants perceived the ChARM device to be more accurate than manual counting using timers for counting RRs to diagnose pneumonia in children. Participants also described ChARM as easy to use and read, with a clear indication of when to refer the patient for further care, as seen in the following quote:</p>", "<p> “<italic toggle=\"yes\">Before ChARM, we used to count children’s breathing using our eyes. But now ChARM made breath counting easier. It is faster than the previous method because it can count the child’s breaths immediately. The previous method could lead us to make a wrong decision. ChARM displays the correct count [and] is more accurate because [it] is supported with a diagnostic tool. It displays the correct figure/count”</italic> [HEW, SNNPR].</p>", "<p> Health workers spoke of benefits related to having age-specific or standardized breathing counts shown in the device, which included improving their confidence to diagnose and manage pneumonia while reducing unnecessary referrals and prescriptions. Some health workers felt the ChARM device saved time or was faster compared to previously used timers and described advantages of completing other tasks while awaiting the results (eg, intake forms, other vitals, charting). HEWs described ChARM as lightweight and easy to transport during household visits.</p>", "<p> However, inadequate numbers of ChARM devices was identified as a challenge since every health worker did not receive a device, especially in pastoralist regions, as seen in the following quote:</p>", "<p> “<italic toggle=\"yes\">We do not have enough devices for the number of health extension workers. We are facing problems when we visit households with sick children”</italic> [HEW, SNNPR].</p>", "<p> Participants recommended that all health workers be provided with a device. Health workers also described increased consultation times using ChARM when the child was moving or agitated, severely malnourished, or fearful of the device, especially in pastoralist areas. They recommended a device that would function in these circumstances. Concerns were also raised about the battery life of the device, with mixed recommendations on preferences for chargeable or non-chargeable devices. Some felt the rechargeable devices allowed for continued use; others felt the non-rechargeable devices were better, as they were not influenced by the electricity fluctuations in the health centre.</p>", "<title> Devices-RadRad-G (Supply and Quality)</title>", "<p> The majority of health workers felt that Rad-G was more accurate and faster than visually counting RR, with some describing it as a one-step device. Health workers felt it improved their knowledge to manage and treat pneumonia by providing more information (eg, age classification, classifying the severity of pneumonia, oxygen saturation, positive and negative results), and allowed them to diagnose and refer based on evidence, as described below:</p>", "<p> “<italic toggle=\"yes\">In the case of the older method [visually counting], we treated with the help of signs according to a chart. Ages are [classified] as a total without [accounting for] age group characterization of cases. But the new device shows the readings according to age groups, which makes it preferable to use. The device gives a signal/message/if the case needs referral – a red light. The device itself tells you to refer the case and also shows whether cases are manageable at health centre level”</italic> [FLHW, SNNPR].</p>", "<p> Challenges in using Rad-G included inadequate numbers of devices for the volume of patients since devices were concurrently used by multiple health facility departments (eg, outpatient and antenatal), as described below:</p>", "<p> “<italic toggle=\"yes\">Sufficient devices were not available in our health centre. We have one Rad-G which is not sufficient to serve the patients on time because of the high load of patients. If we get one additional device, two health workers can serve patients on time”</italic> [FLHW, Oromia].</p>", "<p> Participants recommended providing additional devices and expanding training to all health workers and facilities, including health posts. Health workers recommended improving the functionality and sensitivity of Rad-G so the probe attachment could be easily used while children are moving or agitated. Some health workers felt Rad-G could be improved by reading temperature and pulse as well [Authors comment: Rad-G does measure pulse rate, but health workers were not trained on this as part of the ARIDA initiative]. Additionally, health workers were concerned that no device maintenance was scheduled and described issues related to device malfunction and charging (eg, lack of electricity, needing to monitor and charge the battery, device not being usable while charging). They recommended providing back-up batteries or increasing the battery life.</p>", "<title> Caregivers’ and Children’s Reactions to the ARIDA Devices (Demand)</title>", "<p> Health workers reported that children had mixed reactions to the devices, identifying trends by age and geography, as described below:</p>", "<p> “<italic toggle=\"yes\">When children get diagnosed, they perceive the device as a toy. Even if children were crying before diagnosis, they get calm and relax when they see the device. All children do not react the same way while being diagnosed. We classify their ages into three groups. Children under age 1 react neutrally; children around age 3 usually perceive them as toys. There are also children who cry or react distressfully to the device”</italic> [HEW, SNNPR].</p>", "<p> Participants felt 2–5-year-olds were more likely to be calmed or entertained by the devices compared to younger children, who may fear an unfamiliar provider or the possibility of injections. They described urban children as more likely to be entertained by images and sounds on the Rad-G devices, or view the devices as toys, compared to rural children, who presumably have less exposure to technology. Positive descriptions of reactions to the devices included words such as ‘calm, happy, or entertained,’ while negative reactions included ‘stressed/distressed, fear/frightened, angry/aggressive, or crying/fussing.’</p>", "<p> Despite some perceived negative reactions that health workers reported in their interactions with children, many health workers felt it had little impact on device use, aside from increasing consultation times. When children exhibited negative reactions health workers allowed caregivers to calm children (eg, breastfeeding), modified the device use (eg, hiding the device from the child’s view, turning off sound, and played with devices) or demonstrated its safe use on another child or adult.</p>", "<p> The majority of health workers felt caregivers reacted positively to the devices and often requested they use the devices since becoming aware of them from HEWs or through community engagement. Many health workers felt caregivers perceived devices to diagnose pneumonia more accurately, which increased parents’ trust in health workers’ diagnoses and capabilities, as seen in the quotes below:</p>", "<p> “<italic toggle=\"yes\">I contacted parents after treatment and asked them what they were told about the device. And they replied to me that formerly their children were clinically assessed by unconfirmed diagnosis, but after the device was introduced, that they are happy when they see the respiration is being counted correctly for their children”</italic> [Regional Health Bureau representative, Benishangul-Gumuz].</p>", "<p> “<italic toggle=\"yes\">They feel very happy with our treatment of their children using the device. They say: ‘Did you have such a device before at health post level?’ The caregivers feel happy with it”</italic> [HEW, Oromia].</p>", "<p> “<italic toggle=\"yes\">The caregivers react happily when I measure their children with the device. They feel that their children are being diagnosed correctly if they are measured by the device. They say: ‘My child got the right diagnosis with a right device and right treatment’”</italic> [FLHW, Tigray].</p>", "<p> If caregivers had negative responses, health workers educated the caregivers and their communities on the benefits and demonstrated its safe use on children. Health workers felt the devices facilitated community diagnosis, saving travel time to facilities for rural patients.</p>", "<title> Community Engagement (Supply)</title>", "<p> The aim of community engagement was to raise awareness about childhood pneumonia and introduce the availability of automated RR devices. Each region led their own engagement. It usually included HEWs informing communities via community networks (eg, health development armies, mothers’ groups, vaccination sessions, and health committees), during household visits, monthly meetings or at the health posts. Some community engagement was provided by nurses, in collaboration with the <italic toggle=\"yes\">woredas</italic> and <italic toggle=\"yes\">kebeles</italic>, or with written letters to the lower levels of the health system and communities (ie, village heads and administration, women’s associations). Another method was to rely on the word of mouth of caregivers visiting the health facilities. Lastly, some participants reported that there was no community engagement outreach done and that the community members were informed of the initiative when they visited the facilities.</p>", "<p> Many health workers reported high community acceptability of the engagement strategies, as demonstrated by perceived high attendance and seeking care when symptoms were present, as described below:</p>", "<p> “<italic toggle=\"yes\">Since [ARIDA] was implemented in our health post, more people who have sick children under 5 visit the health post for diagnosis and treatment. The community’s awareness about the device has increased. Whenever we go for outreach and whenever they come to the health facility, we teach them about the device, which created awareness</italic>” [HEW, Oromia].</p>", "<p> “<italic toggle=\"yes\">When the community is aware of the device, it allows increased service utilization, which in our case resulted in increased health facility visits</italic>” [Facility Manager, Benishangul-Gumuz].</p>", "<p> Some participants felt engaging communities (including HEWs) early and allowing for their recommendations on who should be engaged and how led to community ownership. This was described as improving trust with the communities, especially increasing the acceptance of HEWs as health workers.</p>", "<p> Many participants reported challenges related to disparities in community engagement activities, with some communities not receiving any engagement and unaware of the initiative or that free services were available at the facilities. They recommended utilizing community organizations and government structures to improve engagement and generate more demand for services. Some challenges to community engagement included low community participation for populations living in difficult-to-access geographical areas (eg, large distances to health facilities, mobile populations, and those impacted by floods), farmers during the harvest season and new mothers, as described below:</p>", "<p> “<italic toggle=\"yes\">Mothers who give birth for the first time may not be aware of this intervention, because these mothers have not participated in immunization sessions. We give health education on danger signs of pregnancy for pregnant mothers. Since we cannot address all mothers, we are unable to address all households”</italic> [HEW, Tigray].</p>", "<p> Participants felt engaging schools, holding conferences targeting pregnant mothers and training community members (eg, HEWs and health development armies) could improve health education and community engagement, as described in the following quote:</p>", "<p> “<italic toggle=\"yes\">Yes, it is better to train health development armies and send them down to the community to train people under them. They use every opportunity to give health education while people are gathered together”</italic> [HEW, SNNPR].</p>", "<p> Some participants described challenges related to lack of budgets for community engagement, including insufficient educational materials and incentives for participation. Participants recommended providing budget, strategic direction and planning for community engagement.</p>", "<title> Initial Utilization/Health-Seeking Behavior (Demand)</title>", "<p> The majority of health workers perceived increases in care seeking behaviors at the community and the health facility levels, with some describing no changes. Many health centre managers and FLHWs reported increased patients seeking pneumonia-related care at the health centres since the initiative, as seen below.</p>", "<p> “<italic toggle=\"yes\">After Rad-G came to our facility, we noticed that even if the under-5 children get the common cold, they bring [them] immediately to our health centre. Recently, our community [has become] aware about the device – whenever they come to health centre they say: ‘Please see my child with this device’”</italic> [FLHW, Oromia].</p>", "<p> Participants ascribed the increases to successful community mobilization and awareness, an interest in new technology, and community members sharing positive experiences after accessing health services with ARIDA devices. Many HEWs described how community members sought care for coughs earlier than before the initiative and felt being able to diagnose and treat children during home visits increased healthcare access to populations who would otherwise not attend the facilities. Many participants felt community members had more confidence or trust in diagnoses where devices were used and perceived increased quality of care received, especially for HEWs, as seen in the following quote:</p>", "<p> “<italic toggle=\"yes\">Before the introduction of the new equipment, patients did not believe in health extension workers’ treatment. But after the training, in collaboration with the woreda, different mobilization efforts were made to advertise and familiarize the device with the community. The number of pneumonia patients seeking treatment has relatively increased, both at facility and health extension level. Therefore, this innovation played a significant role in building trust in health workers from the community”</italic> [Health Centre Manager, SNNPR].</p>", "<p> The challenges to seeking diagnosis and treatment for pneumonia and other childhood illnesses described by participants were related to access to health facilities and posts and a lack of drugs at the facilities. Many participants felt remote communities were unable to access services due to large distances to the facilities and health posts, poor road conditions, poor health post conditions and weak transportation networks. Some participants felt there were gaps in health workers’ knowledge of pneumonia treatment, which decreased the communities’ confidence in the health workers and reduced their motivation to engage in the initiative.</p>", "<title> Drug Supply and Medical Oxygen (Supply)</title>", "<p> All participants confirmed that amoxicillin was available at the facilities but identified gaps with continuous and appropriate supply (ie, correct dosage and formulation). Many participants reported that gentamicin was not available in all health centers, especially in pastoralist areas. Stockouts of gentamicin were reported as lasting one month to over a year and were due to failure to order on time, lack of standardized supply chains, lack of budget and difficulties with drug importation, as described below:</p>", "<p> “<italic toggle=\"yes\">From the facilities, there is drug request [every] quarter or three months. We collect our share [of medication] and if there is lack of adequate drug, we buy [it] by allotting the budget of the health facility. Gentamicin is difficult to find. There are budget-related problems [i.e. lack of budget]. There is amoxicillin named DT tablet [that is] donated”</italic> [Policy Influencer and Decision-Maker, Oromia].</p>", "<p> The most widely discussed impacts from drug stockouts were that patients were referred to higher-level facilities to collect drugs, required to purchase drugs, or children not receiving timely and appropriate treatment. Recommendations to improve the drug supply chain and prevent stockouts included stockpiling extra medication at health centres, early reporting and requesting of drug supplies, and timely availability of budget to purchase drugs. Many participants recommended strengthening the procurement and supply chains, and some recommended that the supply chain should be managed by the central government, rather than donors, to ensure harmonized coordination. Stockouts were described as compromising communities’ confidence and trust in health workers and the health system and decreasing health workers’ motivation.</p>", "<p> The majority of participants described a lack of oxygen at facilities where Rad-G devices were implemented or at linked referral facilities, despite the availability of cylinders for refill. Determinants of the lack of oxygen supply and its use included shortages of staff trained in oxygen administration and maintenance, lack of budget at health centres and within districts, and a national deficiency of supplies and equipment related to oxygen. Concerning the national distribution of oxygen, high-level participants discussed challenges related to poor transportation networks to provide oxygen to areas outside the central distribution points, shortages of cylinders and compressors, and poor communication between the government and stakeholders (eg, FMoH, implementing partners, etc), as described below:</p>", "<p> “<italic toggle=\"yes\">Coming from far to refill oxygen cylinders is very tedious and difficult. Even travelling 100 km to fill oxygen is difficult. So, to solve this problem the supply of the oxygen should be facilitated at the nearest centre. The capacity of the professionals should be upgraded – they must be equipped with the knowledge: how they administer, how they distribute it at the level of health station. They need to upscale their understanding. But the provision is the greatest problem”</italic> [Policy Influencer and Decision-Maker, Oromia].</p>", "<p> “<italic toggle=\"yes\">In health centres, only an empty cylinder is available, with no oxygen … There are times when the children die because of a lack of oxygen. If a child has caught pneumonia, they need oxygen to breathe. The hospital may lack oxygen. But if oxygen is available at the health centre, there will be a chance to save the life of the child”</italic> [Health Centre Manager, Oromia].</p>", "<p> The uninterrupted provision of oxygen was a widely discussed health system requirement for improving pneumonia case management. Many of the challenges identified are addressed in Ethiopia’s National Medical Oxygen and Pulse Oximetry Scale-Up roadmap (2016-2020/2021).<sup>##UREF##8##31##</sup></p>", "<title> Referral Pathways (Demand)</title>", "<p> Many participants felt referral pathways for children with severe pneumonia or hypoxemia functioned adequately after being diagnosed using ARIDA devices, despite describing many challenges. There were large variations in reported time and distance patients travelled when referred for oxygen therapy/treatment of severe pneumonia (range 3-75 km, average 17 km). The time it took to travel these distances ranged from 10 minutes (walk) to 1.5 hours (car), up to 3 hours (walk).</p>", "<p> Participants described successes with referral pathways including HEWs treating patients prior to referral and perceived reductions in unnecessary referrals to higher-level health facilities based on the devices’ readings. Many FLHWs felt that with the additional measure of pulse oximetry in RadG decisions to refer patients were easier than before. They felt health workers followed up with receiving hospitals appropriately.</p>", "<p> Challenges to the referral pathways were related to staff knowledge and motivation, transportation access, communication, inadequate referral forms and patient-related factors. Some participants felt health workers lacked knowledge of when to refer patients and motivation to refer patients, as it increased their already high workloads. Participants recommended that training on adequately filling out referral forms could facilitate referrals. Many participants described large distances, poor road conditions, and insufficient numbers and distributions of clinics as challenges to referrals. Providing functioning ambulances with fuel and improving road conditions were discussed as ways to facilitate timely and appropriate referrals. Communication was a determinant in strong referral networks and participants described gaps in communication between health facilities and hospitals to arrange referrals, especially concerning hospital bed availability. Health workers discussed a lack of stationery or forms for referrals, or forms that did not contain the necessary information, as challenges to referring patients. Some participants described challenges of patients not wanting to be referred, or patients bypassing the existing protocols and self-referring to higher-level facilities. This was often described as being related to the low knowledge levels of staff and the low quality of services provided at lower-level health facilities. Participants described how improvements in the supply of oxygen in facilities with Rad-G would reduce referrals. Participants recommended strengthening referral networks for timely referral of sick children. Recommendations included building the capacity of health workers, improving transportation and communication networks, educating the communities, ensuring adequate supplies and commodities, and more commitment from higher levels of the health system.</p>", "<title> Staff Satisfaction and Motivation, Training and Supportive Supervision (Enabling Environment)</title>", "<title> Staff Satisfaction and Motivation</title>", "<p> Health workers described being more satisfied and motivated since using the ARIDA devices and receiving the training, as seen below:</p>", "<p> “<italic toggle=\"yes\">It has a big influence. It has reduced my burden of work. Before, it was very difficult to count their beat [RR] because children could be unstable. But now, once we tie the instrument over the breast line, there is nothing to worry about. You just stop it when you see a red or green light. This has solved all these problems and enabled us to get an accurate count”</italic> [HEW, Benishangul-Gumuz].</p>", "<p> “<italic toggle=\"yes\">This ARIDA package influenced our motivation and job satisfaction in positive ways. Since with full confidence, i.e., without any uncertainty we obtain accurate diagnostic results and save our time, we are happy with the device and more satisfied in our jobs”</italic> [FLHW, Oromia].</p>", "<p> They attributed this to having increased confidence in their ability to diagnose and treat pneumonia and perceived simplification of their jobs. Many felt the devices saved time and allowed them to complete their jobs more efficiently while decreasing workload. HEWs felt it added value to their profession.</p>", "<p> Challenges related to staff satisfaction and motivation included increased workload due to more cases being screened and treated for pneumonia. Health workers also felt frustrated when they could diagnose but not treat patients due to a lack of treatments and health infrastructure. A few participants felt that devices malfunctioning or not being sufficiently charged for use compromised gains made by the initiative.</p>", "<title> Training</title>", "<p> Health workers reported the training they received as part of the ARIDA initiative as highly acceptable and described it as practical, simple, accessible and participatory. The language used was clear, with adequate access to local languages and at appropriate levels for the health workers. The content was described as adequate to implement the devices and contained refreshers on MNCH (Maternal, Newborn, and Child Health) and IMNCI/iCCM. Health workers described facilitators to the training, which included the provision of chart booklets, practicing on volunteer children, and good mentorship and support throughout the training. Trainers were often described as well-qualified and accessible and some health workers described additional support from managers at facility, zonal and <italic toggle=\"yes\">woreda</italic> levels.</p>", "<p> However, health workers felt more training days (eg, 3 days) were needed to be fully competent in correctly applying either of the two devices and making decisions on treatment and/or referral based on results. Some health workers felt the training needed more practical sessions (eg, demonstrating the use of devices in facilities and communities) and trainings. Many health workers recommended that more staff needed to be trained, ranging from HEWs on the device use at household levels to higher-level staff within the health system (ie, all facility, zonal and <italic toggle=\"yes\">kebele</italic> managers). High staff turnover, low numbers of human resources and absenteeism were described as challenges to having only one health worker trained per facility.</p>", "<title> Supportive Supervision</title>", "<p> Supportive supervision was described as having many benefits, including refreshing information learned, improving clinical practice, correcting mistakes and problem solving, identifying device malfunctions, and motivating staff. Many health workers reported receiving little or no supportive supervision; this was described as inadequate. Challenges to providing supportive supervision included lack of designated budget for supervision and no dedicated staff to provide technical support, not being requested to provide updates on the project successes or challenges, and a lack of management’s technical knowledge of the ARIDA initiative.</p>", "<p> Recommendations to improve supportive supervision included mandating supervision to occur monthly or every three months and including higher-level management in the process. Recommendations included federal-level support, providing budget and transportation to facilitate supervision, especially in rural areas, and improving reporting of the project throughout the health system.</p>", "<title> Considerations for Scale-up (Demand)</title>", "<p> All participants recommended scaling-up nationally and integrating the devices into iCCM/IMNCI in all regions interviewed. The most widely discussed reasons for scale-up were that the intervention is perceived to save lives by improving early diagnosis and treatment for pneumonia and reducing pneumonia-related morbidity and mortality. Participants felt scale-up should be government-led with support from implementing partners (eg, inputs and logistics, including the purchase of devices). A few participants described the need for memorandums of understanding on the roles of stakeholders involved in scaling up ARIDA devices, as well as guidelines for use of the devices. Many participants also felt the intervention needed to be integrated and absorbed by the national health system in order to be sustainable and equitable.</p>", "<p> Many high-level participants involved with policy-making in the ministry felt the intervention could be easily integrated with IMNCI and iCCM guidelines given that the devices’ algorithms are congruent with diagnosis and treatment guidelines and with Ethiopia’s strong primary healthcare-based health system and efforts to improve quality of care. The most widely discussed challenges to integration were related to data collection and reporting (eg, lacking space in registers to record oxygen saturation, lack of data fields in the health information systems). Many higher-level participants felt that adequate financial resources existed to absorb the scale-up of ARIDA devices into the health system nationally, while fewer felt the budget for devices and training may hinder successes. Many participants described the need for adequate budget related to supplies (drugs, oxygen and device procurement) and human resources (training and follow-up).</p>", "<p> While all participants interviewed recommended scaling up nationally, further information is needed on costing with considerations for sustainability and scalability.</p>", "<title> Policy Engagement and Evidence Needed (Enabling Environment)</title>", "<p> Ministry participants and policy-makers recommended engaging the following groups in policy dialogue: international implementing partners (including WHO, UNICEF, World Vision), non-governmental organizations, political leaders, FMoH, and researchers from universities. Input from lower levels of the health system was discussed as essential — including HEWs, health centre board members, health workers, pharmacists, primary healthcare unit staff and <italic toggle=\"yes\">kebele</italic>, zonal and regional health bureaus. Engagement was recommended via technical working groups with roundtable discussions and experience sharing/workshops across all levels of the health systems.</p>", "<p> Participants identified the need for further evidence prior to health system scale-up and integration. This included evidence on the effectiveness of the devices in reducing mortality and morbidity. Participants recommended that evidence on acceptability and adaptability results from the pilot study be shared, including numbers of children identified and treated for pneumonia, clinics access to power, benefits of the devices and how they are being used, and health-seeking data. Participants from the Ministry identified the need for evidence, including return-on-investment studies, costing and forecasting that are adaptable by region, and how many people have been and need to be trained to render the services to the population.</p>" ]	[ "<title>Discussion</title>", "<p> Practical health system-level lessons were identified from the implementation of the ARIDA initiative in 5 regions of Ethiopia. The newly-introduced automatic RR devices were acceptable by health workers and parents, and all participants recommended scale-up of the devices nationally. However, for the devices to have maximum impact on diagnosis and management of childhood pneumonia, considerations of scale-up must be accompanied by broader health system strengthening of all relevant components along the pneumonia and broader child healthcare pathway.</p>", "<p> Our study builds upon evidence from Ethiopia and Malawi, which has shown that the addition of pulse oximeters within Integrated Management of Childhood Illness can improve the identification of severe pneumonia and hypoxia in children.<sup>##UREF##9##32##,##REF##27994282##33##</sup> Furthermore, the results of our study suggest that the additional evidence provided by the devices could help to identify children with pneumonia who may not otherwise have visited healthcare facilities. Moreover, the provision of additional devices could improve equity and access to care while also increasing healthcare workers’ confidence in their ability to diagnose, treat, and refer pneumonia cases. While all of these factors suggest that the ARIDA devices have the potential to reduce pneumonia-related morbidity and mortality, several important considerations remain regarding widespread scale-up of this initiative.</p>", "<p> First, disparities in community engagement during the ARIDA initiative were identified. Effective community engagement and participation can lead to improvements in health-seeking behaviour in low resource settings.<sup>##UREF##10##34##</sup> Engaging communities can ensure demand generation, improved care seeking and improving education during the implementation of automated RR counters. Equitable engagement should be facilitated through strategic community engagement guidelines and adequate budget for child health that includes leveraging and training existing community networks and groups to provide education and disseminate pneumonia related counselling.</p>", "<p> Second, although health workers felt the training and device implementation improved their job satisfaction and morale, health worker capacity must be considered. Our study findings are similar to a study in Ethiopia where the authors identified high acceptability and usability from health workers of Rad-G, but also highlighted the need for additional training.<sup>##REF##33220086##24##</sup> Training additional health workers in facilities and communities on the use of ARIDA devices would allow more health workers to use the devices simultaneously and create a more equitable workload distribution. However, supportive supervision and mentorship are critical determinants of the provision of consistent and high-quality child healthcare at decentralized levels of the health system,<sup>##REF##25845075##35##</sup> and these supports were not always adequate in our study. Dedicated resources for supportive supervision would facilitate uptake of the devices, but these resources may not be readily available in many regions.</p>", "<p> Third, additional resources must be allocated for pneumonia treatment and management in local health centres. Although amoxicillin was readily available during the study period, streamlining and strengthening supply chains for essential medicines in primary healthcare is recommended. In particular, there is an urgent need to improve access to medical oxygen in health centres by availing oxygen-related budget, providing training and supplies at all levels of the health system, supporting capacity building of human resources and developing decentralized oxygen distribution networks as described in the Oxygen Roadmap for Ethiopia.<sup>##UREF##8##31##</sup> The availability of oxygen is especially important for care of children with severe pneumonia as well as other conditions, before, during referral and at referral level. As noted by participants in our study, the inability to provide adequate treatment to patients who were diagnosed as having pneumonia by the devices is frustrating, and improving the availability of oxygen would improve patient outcomes and access to care, and would reduce the need for referrals to other facilities.</p>", "<p> Fourth, our study revealed a need for increased communication and collaboration between health centres and hospitals when referrals are required. This finding is consistent with a study Southern Ethiopia where the addition of pulse oximetry to primary healthcare centres increased the number of children diagnosed with severe pneumonia but children referred to hospital often did not go due to lack of transportation.<sup>##UREF##9##32##</sup> Strengthened referral networks and communication between health centres would help to ensure patient follow-up and connect patients to the care they need, consistent with other studies in Ethiopia.<sup>##REF##36698154##36##,##REF##35465631##37##</sup> Additionally, consistent and equitably distributed resources to treat childhood pneumonia must be available at referral centres to improve access and build trust from the communities. For example, access to X-ray machines varies by facility in Ethiopia, with approximately one-third of referral and primary hospitals having access to one-half of general hospitals.<sup>##UREF##11##38##</sup>.</p>", "<p> Despite the encouraging uptake of the ChARM and RadG devices in the health system context in Ethiopia, several outstanding knowledge gaps remain on their optimal use. Discussions on the merits of using automated RR for diagnosis of pneumonia in LMICs have prevailed,<sup>##REF##31388660##3##,##REF##31832612##39##, ####REF##31832613##40##, ##REF##31388657##41####31388657##41##</sup> but rigorous evidence is needed to understand the impact on pneumonia management and outcomes.<sup>##REF##31638714##13##</sup> Therefore, quantitative data on the use of automated RR counters in the pneumonia pathway, including assessment classification, treatment, referral completion, and rational antibiotic use are needed. While the availability of the devices was perceived to improve care seeking behavior and clinical management in this study, cost is a significant factor in the implementation of automated RR counters and further evidence is needed on costing within broader budgets and return on investment.<sup>##UREF##8##31##</sup> This should include costs related to supplies (drugs, oxygen and device procurement) and human resources (training, follow-up) that are adaptable by differences in regional health systems.</p>", "<title> Strengths and Limitations</title>", "<p> This study’s strengths include its diverse sample of participants, which allowed for the identification of health system bottlenecks and key considerations related to scaling-up automated RR devices in Ethiopia. The data were collected less than six months following implementation, thereby reducing the potential for recall bias. However, limitations do exist. Conclusions reached from data representing five geographic regions from participants who were purposively selected may not be generalizable to the wider population. Ethiopia has a unique model of HEWs that may compromise generalizability outside the country. Since we captured data six months after implementation, we were unable to capture long-term impact including changes in care seeking behavior or resources. Additionally, health workers provided opinions of the caregiver and patient experiences, which could lead to erroneous interpretation. Although the acceptability of the devices has already been established in research involving caregivers in this context,<sup>##REF##31638714##13##</sup> additional studies inviting caregivers and patients to participate is recommended. Lastly, although we attempted to minimise social desirability bias by conducting interviews in private locations and ensuring participant confidentiality, we cannot confirm that responses given were not biased.</p>", "<title> Recent Developments</title>", "<p> Since the implementation of the ARIDA initiative, the manufacturer has discontinued ChARM production because of a lack of market viability. Despite stand-alone automated RR counters being cost-effective, validating their accuracy remains limited, especially in those 2 months old and under. Therefore, multimodal devices which have RR counters along with other capacities (eg, Rad-G Continuous, which includes measurements for hypoxemia and temperature) have gained increased interest to support child healthcare providers.<sup>##UREF##12##42##</sup> They add little or no costs when compared to pulse oximeters developed for LMICs. During the COVID-19 response in India, multimodal devices like Rad-G facilitated classification, treatment and referral for childhood pneumonia in outpatient settings, allowing for timely diagnosis while limiting physical contact for health workers and patients.<sup>##REF##34041052##43##</sup> Prior to the pandemic, health workers in this setting checked the child with a stethoscope and touched them to check for fever. Adoption of devices like Rad-G can help to reduce physical contact to prevent the spread of pathogens by allowing healthcare providers to maintain distance. During the COVID-19 response in Ethiopia the demand for multi-modal devices like Rad-G increased along with improved access to oxygen concentrators. Building on findings from this study and the ARIDA project more widely, UNICEF used its supply catalogue to generate and catalyze demand for oxygen therapy, backed by decision support tools and programmatic support. The ARIDA project played an important role in evolving UNICEF’s approach against pneumonia and other respiratory diseases and increasing access to oxygen.</p>" ]	[ "<title>Conclusion</title>", "<p> Automatic RR counters for the decentralized diagnosis of childhood pneumonia could have positive impacts on improving the quality of diagnosis and management of pneumonia in children. However, the study has shown that a health system approach is required to ensure all steps along the pneumonia pathway are adequate, including drug and oxygen supply, community engagement, health worker strengthening including training and support, and referral pathways. The introduction and scaling of innovations (such as automated RR counters) provides an opportunity for broader health system strengthening of all relevant components of the pneumonia care continuum.</p>" ]	[ "<p>\n<bold>Background:</bold> In Ethiopia, childhood pneumonia is diagnosed in primary healthcare settings by measuring respiratory rate (RR) along with the presence of cough, chest indrawing, difficulty breathing, and fast breathing. Our aim was to identify health system-level lessons from implementing two automated RR counters, Children’s Automated Respiration Monitor (ChARM) by Phillips<sup>®</sup> and Rad-G by Masimo<sup>®</sup>, to provide considerations for integrating such devices into child health programmes and health systems. This study was part of an initiative called <italic toggle=\"yes\">the Acute Respiratory Infection Diagnostic Aids (ARIDA)</italic>.\n</p>", "<p><bold>Methods:</bold> Key informant interviews (KIIs) were conducted with 57 participants (health workers in communities and facilities, trainers of health workers, district management, and key decision-makers) in five regions of Ethiopia. Data were analyzed in ATLAS.ti using thematic content analysis and themes were categorized using the Tanahashi bottleneck analysis.\n</p>", "<p><bold>Results:</bold> All participants recommended scaling up the ARIDA initiative nationally as part of Integrated Management of Newborn and Childhood Illness (IMNCI) in primary healthcare. Health workers perceived the devices as: time saving, acceptable by parents and children, and facilitating diagnosis and referrals. Health workers perceived an increased demand for services and reduced numbers of sick children not seeking care. Participants recommended increasing the number of devices distributed and health workers trained. Strengthening drug supply chains, improving oxygen gas availability, and strengthening referral networks would maximize perceived benefits. While training improved knowledge, more supportive supervision, integration with current guidelines and more guidance related to community engagement was recommended.\n</p>", "<p><bold>Conclusion:</bold> Automatic RR counters for the decentralized diagnosis of childhood pneumonia could have positive impact on improving the quality of diagnosis and management of pneumonia in children. However, the study has shown that a health system approach is required to ensure all steps along the pneumonia pathway are adequate, including drug and oxygen supply, community engagement, health worker training and support, and referral pathways.</p>", "<p>\n<bold>Citation:</bold> Rawat A, Ameha A, Karlström J, et al. Health system considerations for community-based implementation of automated respiratory counters to identify childhood pneumonia in 5 regions of Ethiopia: a qualitative study. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7385. doi:10.34172/ijhpm.2023.7385</p>" ]	[ "<title>Acknowledgements</title>", "<p> We gratefully acknowledge the study participants who volunteered their time to share their expertise with us as well as the researchers from the Frontieri research group who conducted the interviews, transcription and translation. We also acknowledge the facilitation and time given to this study by the UNICEF Ethiopia country office, the FMoH and the respective field offices and health bureaus. This study was supported by a UNICEF grant provided by the La Caixa Foundation. We gratefully acknowledge their support. The funders played no role in the design, evaluation or interpretation of the study.</p>", "<title>Ethical issues</title>", "<p> We have no ethical issues to declare. All participants were voluntary and provided written, informed consent.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This study was made possible through a grant to UNICEF by the La Caixa Foundation. We acknowledge their support. The funders had no influence on the study design, execution, or interpretation of the results of this study for this manuscript.</p>", "<title>Supplementary files\n</title>" ]	[]	[]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Participants by Geography\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Region</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Zone</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Woredas</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>n</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Months Since Implementation at the</bold><break/>\n<bold>Time of the Interview</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Afar</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Zones 1 and 4</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Dubti and Asayita </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">5</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Benishangul-Gumuz </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Asossa</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Asossa and Bambasi</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Southern Nations, Nationalities, and Peoples’ Region</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Kaffa</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Chena and Gnimbo </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Sidama</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Bona Zuria and Bensa</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Tigray</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Central</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Adwa and Laelay Maichew</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Oromia </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">East Hararghe</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Gursum and Jarso</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">West Shoa</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Ambo Zuria and Ada’a Berga</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Total</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">57</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Participants by Role in ARIDA Implementation\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Role</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>n</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">HEW</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">14</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Facility level health worker</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Health centre manager</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Regional and zonal health system manager</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Trainers of health workers</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Policy influencer and decision-maker</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Total</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>57</bold>\n</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Automatic respiratory rate (RR) counters for the decentralized diagnosis of childhood pneumonia could have a positive impact on improving the quality of diagnosis and management of pneumonia in children. </p></list-item><list-item><p>However, the study has shown that a health system approach is required to ensure all steps along the pneumonia care pathway are adequate, including drug and oxygen supply, community engagement, health worker training and support, and referral pathways. </p></list-item><list-item><p>The introduction and scaling of innovations (such as automated RR counters) provides an opportunity for broader health system strengthening of all relevant components of the pneumonia care continuum. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> Automatic respiratory rate (RR) counters for the decentralized diagnosis of childhood pneumonia have the potential to improve the quality of diagnosis and management of pneumonia in children. This is particularly important in the community settings and at primary care levels which are often the first points of contact of patients with their health systems. The study highlights the need for adequate training, drug and oxygen supply, community engagement, health worker training and support, and referral pathways. The introduction and scaling of innovations (such as automated RR counters) provides an opportunity for broader health system strengthening of all relevant components of the pneumonia care continuum. This, in turn could improve early diagnosis, management and treatment for children with pneumonia.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Application of the Modified Tanahashi Bottleneck Framework.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: ARIDA, Acute Respiratory Infection Diagnostic Aids; HEW, health extension worker.</p></fn></table-wrap-foot>" ]	[]	[ "<media xlink:href=\"ijhpm-12-7385-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["2"], "mixed-citation": [" World Health Organization (WHO). Revised WHO Classification and Treatment of Pneumonia in Children at Health Facilities: Evidence Summaries. Geneva: WHO; 2014. "], "uri": ["http://apps.who.int/iris/bitstream/10665/137319/1/9789241507813_eng.pdf?ua=1"]}, {"label": ["5"], "person-group": ["\n"], "surname": ["Uwemedimo", "Lewis", "Essien"], "given-names": ["OT", "TP", "EA"], "article-title": ["Distribution and determinants of pneumonia diagnosis using Integrated Management of Childhood Illness guidelines: a nationally representative study in Malawi"], "source": ["BMJ Glob Health"], "year": ["2018"], "volume": ["3"], "issue": ["2"], "fpage": ["e000506"], "pub-id": ["10.1136/bmjgh-2017-000506"]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Rees", "Basnet", "Gentile"], "given-names": ["CA", "S", "A"], "article-title": ["An analysis of clinical predictive values for radiographic pneumonia in children"], "source": ["BMJ Glob Health"], "year": ["2020"], "volume": ["5"], "issue": ["8"], "fpage": ["e002708"], "pub-id": ["10.1136/bmjgh-2020-002708"]}, {"label": ["22"], "mixed-citation": [" UNICEF. ARIDA (Acute Respiratory Infection Diagnostic Aid). "], "uri": ["https://www.unicef.org/innovation/arida"]}, {"label": ["23"], "mixed-citation": [" Kallander K, Baker K, Tarekegn H, Getachew D, Tariku Fantaye A. Acute Respiratory Infection Diagnostic Aids (ARIDA) for children under five years when used in the community setting: Study protocol for the acceptability evaluation. 2018. "]}, {"label": ["26"], "mixed-citation": [" Peters DH, Tran NT, Adam T. Implementation Research in Health: A Practical Guide. Geneva: World Health Organization; 2013. "]}, {"label": ["27"], "mixed-citation": [" World Health Organization (WHO). World Health Report: Health Systems Improving Performance. Geneva: WHO; 2000. "]}, {"label": ["29"], "mixed-citation": [" World Health Organization, Alliance for Health Policy and Systems Research. Embedded Health Policy and Systems Research. "], "uri": ["http://tdr.who.int/alliance-hpsr/resources/Alliance-embedded-hpsr-BriefingNote-WEB.pdf"]}, {"label": ["31"], "mixed-citation": [" The Federal Democratic Republic of Ethiopia, Ministry of Health. National Medical Oxygen and Pulse Oximetry Scale Up Road Map (2016-2020/21). 2016. "], "uri": ["https://www.medbox.org/pdf/5e148832db60a2044c2d35ae"]}, {"label": ["32"], "person-group": ["\n"], "surname": ["Tesfaye", "Gebeyehu", "Loha", "Johansson", "Lindtj\u00f8rn"], "given-names": ["SH", "Y", "E", "KA", "B"], "article-title": ["Pulse oximeter with integrated management of childhood illness for diagnosis of severe childhood pneumonia at rural health institutions in Southern Ethiopia: results from a cluster-randomised controlled trial"], "source": ["BMJ Open"], "year": ["2020"], "volume": ["10"], "issue": ["6"], "fpage": ["e036814"], "pub-id": ["10.1136/bmjopen-2020-036814"]}, {"label": ["34"], "person-group": ["\n"], "surname": ["Farnsworth", "B\u00f6se", "Fajobi"], "given-names": ["SK", "K", "O"], "article-title": ["Community engagement to enhance child survival and early development in low- and middle-income countries: an evidence review"], "source": ["J Health Commun"], "year": ["2014"], "volume": ["19 Suppl 1"], "fpage": ["67"], "lpage": ["88"], "pub-id": ["10.1080/10810730.2014.941519"]}, {"label": ["38"], "mixed-citation": [" Ethiopian Public Health Institute, Ethiopian Ministry of Health. Ethiopia Service Provision Assessment 2021-2022: Preliminary Report. Addis Ababa, Ethiopia; 2022. "]}, {"label": ["42"], "mixed-citation": [" PATH. Tools for Integrated Management of Childhood Illnesses. "], "uri": ["https://www.path.org/resources/improving-access-tools-detect-severe-illness/"]}]	{ "acronym": [], "definition": [] }	43	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 18; 12:7385	oa_package/81/d9/PMC10699823.tar.gz
PMC10699824	0	[ "<title>Background</title>", "<p> Improvements in social and economic conditions were responsible for significant population-level mortality declines in the 20th century.<sup>##UREF##0##1##</sup> This led to an understanding that good health can be supported or inhibited by broader social circumstances. This resulted in social organising, policy efforts and research to prevent ill-health and promote health equity through collective action on structural determinants.</p>", "<p> Over the past 45 years, initiatives such as the Declaration of Alma Ata,<sup>##UREF##1##2##</sup> the Ottawa Charter on Health Promotion<sup>##UREF##2##3##</sup> and the Commission on Social Determinants of Health (SDoH)<sup>##UREF##3##4##</sup> served as seminal moments to address the underlying conditions that lead to healthy societies. Yet, the predominant approach to creating health remains biomedical; focused on healthcare and treatment. Various analysts provide evidence, particularly in high-income settings, that the impact on health from medical care is limited<sup>##UREF##4##5##</sup>; there are estimates that at least 80% of health is related to socio-economic status, the physical environment and health behaviours.<sup>##UREF##5##6##,##UREF##6##7##</sup> Within the health sector there is an underinvestment in preventing ill-health. Estimates suggest less than 10% of health spending is allocated to prevention.<sup>##UREF##7##8##,##REF##19548511##9##</sup> Societal efforts to prevent ill-health, enhance well-being and achieve social justice are neglected; consequently, health inequities continue to grow.</p>", "<p> The World Health Organization’s (WHO’s) 13th Global Programme of Work set three “one billion people targets,” one of which is to ensure one billion more people can enjoy better health.<sup>##UREF##8##10##</sup> Under WHO’s present leadership, a new division has been created focusing on Healthier Populations, including departments dedicated to environment and climate change, SDoH, food safety and nutrition as well as health promotion. Yet compared to the two other one billion targets (on universal health coverage and health emergencies), this third billion is under-invested and under-studied. There is little clarity or agreement on the meaning of the terms “Healthier Populations” or “healthy societies,” its conceptual terrain, or its action and research agendas, even as similar debates are underway across regions of the world.<sup>##UREF##9##11##</sup> This limits efforts to develop and implement relevant policies.</p>" ]	[ "<title>Methods</title>", "<p> This study was initiated following conversations that senior authors were involved with on defining the scope of healthy societies. These interactions included some aimed at articulating what the WHO’s third “Triple Billion” target<sup>##UREF##8##10##</sup> would encompass. Alongside this, some co-authors were involved with an institutional strategy-building on societal determinants of health and on articulating a research vision for “healthier societies.” These discussions were the starting point of our document selection which itself emanated from two reviews — namely Maani et al<sup>##REF##31953933##13##</sup> (reviewing how the commercial determinants of health [CDoH] are represented in social determinants frameworks) and van Olmen et al<sup>##REF##22971107##14##</sup> (a review of health systems frameworks).</p>", "<p> Our initial sample included purposively selected English language political declarations, commission and United Nations (UN) reports, peer-reviewed papers, commissioned evidence reviews and non-governmental organisation guidance notes (##SUPPL##0##Supplementary file 1##). Using the two initial review papers<sup>##REF##31953933##13##,##REF##22971107##14##</sup> as a base, we determined inclusion criteria starting from the 1974 Lalonde Commission Report,<sup>##UREF##11##15##</sup> as this report reinvigorated discussion around McKeown’s hypothesis about the determinants of health and marked a turning point in the global discourse.<sup>##REF##9786043##16##</sup></p>", "<p> Additional documents were identified using Google Scholar searches (using terms “Healthier Societies + Framework,” “Health + Framework,” “Health + Societies,” “Healthier Societies + approach,” “Health Systems + Framework”) covering the period 1974 to 2022. Through snowball sampling an additional 45 documents were proposed by the senior authors based on discussions during the analysis which were thought to be relevant to understanding the concept of “healthy societies.” We initially screened 202 documents using title and abstract details, and extracted data from 97 documents. We chose to exclude documents focussed on healthcare systems that added little to the discussion on keeping people out of such systems.</p>", "<p> Data about each paper were extracted into a coding template (##SUPPL##1##Supplementary file 2##). After reviewing extracted data, following consensus among co-authors, documents focusing on healthcare systems alone or those that do not add to the discussion on keeping people healthy and out of the healthcare system were excluded. Ultimately, 68 documents were used as the database for extraction (12 documents from the original review papers,<sup>##REF##31953933##13##,##REF##22971107##14##</sup> 31 documents from Google Scholar search and 25 documents from snowballing or author suggestions). A PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) flowchart detailing this process is presented in ##SUPPL##2##Supplementary file 3##. Additionally, in our paper, we draw on related publications to inform the analysis.</p>", "<p> Three researchers extracted data from included documents, initially independently followed by code-checking and discussions with two senior authors. Initial analysis, of both peer-reviewed and grey literature together, focused on basic descriptive details (date published, authors, affiliations, type of document, funder) and analytical information (aim, broad topics, policy approaches, and action and research agendas). Following initial analysis, a thematic approach was used for analysis. The findings focus on the presence of key themes, rather than the number of documents that refer to specific themes. Given the variation in our sample and our aim to explore the “what” of healthy societies, rather than the strength of evidence, a quality assessment of included documents was not conducted.</p>", "<p> Through an iterative process that included reviewing the extracted text in relation to different codes, noting themes and tabulations and reflecting on the implications, a heuristic was inductively developed to structure the presentation of the material (##FIG##0##Figure##). As data analysis progressed, this heuristic evolved. This paper focuses on the findings of the two inner parts of the heuristic: values and components. Levers, defined as instruments used by governments to elicit system-wide and societal change to meet objectives and/or respond to key stakeholders,<sup>##UREF##12##17##</sup> and “enablers” are discussed in a companion paper on how to create healthy societies.<sup>##UREF##10##12##</sup></p>", "<p> Guiding principles or frames through which frameworks/authors view the world and/or promote health were extracted. These are considered as “values.” Values were included where specifically identified in the document or if they constituted a fundamental guiding concept. Based on an initial inductive search of documents for values, a coding template of values was developed and applied to the sample. Values were often mentioned in a preambulatory fashion; however, we included them in the analysis only if they were elaborated in a substantive manner. We do not report on how authors defined these values.</p>", "<p> The “components” in the heuristic were identified, defined and elaborated through an iterative process. Documents were categorised inductively. From this broad list, topics were grouped, discussed and then recategorised. As higher-level themes were identified we drew links between key themes and ultimately identified four related components: people; places; products; and planet. For each component illustrative examples extracted from the papers are presented.</p>", "<p> The findings section describes the heuristic and presents the values and each of the components. This is followed by a discussion that reflects on the frameworks, the positionality of the literature and the way the selected literature engages with wider paradigms. After considering limitations, the paper concludes with reflections.</p>" ]	[ "<title>Results</title>", "<title> Elaborating a Healthy Societies Heuristic </title>", "<p> Figure presents a heuristic derived inductively from the included literature. The literature, particularly related to the social determinants, describes a range of inequalities across societies — pertaining to the political, social and/or economic position of individuals, groups, institutions, countries — which drive health inequities (these challenges are listed on the left of Figure). Outcomes are diverse and include improvements across the health and well-being related Sustainable Development Goals (SDGs) targets as well as building population resilience for health emergencies, and fostering sustainability. Societal inequalities shape the afore-mentioned outcomes through many pathways — in what we term the “black box”<sup>[<xref rid=\"fn1\" ref-type=\"fn\">1</xref>]</sup> of healthy societies.</p>", "<p> Inside the healthy societies’ black box, the relationships between the components and levers and enablers can transform (or not transform) inputs to outcomes. For instance, relationships among people relate to the concepts of social capital and social cohesion.<sup>##UREF##3##4##</sup> Relationships between people and the planet reflect the intertwined nature of population health and environmental sustainability (which can disproportionately harm the health of already disadvantaged populations worsening inequity).<sup>##UREF##14##19##</sup> Similarly, the extent to which society allows powerful groups to finance, produce, promote and lobby for the consumption of health-harming products (ie, CDoH) impacts people’s health and well-being.<sup>##UREF##15##20##</sup> The final set of fields relate to the interplay between different geo-political levels: communities, countries, regions and global — reflecting that components and levers interact across levels. Some documents focus on one level,<sup>##REF##21029401##21##,##UREF##16##22##</sup> while others cover several<sup>##UREF##17##23##</sup> (Table S1, ##SUPPL##0##Supplementary file 1##).</p>", "<p> While the fields within the heuristic are presented as discrete, there are many overlaps and linkages. For example, some environmental frameworks view “the environment and its ecosystems as socially determined”<sup>##REF##27814893##24##</sup> (this reflects the linkage between people, places and planet in our heuristic). It is for these reasons we sought to elaborate a heuristic that integrates and elucidates these connections across often linked concepts.</p>", "<title> Values</title>", "<p> We situate values at the centre of the black box. Values drive relationships between the “components” and influence which policy levers are pulled and how hard. Values both reflect and are integral in shaping social norms, and point to the needed cultural shifts towards healthy societies.<sup>##UREF##14##19##,##UREF##18##25##, ####UREF##19##26##, ##REF##28830297##27##, ##REF##30700377##28####30700377##28##</sup> For example, overcoming the “empathy failure” described in the Lancet Commission on Planetary Health.<sup>##REF##26188744##29##</sup> The analysis identifies 21 values in the sample (##SUPPL##3##Supplementary file 4##). We focus on the six that appear most frequently. These values contrast with those that give rise to growing health inequities — in part, presumably, due to inadequate emphasis (or value) that has historically been given to healthy societies’ values in health policy and practice.</p>", "<p> Many frameworks position health, well-being, and even happiness as among the highest of societal values. For example, New Zealand complements economic growth with the value of well-being in its 2019 budget<sup>##UREF##20##30##</sup> and Bhutan position gross national happiness as the endpoint of development.<sup>##UREF##21##31##</sup> However, critics have noted that the latter framework has overlooked human rights.<sup>##REF##27781010##32##</sup> In 2013, drawing on the “Stiglitz-Sen-Fitoussi” Commission on metrics for well-being and previous Human Development Reports,<sup>##UREF##22##33##,##UREF##23##34##</sup> the WHO Europe Regional Office shifted from a focus on disease to one encompassing well-being, and identifies one of six 2020 targets as enhancing the well-being of Europeans.<sup>##UREF##15##20##</sup> In short, several frameworks seek to elevate the societal value of well-being.</p>", "<p> The value identified most frequently is equity (in just over half of the documents). Throughout these texts, equity is closely related to the values of social justice and fairness.<sup>##UREF##2##3##,##UREF##3##4##,##UREF##24##35##, ####REF##16533108##36##, ##UREF##25##37##, ##UREF##26##38##, ##UREF##27##39####27##39##</sup> Tackling inequity features across the literature over the period under review.<sup>##UREF##2##3##,##UREF##3##4##,##UREF##28##40##,##UREF##29##41##</sup> This includes guidance to incorporate equity-based principles in socio-economic policies that influence health<sup>##UREF##30##42##</sup> (for example, on fair wages, taxation, poverty alleviation, or social insurance), calls for equitable distribution of health-creating resources and a general concern with health equity.<sup>##REF##18619394##43##</sup> Given that equity is a comparative principle, or judgment about how a person or group of people are situated relative to others, it is intriguing that few, if any, frameworks are explicit about underlying theories that provide for sense making of what is avoidable, unfair and unjust.The absence of clear guidance on determining how conditions are unjustly produced, raises questions about how this value may be translated into practice. Generally speaking, the frameworks would benefit from greater operational guidance to inform policy and practice on equity.</p>", "<p> Another prominent equity-oriented value is gender equality.<sup>##UREF##31##44##, ####UREF##32##45##, ##UREF##33##46####33##46##</sup> Gender inequality interacts with a range of other social and economic determinants of health and is described as a driver and consequence of health inequities.<sup>##UREF##14##19##,##UREF##29##41##,##UREF##34##47##</sup> For example, gender inequality experienced in early years can impact on agency and empowerment in adulthood.<sup>##UREF##32##45##</sup> While documents refer to the need to reduce gender inequalities,<sup>##UREF##8##10##,##UREF##28##40##,##REF##21091195##48##</sup> only a small number considered specific actions such as addressing the gender pay gap, or equalizing parental leave to reduce gender inequality and the gendered determinants of health inequities.<sup>##UREF##16##22##</sup> While older frameworks largely ignore gender considerations,<sup>##UREF##2##3##,##UREF##11##15##,##UREF##27##39##</sup> newer ones recognise, for example, the differential impacts of climate change on different genders.<sup>##REF##26188744##29##</sup></p>", "<p> The value of collaboration, as well as the value of authentic partnership, is prominent across the sample.It is most evident in scholarship and commitments to all-of-government and all-of-society approaches.<sup>##REF##15296629##49##,##REF##17152313##50##</sup> Collaborative mind-sets are crucial for people working across ministries, disciplines and the private sector as well as for effective community–researcher — policy-maker engagement, which is seen a driver of healthy societies.<sup>##REF##17152313##50##, ####REF##22267868##51##, ##UREF##35##52##, ##REF##30426875##53####30426875##53##</sup> Despite this, in the sample, there was a distinct lack of research collaboration between the Global North and South. Of the 57 papers that listed author and affiliations in our sample only five documents included affiliations from authors from low- and middle-income countries (LMICs),<sup>##REF##30700377##28##,##REF##26188744##29##,##REF##31565397##54##, ####REF##30660336##55##, ##REF##32386579##56####32386579##56##</sup> comprising 23 (10%) of the 225 author affiliations. A quarter of documents were from international or regional groups that did not identify specific authors such as the People’s Health Movement or the Ottawa Charter.<sup>##UREF##2##3##,##UREF##33##46##</sup> As with equity, collaboration features across the heuristic, for example, in the governance lever,<sup>##UREF##35##52##,##REF##30426875##53##</sup> and through calls for collective action related to political mobilisation.<sup>##UREF##2##3##,##UREF##17##23##,##REF##26188744##29##,##REF##28619031##57##, ####UREF##36##58##, ##UREF##37##59####37##59##</sup> In contrast, to the value of collaboration, the literature offered less on the role of contestation, disruption and resistance in overcoming the status quo to foster healthy societies.</p>", "<p> While less prominent than other values, human rights and rights-based approaches are identified in many frameworks to ensure fairness, dignity and accountability<sup>##UREF##16##22##,##UREF##38##60##</sup> (##SUPPL##3##Supplementary file 4##). The Alma Ata Declaration describes health as a fundamental human right.<sup>##UREF##1##2##</sup> Several frameworks called for human rights to underpin actions for healthy societies and that they be protected through laws and fulfilled through a range of policy levers and enablers across multiple sectors.<sup>##UREF##2##3##,##REF##30700377##28##,##REF##17496254##61##, ####UREF##39##62##, ##REF##28125390##63####28125390##63##</sup> Several human rights are invoked including to development, participation, and respect for human dignity.<sup>##REF##19531164##64##</sup> Fox and Meier urge more attention to the collective right to development (rather than individual-oriented approaches), among other things“to bring about greater justice and fairness in economic relations between rich and poor countries.”<sup>##REF##19531164##64##</sup> Calls are made for the right to meaningful representation of a variety of civic groups in decision-making.<sup>##UREF##15##20##</sup> More recent documents call for greater attention to rights to improve equity in relation to specific health outcomes,<sup>##REF##19531164##64##</sup> such as non-communicable diseases<sup>##UREF##17##23##,##REF##30700377##28##</sup> and COVID-19.<sup>##UREF##28##40##</sup> Critics have called out the rights “blind spots” of some frameworks, arguing that the role of international conventions and rights-based responsibilities of nation-states are not sufficiently addressed by those working on the SDoH.<sup>##UREF##32##45##</sup> Similarly, Givens et al review of 27 frameworks on health and equity, find only two explicitly mention the rights-related concerns of prejudice and stigma.<sup>##REF##33111031##65##</sup></p>", "<p> Empowerment refers to a person’s ability and power to act on behalf of themselves, and more broadly the opportunity to create “genuine possibilities” for such a situation.<sup>##UREF##38##60##</sup> This value also encompasses collective empowerment for healthy societies.<sup>##UREF##15##20##,##UREF##17##23##,##UREF##37##59##,##UREF##38##60##</sup> The structural capabilities that enable empowerment (or agency) are tied to policies and determinants (such as liberties, rights, income, wealth and resources) that enable “well-being” but also, the “freedom to pursue well-being.”<sup>##UREF##40##66##</sup> While some authors note considerable ambiguity surrounding the concept,<sup>##UREF##41##67##</sup> the suggestion is that more empowered individuals have control over the factors that influence their health and well-being.<sup>##UREF##37##59##</sup> In the context of planetary health, the United Nations Development Programme describes the contingency of individual agency, stating “people can be agents of change if they have the power to act.”<sup>##UREF##14##19##</sup> Sen’s work around capabilities provides additional context for arguments for empowerment as a key value for societal well-being.<sup>##UREF##42##68##</sup> Rather than examining the “well-ness” of an individual, Sen considers an individual’s success in pursuit of their “actual freedom to live well and be well.”<sup>##UREF##42##68##</sup> A small number of documents in our sample identify empowerment as critical to the realisation of other values, such as equity and human rights.<sup>##UREF##2##3##,##UREF##15##20##,##UREF##17##23##,##UREF##38##60##</sup></p>", "<p> The value placed on sustainability increases over the period concerned with more recent documents emphasising the role of the planet as the life support system for the health and future generations’ survival — and is given further impetus with attention to planetary health.<sup>##REF##30700377##28##,##REF##26188744##29##</sup> However, sustainability is not linked solely to the environment, some frameworks consider it in relation to the sustainability of government programmes. For example, Cerf calls for sustainable infrastructure, particularly in LMICs.<sup>##REF##31565397##54##</sup> Similarly in COVID-19 recovery efforts, the UN asked how research can be better designed to foster sustainability.<sup>##UREF##28##40##</sup> Others advocate for investment in social capital alongside structural interventions to ensure sustainability.<sup>##UREF##43##69##</sup></p>", "<p> Values such as equity, collaboration and empowerment have been championed as critical to healthy societies. These values, as well as those listed in ##SUPPL##3##Supplementary file 4##, imbue healthy societies with a moral compass. Nonetheless, a critical reflection on the treatment of values in this literature reveals that it is silent or does not question the prevailing values promoted in mainstream society, namely of neo-liberalism, personal responsibility, rejection of the nanny state, the primacy of efficiency and markets, etc — in other words it implicitly legitimises the hegemony of prevailing grossly unfair distribution of power and protection of economic interests that undermine each component of healthy societies.<sup>##UREF##44##70##</sup></p>", "<title> Components of Healthy Societies</title>", "<title> People</title>", "<p> Building upon the work of Wilkinson and Marmot,<sup>##UREF##45##71##</sup> the Commission on the SDoH identifies the role of people’s social environment in creating “<italic toggle=\"yes\">flourishing societies.</italic>”<sup>##UREF##3##4##</sup> As per this literature, we use the term “people” to encompass people’s positions in social hierarchies, the interactions, interdependencies and social networks among them, and the social environments in which interactions occur. How societies treat people shapes whether and how societies flourish. Across the sample, a focus on how people are empowered to engage in policy making for healthy societies is apparent,<sup>##UREF##1##2##,##UREF##2##3##,##UREF##33##46##,##UREF##35##52##,##UREF##37##59##</sup> yet the field has been largely apolitical and atheoretical.<sup>##UREF##46##72##</sup></p>", "<p> Peoples’ social environments cover a range of conditions (such as living, networks, socio-economic and social protection) that affect health.<sup>##UREF##3##4##,##UREF##31##44##</sup> In 1974, Lalonde argued that health is influenced by factors beyond an individual’s control.<sup>##UREF##11##15##</sup> Subsequent frameworks emphasise improving health equity by focusing on upstream and distal determinants.<sup>##REF##21091195##48##,##UREF##47##73##,##REF##10972429##74##</sup> These factors include the distribution of wealth and income, legal status (eg, migrant) and educational opportunities.<sup>##UREF##29##41##,##UREF##30##42##</sup> Others draw attention to personal characteristics such as race, gender and forms of discrimination impacting on health equity.<sup>##UREF##30##42##,##UREF##31##44##,##UREF##34##47##</sup></p>", "<p> A focus on people draws attention to impacts of societal inequalities on health outcomes over the life-course.<sup>##UREF##8##10##</sup> This approach reveals opportunities to intervene in critical windows of vulnerability and transition such as early child development<sup>##UREF##30##42##,##UREF##32##45##</sup> or during adolescence<sup>##UREF##48##75##</sup> as well as the role of policies on future health outcomes, such as policies that impact on access to formal employment, income equality, parental leave and access to early childhood education.<sup>##UREF##30##42##,##UREF##32##45##</sup> At the other end of the life course, a range of other social determinants, such as access to social care, living alone,<sup>##REF##28830297##27##</sup> impact on older people’s health.<sup>##UREF##50##77##</sup> Actors outside the health sector are critical in addressing inequalities across the lifecourse that can improve health equity and enable healthy societies.<sup>##UREF##3##4##,##UREF##32##45##,##UREF##49##76##</sup></p>", "<p> Some of the literature considers the intergenerational features of healthy societies,<sup>##REF##26188744##29##,##UREF##20##30##,##UREF##28##40##,##UREF##30##42##</sup> reflecting on how societal choices and policies adopted by one generation may impact the health of succeeding generations.<sup>##UREF##15##20##</sup> For example, the Lancet Commission on Planetary Health is stark: “we have been mortgaging the health of future generations to realise economic and development gains in the present.”<sup>##REF##26188744##29##</sup> Dyck draws attention to the influence of culture and tradition, (and loss of knowledge due to colonization) on the health and well-being of current and future generations of Aboriginal people<sup>##UREF##51##78##</sup> given the relationship between the environment, culture and health. More recent reports call for indigenous and traditional knowledges to inform action on healthy societies.<sup>##REF##30700377##28##,##UREF##52##79##</sup></p>", "<p> The literature argues that healthy societies cannot occur without “comprehensive” strategies to address people’s needs more holistically.<sup>##UREF##11##15##,##UREF##26##38##,##UREF##53##80##</sup> Some authors focus on identifying ways to address social determinants of specific health issues. For example, Friel and colleagues<sup>##UREF##54##81##</sup> review evidence on inequities in healthy eating. They argue that strategies must cover: (1) governance structures; (2) policies directly influencing the food environment; (3) macroeconomic and social policies; (4) cultural and societal norms and values; and (5) daily living conditions.<sup>##UREF##54##81##</sup> In other words, a range of strategies are required to make healthy choices possible or easier for people. Other authors identify the need for comprehensive strategies to address the mental well-being of children and adolescents,<sup>##UREF##48##75##</sup> physical activity,<sup>##UREF##55##82##</sup> tobacco use,<sup>##UREF##19##26##</sup> alcohol consumption,<sup>##UREF##18##25##</sup> and other health issues.</p>", "<p> Several frameworks examine the impacts of social capital and social cohesion.<sup>##UREF##15##20##,##REF##21311607##83##, ####REF##22542441##84##, ##UREF##56##85####56##85##</sup> Recognising that social capital does not occur in a “vacuum,” Kawachi et al call for investigation into power and the structural forces that shape social capital.<sup>##UREF##43##69##</sup> While there is some treatment of collective action through framing of concepts like social capital,<sup>##UREF##24##35##,##UREF##43##69##</sup> we found that the literature continues to focus on behaviour at the individual level and only recently have nudge or population level interventions been brought to the fore. Many frameworks call for greater civic engagement, for example in governance, policy making and research,<sup>##UREF##15##20##,##UREF##57##86##</sup> but less attention is given to how to support them to do so or ensure accountability for systems to enable it.</p>", "<title> Places</title>", "<p> The Shanghai Declaration on Health Promotion states that “health is created in the settings of everyday life.”<sup>##UREF##36##58##</sup> “Places” include the physical environments where individuals live, work, commute and play. Much literature focuses on the health impacts of the built environment<sup>##REF##15296629##49##,##REF##30426875##53##,##REF##22542441##84##,##UREF##58##87##</sup> (including housing),<sup>##UREF##3##4##</sup> urban planning (including active transport<sup>##REF##15296629##49##,##REF##30426875##53##,##REF##22542441##84##</sup> and access to green spaces<sup>##REF##29510520##88##</sup>) and environmental exposures.<sup>##REF##15296629##49##</sup> Some explore how institutionalised racism, sexism and social class impact on the nature of built environments, who inhabits them, and how this affects health.<sup>##REF##15296629##49##</sup></p>", "<p> The reviewed literature also covers settings-based interventions.<sup>##REF##27814893##24##,##REF##31565397##54##,##UREF##47##73##,##REF##19692738##89##</sup> Housing and workplaces show the most promise to reduce health inequalities, however the literature notes a gap on the impacts of transport, education and workplace policies on inequality.<sup>##REF##19692738##89##</sup> Sampled papers examine the impact of housing on health-related outcomes such as early childhood development,<sup>##UREF##56##85##</sup> general well-being<sup>##UREF##16##22##</sup> and access to nutritious food, education, and healthcare.<sup>##UREF##30##42##</sup></p>", "<p> The Commission on SDoH<sup>##UREF##3##4##</sup> asserts that “safe, secure, and fairly paid work, year-round work opportunities, and healthy work–life balance” are required. A Knowledge Network supported the Commission and its report drew attention to power relations across government, markets and labour as it affects health inequities and recommended taking a rights-based approach to decent work.<sup>##UREF##59##90##</sup> Other workplace factors identified included exposure to material hazards, work-related stress and health damaging behaviours (such as smoking) within workplaces,<sup>##UREF##3##4##</sup> as well as the role of work insecurity, such as temporary contracts or part-time work.<sup>##UREF##3##4##,##UREF##28##40##,##REF##17496254##61##</sup></p>", "<p> A key concept related to the places component of healthy societies is attention to inclusive “systems approaches” to address environment-related burdens of disease by hardwiring health impacts into the planning departments of housing, transport and energy<sup>##REF##30426875##53##</sup> and collaborative decision-making by planning and health sectors.<sup>##REF##17152313##50##</sup> Better identification and measurement of environmental inequalities could promote access to green space, opportunities for active transport,<sup>##REF##15296629##49##,##UREF##50##77##</sup> zoning laws that address social inequalities<sup>##REF##15296629##49##</sup> and reducing environmental hazards such as air pollution.<sup>##UREF##11##15##,##UREF##56##85##</sup> This literature stresses equity considerations as critical in guiding urban planning processes, including equity between rural and urban and within urban settings,<sup>##UREF##3##4##</sup> and argues for incentives for developers to better meet the needs of low-income communities.<sup>##REF##15296629##49##</sup> Approaches focusing on specific health outcomes (eg, childhood development<sup>##UREF##32##45##</sup> and childhood cancer<sup>##REF##18619394##43##</sup>) similarly call for more coordinated approaches to address intersecting built, social and economic environments.</p>", "<p> The literature highlights the interdependencies between interventions focusing on people and places.<sup>##REF##30426875##53##</sup> Frameworks dealing with places tend to address urban settings in high-income income countries.<sup>##UREF##32##45##,##UREF##35##52##,##UREF##38##60##</sup> It has also tended to focus on physical spaces, yet important emerging places for the creation of health and illness are now also found in virtual settings.<sup>##UREF##28##40##</sup> The role of ownership of spaces, related to privatization of the commons and of resources that affect well-being is relatively underdeveloped. Tenure affects access to several social resources, be it in the rural context, or in the context of the urban poor. There was relatively limited consideration of this in the literature.</p>", "<title> Products</title>", "<p> The term “products” is used as shorthand for commodities that improve health and those that create ill-health. These CDoH also include the practices and attributes of commercial entities (including financing, extracting, producing, marketing, and distributing these products). As early as 1986, the Ottawa Charter recognised the need to “counteract the pressures towards harmful products,”<sup>##UREF##2##3##</sup> presenting the first reference to these determinants in our sample.</p>", "<p> Most documents in our sample focus on products (or industries) responsible for ill-health and the required but often inadequate regulatory environments. This includes the impact of globalisation and trade liberalisation on such regulation.<sup>##REF##28110222##92##</sup> Across the sample, emphasis is placed on tobacco,<sup>##UREF##19##26##</sup> alcohol<sup>##UREF##18##25##</sup> and unhealthy foods.<sup>##REF##30660336##55##,##UREF##54##81##</sup> The reviewed literature largely overlooks the gambling, arms, fossil fuel, social media and other industries which also harm health. There is reasonably little about the investment community or the legal, accountancy, and management consultant industry and the role they play in supporting and defending unhealthy societies.</p>", "<p> The “products” literature in our sample often consider the impact of the commercial determinants in relation to other components in our heuristic, ie, people,<sup>##UREF##3##4##</sup> places,<sup>##UREF##18##25##,##UREF##47##73##</sup> and planet.<sup>##UREF##14##19##</sup> We have seen a growth of literature on commercial determinants in recent years.<sup>##REF##31953933##13##,##REF##32600398##93##</sup> Lacy-Nichols and Marten<sup>##UREF##60##91##</sup> illuminate how corporate power can keep commercial drivers off policy agendas and the perpetuation of societal investment in the downstream “illness industry.”</p>", "<p> The role of “powerful players”<sup>##UREF##47##73##</sup> and their framing of lifestyles, personal responsibility and choice as presenting roadblocks to healthy societies represents a thread through the literature.<sup>##REF##30700377##28##,##UREF##30##42##,##UREF##60##91##</sup> Some frameworks encourage equity-oriented policies. For example, we saw calls for tobacco and alcohol policies to consider the unequal distribution of power and resources,<sup>##UREF##18##25##,##UREF##19##26##,##UREF##30##42##</sup> by enforcing, for example, the prohibition of sales to minors in disadvantaged communities.<sup>##UREF##19##26##</sup> Others call for support to civil society to apply pressure for government action to curb industry harms and influence on public policy.<sup>##REF##30700377##28##</sup> However, despite repeated calls to address CDoH, the public health responses to such drivers remain inadequate, including in the prevention of non-communicable diseases. Some argue this may be due to: (1) institutional inertia in governance processes, priorities and policies; (2) minimal civil society activism demanding political and policy responses; and (3) resistance to change from the commercial actors profiting from prevailing arrangements.<sup>##UREF##45##71##</sup></p>", "<p> We found little treatment of healthy products, ensuring access to healthy diets, or devices and technology in ways that can be empowering and enhance well-being.<sup>##UREF##30##42##,##REF##30660336##55##</sup> Alongside this, who ought to be targeted to access subsidised healthy products was given very limited coverage.<sup>##UREF##54##81##</sup> However, there was some attention to the need for sustainable food systems.<sup>##UREF##17##23##,##REF##30700377##28##,##REF##30660336##55##</sup></p>", "<p> The role of the commercial sector in influencing political and scientific processes receives scant attention in our sampled documents. Lobbying by companies and their associations for favourable policy environments as well as their role in underpinning the political, economic and normative systems that enable these actors to operate are considered in more recent work.<sup>##UREF##60##91##,##REF##36966782##94##,##REF##36966783##95##</sup></p>", "<title> Planet</title>", "<p> The planet is the final component of our heuristic. While consideration of the natural environment on health is evident in some early documents,<sup>##UREF##2##3##,##UREF##11##15##</sup> concepts such as One Health<sup>##REF##27814893##24##,##UREF##28##40##,##REF##32386579##56##</sup> and planetary health<sup>##REF##26188744##29##,##REF##30660336##55##</sup> are more recent. A unique feature of this literature is the call for urgent action, at all levels.<sup>##REF##30660336##55##</sup> Placed in a broader context, the planetary health literature seeks to expand understanding of what had until that point been the somewhat more technically confined concept of One Health – examination of health and disease occurrence in human and animal populations.<sup>##REF##34729391##96##,##REF##29085825##97##</sup></p>", "<p> In line with the discussion on values above,<sup>##UREF##14##19##</sup> documents in our sample challenge an over-reliance on gross domestic product as a measure of human progress, calling for the inclusion of indicators relating to human-caused health and environmental harms.<sup>##REF##26188744##29##</sup> Such calls for rebalancing of societal values are increasingly prominent.<sup>##UREF##14##19##,##UREF##28##40##</sup> Some argue that planetary health is not a new concept or discipline, but rather has historical threads in integrative medicine, science of the microbiome and holistic medicine approaches.<sup>##REF##29085825##97##</sup> It is further argued that if analysts and advocates continue to perpetuate the neo-colonial capitalist world order that de-politicises and de-historicises the environment and the beings residing within it, equitable healthy societies will remain elusive.<sup>##REF##34178913##98##</sup></p>", "<p> Criticisms of the planetary health literature<sup>##REF##26188744##29##</sup> include that they continue to draw boundaries and attempt to exert control around natural phenomenon, reinforcing “a Western representation of our relationship to nature…founded on mastery” and techno-financial fixes located in the dominant neo-liberal paradigm.<sup>##REF##33635169##99##</sup> For example, while planetary health calls for training of indigenous community members to protect health and biodiversity, the possibility that learning, knowledge and capacity can flow in the opposite direction, ie, from indigenous peoples, is too often ignored.<sup>##REF##30316687##100##</sup> Proponents of alternative concepts like “One Health of Peripheries” argue that “Planetary Health and One Health can be read as proposals for preserving the capitalist order; more specifically, these two approaches arguably perpetuate the prevention and control of environmental deterioration and animal diseases to avoid more instability in the capitalist order. As might be expected, the colonial aspects of these proposals have not gone unnoticed.”<sup>##REF##34178913##98##</sup> Monbiot<sup>##UREF##61##101##</sup> adds the additional concern that approaches to planetary health create silos (ie, climate change, deforestation) and depoliticise the challenge by focusing on individuals rather than economic and political systems to respond to planetary challenges.<sup>##REF##33635169##99##</sup> Recent contributions draw attention to the economic losses of climate change and the cost of inaction.<sup>##REF##36306815##102##, ####REF##37286239##103##, ##REF##36754470##104####36754470##104##</sup> These include food unavailability, food insecurity and income inequality,<sup>##REF##36306815##102##</sup> perpetuated by vested interests to “preserve the status quo”<sup>##REF##37286239##103##</sup> and run against healthy societies. More progressive approaches call for fundamental “reorientation of human systems,”<sup>##REF##30700377##28##</sup> while others critique the approach for its often myopic consideration of other planetary inhabitants — animals, plants — in instrumentalist terms (as vectors of disease transmission or as food).<sup>##REF##29085825##97##,##REF##36306815##102##,##REF##37286239##103##</sup></p>" ]	[ "<title>Discussion</title>", "<p> The discourse on health in the health sector rarely concerns itself with health, but rather with illness, treating disease or strengthening healthcare systems. We sought to better understand what similar discussions about “health” rather than disease offer.</p>", "<title> Not Another Framework</title>", "<p> The literature provides numerous frameworks to help guide analysis and inform action. These include Dahlgren and Whitehead’s seminal work on social determinants.<sup>##UREF##30##42##</sup> The VicHealth’s Fair Foundation Framework builds on this.<sup>##UREF##24##35##</sup> The structural violence framework takes the SDoH in more radical directions, drawing on political economy to focus on the upstream social and political systems that beget “causes of causes.”<sup>##UREF##25##37##</sup> The framing of health inequities as the result of deliberate acts of violence as well as the far-reaching questions about how to achieve healthy societies set this framework apart from the work on social determinants.<sup>##UREF##25##37##</sup> The 2019 Commission on the “global syndemic of obesity, undernutrition, and climate change” provides a different kind of framework presenting double- and triple-duty actions, simultaneously addressing multiple determinants driving the concurrent epidemics.<sup>##REF##30700377##28##</sup></p>", "<p> While these frameworks provide useful insights on some issues, they often overlook others. For example, one identifies policy levers to deliver SDG 3 (ensure healthy lives and promote well-being), yet it does so by focusing on universal health coverage neglecting considerations of societal drivers of health.<sup>##REF##31565397##54##</sup> These frameworks all have utility, yet as Givens et al<sup>##REF##33111031##65##</sup> note, the diversity and inconsistency of “inclusion of the potential categories or dimensions of drivers of health and equity” result in frameworks often failing to deliver “conceptual clarity on what shapes health and equity for the field of population health.”</p>", "<p> It is sobering to consider that the frameworks have failed to achieve their desired outcomes. For example, Alma Ata<sup>##UREF##1##2##</sup> called for action on the underlying causes of ill health, yet “health for all” remains little more than a slogan. Is this a problem with the frameworks (for example that they are northern-centric and fail to consider a plurality of ideas<sup>##UREF##9##11##</sup>) or with the implementation of the frameworks? It was rare to find frameworks with the ambition to unify elements identified across literatures into one framework. This finding is echoed in a review of health and equity frameworks.<sup>##REF##33111031##65##</sup> As a result, the social determinants approach, for example, is considered inadequate and in need of expansion.<sup>##REF##27814893##24##,##REF##33111031##65##,##REF##24560252##105##</sup></p>", "<p> The majority of frameworks were created in an era dominated by neo-liberal ideology. Their failure to acknowledge, critique or offer alternatives to prevailing orthodoxy or consider the implications of neo-liberalism for the goals advocated, suggests the limited utility of the frameworks. It is equally tenable that there is no perfect framework that can address all the components and their political dimensions. This suggests that the place to start is from commitments already made and to understand their implications: what levers can be used and how those levers may be “activated” or enabled. We expand on this in our companion paper.<sup>##UREF##10##12##</sup></p>", "<title> Blinkered Boundary Thinking</title>", "<p> Another reflection on our sample relates to the interconnected nature of the elements (and concepts). Our heuristic presents a two-dimensional canvas onto which to map how inputs can be transformed through a set of values, components, and, as explored in our companion piece, policy levers and enablers.<sup>##UREF##10##12##</sup> While these parts are often acted upon separately, these factors interact either exacerbating health inequities or enhancing the conditions which enable health and well-being.</p>", "<p> Drawing boundaries for the purposes of research and policy is understandable–putting boxes around social determinants, urban health, healthy diets, and so on enables us to make sense of complexity. Yet these categories are not, as argued by Kant and others more recently, the “thing in itself”– they are artifacts and fields created in our minds and actions.<sup>##UREF##61##101##</sup> They reinforce silos and create artificial lenses obscuring complexity. In so doing, they fail to appreciate potential cascading benefits of interventions and/or fail to consider potential negative externalities. Overcoming this tendency to compartmentalise requires complexity-based approaches and systems thinking<sup>##UREF##15##20##,##REF##30426875##53##,##UREF##57##86##</sup> that consider the interconnections required to nurture and sustain healthy societies.</p>", "<title> Privileged Positions and Paradigms</title>", "<p> Adding to the complex terrain are the lenses through which the challenges are analysed. The examined literature focuses primarily on high-income settings. There is a particular gap in documents that examined environments occupied by the urban poor—something that is increasingly recognised in some of the CDoH literature.<sup>##REF##34648410##106##,##REF##34615652##107##</sup> The lack of LMIC perspectives (See ##SUPPL##0##Supplementary file 1##) suggests these frameworks may not address the issues in ways meaningful to the majority of the world’s population.<sup>##UREF##9##11##</sup> However, even within LMICs, due in large part to the political economy and history of public health — which has placed a great deal of emphasis on population control in LMICs — the health sector has been largely preoccupied with maternal and child health limiting broader considerations.</p>", "<p> The literature also reflects the dominant influence of biomedical conceptualisations of health and illness, a feature also concluded by Loewenson et al in their regional review of healthy societies.<sup>##UREF##9##11##</sup> Yet, given the biomedical orientation within much of the health sector, how can leaders within the sector promote healthy societies approaches across other sectors that do not fall back on bio-medical solutions? Acknowledging and addressing this challenge appears to be critical to advancing the healthy societies agenda.</p>", "<title> What Is Valued in a Healthy Society?</title>", "<p> Our analysis highlighted the integral role of values to the creation of healthy societies. A healthy societies paradigm promotes alternative endpoints to development, eschewing short-term economic growth in favour of health, equity and well-being. It also embraces a set of supportive values to guide investment, research and action. However, like Givens and colleagues,<sup>##REF##33111031##65##</sup> this review identified a lack of attention to the strategic actions required to shift societal values. For example, while equity was the value identified in the greatest number of documents, few frameworks were explicit about the underlying theories of inequity, the neo-liberal values which sustain them, or actions to redress inequities.<sup>##UREF##29##41##,##UREF##31##44##</sup> More recent documents encourage consideration of not merely equity in the distribution of outcomes but the costs associated with prioritising specific social values over others. For example, the social costs of prioritising economic outcomes over health and well-being focused outcomes.<sup>##UREF##14##19##</sup> Encouragingly, the planetary health frameworks increasingly call for reconsideration of core societal values.<sup>##UREF##14##19##,##REF##26188744##29##</sup></p>", "<p> In many of the government documents, the presentation of value statements in the preambulatory sections placed relatively less emphasis on what equity should look like, particularly in terms of institutional, community or system arrangements and processes.<sup>##UREF##20##30##,##UREF##29##41##</sup> Despite sustained calls for the privileging of a set of core values for healthy societies — calls reinforced by the COVID-19 pandemic — societies continue to prioritize a competing set of values (eg, economic growth or efficiency) which often undermine public health given the nature of growth and the distribution thereof.<sup>##UREF##14##19##</sup> Future research should monitor the outcomes associated with value-based actions and their impact on influencing health-facilitating societal norms.</p>", "<p> Several values arguably crucial to healthy societies were not addressed in our sample. This includes contestation and resistance. If we are to change the systems that perpetuate poor health, we need to allow/create spaces for voices that challenge prevailing interests. A study of intersectoral collaboration around deforestation argued that where collaboration does not work, contestation does in relation to environmental justice.<sup>##UREF##62##108##</sup> The history of the AIDS movement reveals that resistance and contestation was critical to reverse the criminalisation of gay sex, drug use and sex work and enable effective HIV prevention measures.<sup>##UREF##63##109##,##UREF##64##110##</sup> The healthy societies literature has yet to take such a subversive turn.</p>", "<title> Capitalism and Neo-Liberalism: Rate Limiting Factors to the Attainment of Healthy Societies</title>", "<p> All four components are mediated by modern capitalism, even if this is underplayed in the literature, except for some focused on products and planet. healthy societies are premised on the ability of people to enjoy a healthy work/life balance, engage in decent and reasonably remunerated work and enjoy access to health promoting environments (places), and to nutritious food (products) that is sustainably produced (planet). To elaborate in relation to food, it is increasingly evident that foods need to be judged not only on their impact on health, but on the environmental, social and economic conditions of their production, processing and distribution<sup>##REF##30660336##55##</sup> — hence the growth of front of pack labelling and Environmental, Social, and Governance investing initiatives. All these interactions are influenced by the structures and practices of capitalism.<sup>##REF##36703840##111##</sup></p>", "<p> The imprint of capitalism, and its neo-liberal globalised variant, and the values of extraction, growth, accumulation and concentration, resulting in the rolling back of the state, regulatory apparatus and social safety nets can be felt across all four components of the framework — as COVID-19 revealed. Yet the literature is largely silent on these systemic drivers of ill-health — except to some extent questing the prevailing narrative of the agency of the individual to protect and promote their own health in a deeply unequal world.</p>", "<title> Limitations</title>", "<p> Given the aims of this research and the volume of associated literature (one review, for example, found 36 frameworks concerning social determinants), select documents were identified to capture key conceptual frameworks. We recognise the limitations of the methodology in relation to both potentially omitting important sources as well as biases inherent in including others given that it would be very difficult to systematically identify every potentially relevant document through a close-ended search. Moreover, given the nature of much the source material, we did not appraise the validity, reliability or quality of concepts proposed in frameworks and literature, but rather reflected on their contribution to understanding healthy societies.</p>", "<p> As a team of researchers from countries in the Global North and South, our process was iterative and recursive, to build, question and rebuild our analytical framework. It would have been influenced by own positionality. All authors are social scientists with strong orientations towards equity, human rights and social justice. The analysis was limited to English-language documents, which may play some role in why we have a preponderance of documents from high-income, anglophone countries. We recognize that this creates a bias in terms of perspectives represented in our analysis. This non-exhaustive research process is limited by our global approach, with limited analysis of region-specific perspectives.</p>" ]	[ "<title>Conclusion</title>", "<p> Our paper provides an overview of the “what” of healthy societies. Calls for what Vinuales and colleagues recently refer to as “deep prevention” (ie, structural and systemic reforms)<sup>##REF##33932327##112##</sup> have been long standing but have gone largely unheeded. Rather than offer a diagnosis of why past efforts have not been successful, most documents envision and re-envision ever more components and connections. The omission of introspection reflects our finding that literature is apolitical and/or fails to grapple with the question of whose interests are at likely to be affected if the frameworks were to be implemented. Future work should seek to identify what did not work in the past while seeking to identify strategies most effective in addressing likely political and ideological opposition.</p>", "<p> The literature provides an alternative vision of sustainable development for healthy societies — including an alternative set of values and approaches to address structural drivers of health inequities. Yet these values have failed to take root in mainstream society while the vision to transform approaches focusing on people, places, products and planet has largely been ignored. This might be explained by the vastness of the terrain and the complexity inherent in comprehensive upstream responses. It might also be a function of the failure of the frameworks to provide convincing narratives or to consider how to engage with or confront vested interests.<sup>##UREF##65##113##</sup></p>", "<p> In their pandemic responses, most states vastly increased investments in social protection (for example, paying wages for furloughed workers). This suggests what is possible with political resolve. Recent initiatives such as the meetings on healthy societies for Healthy Populations, convened by the Government of Sweden, WHO, the Alliance for Health Policy and Systems Research, Wilton Park, and the Wellcome Trust from 2020-2022<sup>##REF##32505243##114##</sup> provide grounds for optimism.<sup>##UREF##66##115##</sup> But what is likely ultimately needed is for social movements to get behind the healthy societies agenda.</p>", "<p> Future study and action would be enhanced by taking more expansive views of the terrain, exploring the intersections and interstices, and applying a more critical lens to what accounts for the limited progress on this agenda to date.</p>", "<p> The COVID-19 pandemic revealed decades of underinvestment in public health that left societies vulnerable and lacking resilience.<sup>##UREF##67##116##</sup> The twin pandemics of COVID-19 and inequality focussed unprecedented attention on the need and opportunities<sup>##REF##33493435##117##</sup> to address structural, social, economic and political drivers of health inequalities. The UN’s research roadmap for recovery argues that the pandemic “brought into sharp focus the need for ambitious plans that reimagine and rebuild health, social and economic systems so that they leave no one behind” while providing an “historic opportunity to reimagine societies using a human rights lens.”<sup>##UREF##28##40##</sup> We agree. And while many of the healthy societies frameworks point in those directions, what remains is mobilising the grass roots politically to create demands to move from aspirations to attainment of health and well-being for all.</p>" ]	[ "<p>\n<bold>Background:</bold> While support for the idea of fostering healthy societies is longstanding, there is a gap in the literature on what they are, how to beget them, and how experience might inform future efforts. This paper explores developments since Alma Ata (1978) to understand how a range of related concepts and fields inform approaches to healthy societies and to develop a model to help conceptualize future research and policy initiatives.\n</p>", "<p><bold>Methods:</bold> Drawing on 68 purposively selected documents, including political declarations, commission and agency reports, peer-reviewed papers and guidance notes, we undertook qualitative thematic analysis. Three independent researchers compiled and categorised themes describing the domains of a potential healthy societies approach.\n</p>", "<p><bold>Results:</bold> The literature provides numerous frameworks. Some of these frameworks promote alternative endpoints to development, eschewing short-term economic growth in favour of health, equity, well-being and sustainability. They also identify values, such as gender equality, collaboration, human rights and empowerment that provide the pathways to, or underpin, such endpoints. We categorize the literature into four \"components\": people; places; products; and planet. People refers to social positions, interactions and networks creating well-being. Places are physical environments—built and natural—and the interests and policies shaping them. Products are commodities and commercial practices impacting population health. Planet places human health in the context of the ‘Anthropocene.’ These components interact in complex ways across global, regional, country and community levels as outlined in our heuristic. </p>", "<p><bold>Conclusion:</bold> The literature offers little critical reflection on why greater progress has not been made, or on the need to organise and resist the prevailing systems which perpetuate ill-health.</p>", "<p>\n<bold>Citation:</bold> Buse K, Bestman A, Srivastava S, Marten R, Yangchen S, Nambiar D. What are healthy societies? A thematic analysis of relevant conceptual frameworks. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7450. doi:10.34172/ijhpm.2023.7450</p>" ]	[ "<title>Aims</title>", "<p> This mapping and framework building exercise does not respond to a narrow research question but aims to broadly understand how several linked concepts inform a broad range of efforts widely considered or conceptualized as efforts to create healthy societies. It is motivated by the hypothesis that a mapping of relevant literature could improve future research, political engagement and eventual policy interventions. This research did not seek to develop a unifying theory, but a heuristic that enables a descriptive analysis of “what” constitutes healthy societies. We also sought to review critically what was and was not included in these conceptualisations and the implications of these formulations for progress on this agenda. In another linked analysis, we sought to describe “how” the same literature proposes that healthy societies may be achieved.<sup>##UREF##10##12##</sup></p>", "<title>Acknowledgements</title>", "<p> The authors acknowledge Sreejini Jaya for initial data extraction and coding.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Disclaimer</title>", "<p> Robert Marten and Sonam Yangchen are staff members of the Alliance for Health Policy and Systems Research, a WHO-hosted partnership.</p>", "<title>Funding</title>", "<p> This research received funding from The Alliance for Health Policy and Systems Research.</p>", "<title>Supplementary files\n</title>", "<title>Endnotes</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nHeuristic of Healthy Societies. Abbreviations: HiAPs, Health in All Policies; M&CH, maternal and child health; NCDs, non-communicable diseases; SDGs, Sustainable Development Goals; SRH, sexual reproductive health.</p></statement></fig>" ]	[]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 1. Sample Documents.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 2. Data Extraction Template.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 3. PRISMA-ScR Flow Diagram.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl4\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 4. Values Present in the Sample Documents.\n</p></caption></supplementary-material>" ]	[ "<fn-group><fn id=\"fn1\"><p> [1] The concept of the black box derives from Easton’s model of the political system through which “inputs” (demands, resources and support) are transformed into “outputs” (public policies and public goods) in what is perceived as an opaque box of policy-making.<sup>##UREF##13##18##</sup></p></fn></fn-group>" ]	[ "<graphic xlink:href=\"ijhpm-12-7450-g001\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7450-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7450-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7450-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7450-s004.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "person-group": ["\n"], "surname": ["McKeown", "Record"], "given-names": ["T", "RG"], "article-title": ["Reasons for the decline of mortality in England and Wales during the nineteenth century"], "source": ["Popul Stud (Camb)"], "year": ["1962"], "volume": ["16"], "issue": ["2"], "fpage": ["94"], "lpage": ["122"], "pub-id": ["10.1080/00324728.1962.10414870"]}, {"label": ["2"], "mixed-citation": [" World Health Organization (WHO). Primary Health Care: Report of the International Conference on Primary Health Care, Alma-Ata, USSR, 6-12 September 1978. WHO; 1978. "]}, {"label": ["3"], "mixed-citation": [" WHO Euro. Ottawa Charter for Health Promotion. WHO Euro; 1986. "]}, {"label": ["4"], "mixed-citation": [" Commission on Social Determinants of Health. Closing the Gap in a Generation: Health Equity Through Action on the Social Determinants of Health: Final Report of the Commission on Social Determinants of Health. World Health Organization; 2008. "]}, {"label": ["5"], "mixed-citation": [" O\u2019Neil Hayes T, Delk R. Understanding the Social Determinants of Health. American Action Forum; 2018. "], "uri": ["https://www.americanactionforum.org/research/understanding-the-social-determinants-of-health/#_edn9"]}, {"label": ["6"], "mixed-citation": [" National Conference of State Legislatures (NCSL). Racial and Ethnic Health Disparities What State Legislators Need to Know. NCSL; 2013. Accessed June 18, 2021. "]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Braveman", "Gottlieb"], "given-names": ["P", "L"], "article-title": ["The social determinants of health: it\u2019s time to consider the causes of the causes"], "source": ["Public Health Rep"], "year": ["2014"], "volume": ["129"], "issue": ["Suppl 2"], "fpage": ["19"], "lpage": ["31"], "pub-id": ["10.1177/00333549141291s206"]}, {"label": ["8"], "person-group": ["\n"], "surname": ["McGinnis", "Williams-Russo", "Knickman"], "given-names": ["JM", "P", "JR"], "article-title": ["The case for more active policy attention to health promotion"], "source": ["Health Aff (Millwood)"], "year": ["2002"], "volume": ["21"], "issue": ["2"], "fpage": ["78"], "lpage": ["93"], "pub-id": ["10.1377/hlthaff.21.2.78"]}, {"label": ["10"], "mixed-citation": [" World Health Organization (WHO). Thirteenth General Programme of Work 2019-2023. Geneva: WHO; 2019. "]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Loewenson", "Villar", "Baru", "Marten"], "given-names": ["R", "E", "R", "R"], "article-title": ["Engaging globally with how to achieve healthy societies: insights from India, Latin America and East and Southern Africa"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["4"], "fpage": ["e005257"], "pub-id": ["10.1136/bmjgh-2021-005257"]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Nambiar", "Bestman", "Srivastava", "Buse"], "given-names": ["D", "A", "S", "K"], "article-title": ["How to build Healthy societies: a thematic analysis of relevant conceptual frameworks"], "source": ["Int J Health Policy Manag"], "year": ["2023"], "volume": ["12"], "fpage": ["7451"], "pub-id": ["10.34172/ijhpm.2023.7451"]}, {"label": ["15"], "mixed-citation": [" Lalonde M. A New Perspective on the Health of Canadians: A Working Document. Ottawa: Minister of Supply and Services Canada; 1974. "]}, {"label": ["17"], "mixed-citation": [" Vedung E, Rist RC, Bemelmans-Videc ML. Carrots, Sticks, and Sermons: Policy Instruments and Their Evaluation. New Brunswick: Transaction Publishers; 1998. "]}, {"label": ["18"], "mixed-citation": [" Easton D. A Systems Analysis of Political Life. New York: Wiley; 1965. "]}, {"label": ["19"], "mixed-citation": [" United Nations Development Programme (UNDP). Human Development Report 2020: The Next Frontier Human Development and the Anthropocene. New York: UNDP; 2020. "]}, {"label": ["20"], "mixed-citation": [" WHO Regional Committee for Europe. Health 2020: A European Policy Framework and Strategy for the 21st Century. WHO Regional Office for Europe; 2013. "]}, {"label": ["22"], "mixed-citation": [" Raphael D, Bryant T, Mikkonen J, Raphael A. Social Determinants of Health: The Canadian Facts. 2nd ed. Oshawa, ON: Ontario Tech University Faculty of Health Sciences and Toronto, York University School of Health Policy and Management; 2020. "]}, {"label": ["23"], "mixed-citation": [" World Health Organization (WHO). WHO Independent High-Level Commission on NCDs. Report of the Technical Consultation (21-22 March 2018). Geneva, Switzerland: WHO; 2018. "]}, {"label": ["25"], "mixed-citation": [" VicHealth. Evidence Review: The Social Determinants of Inequities in Alcohol Consumption and Alcohol-Related Health Outcomes. Victoria: Victorian Health Promotion Foundation; 2015. "]}, {"label": ["26"], "mixed-citation": [" Purcell K. Evidence Review: Addressing the Social Determinants of Inequities in Tobacco Use. Victoria: Victorian Health Promotion Foundation; 2015. "]}, {"label": ["30"], "mixed-citation": [" Government of New Zealand. The Wellbeing Budget 2019. New Zealand Treasury; 2019. "]}, {"label": ["31"], "person-group": ["\n"], "surname": ["Verma"], "given-names": ["R"], "article-title": ["The eight manifestations of GNH: multiple meanings of a development alternative"], "source": ["J Bhutan Stud"], "year": ["2019"], "volume": ["41"], "fpage": ["1"], "lpage": ["33"]}, {"label": ["33"], "mixed-citation": [" Stiglitz J, Fitoussi JP, Durand M. For Good Measure: Advancing Research on Well-Being Metrics Beyond GDP. Paris: OECD Publishing; 2018. "], "pub-id": ["10.1787/9789264307278-en"]}, {"label": ["34"], "mixed-citation": [" United Nations Development Programme (UNDP). Human Development Report 2010 (20th Anniversary Edition). The Real Wealth of Nations: Pathways to Human Development. New York: UNDP; 2010. "]}, {"label": ["35"], "mixed-citation": [" VicHealth. Fair Foundations: The VicHealth Framework for Health Equity. Victoria: Victorian Health Promotion Foundation; 2015. "]}, {"label": ["37"], "person-group": ["\n"], "surname": ["Herrick", "Bell"], "given-names": ["C", "K"], "article-title": ["Concepts, disciplines and politics: on \u2018structural violence\u2019 and the \u2018social determinants of health"], "source": ["\u2019 Crit Public Health"], "year": ["2022"], "volume": ["32"], "issue": ["3"], "fpage": ["295"], "lpage": ["308"], "pub-id": ["10.1080/09581596.2020.1810637"]}, {"label": ["38"], "mixed-citation": [" Hamilton N, Bhatti T. Population Health Promotion: An Integrated Model of Population Health and Health Promotion. Ottawa: Health Promotion Development Division; 1996. "]}, {"label": ["39"], "mixed-citation": [" Participants of the Conference on \u201cHealth Care for All\u201d. Declaration on \u2018Health Care for All.\u2019 Antwerp: Health Care for All; 2001. "]}, {"label": ["40"], "mixed-citation": [" United Nations. UN Research Roadmap for the COVID-19 Recovery: Leveraging the Power of Science for a More Equitable, Resilient and Sustainable Future. United Nations; 2020. "]}, {"label": ["41"], "mixed-citation": [" US House of Representatives. A Bold Vision for a Legislative Path Toward Health and Economic Equity. House of Representatives (USA), Chair Richard E. Neal; 2021. "]}, {"label": ["42"], "mixed-citation": [" Dahlgren G, Whitehead M. European Strategies for Tackling Social Inequities in Health: Levelling up Part 2. Copenhagen: WHO Regional Office for Europe; 2006. "]}, {"label": ["44"], "mixed-citation": [" Whitehead M, Dahlgren G. Concepts and Principles for Tackling Social Inequities in Health: Levelling up Part 1. Copenhagen: WHO Regional Office for Europe; 2006. "]}, {"label": ["45"], "mixed-citation": [" Siddiqi A, Irwin L, Hertzman C. Total Environment Assessment Model for Early Child Development: Evidence Report for the World Health Organization\u2019s Commission on the Social Determinants of Health. Vancouver, BC: Human Early Learning Partnership (HELP); 2007. "]}, {"label": ["46"], "mixed-citation": [" People\u2019s Health Movement. The People\u2019s Charter for Health. Dhaka, Bangladesh: First People\u2019s Health Assembly; 2000. "]}, {"label": ["47"], "mixed-citation": [" Hawkes S, Buse K. The politics of gender and global health. In: McInnes C, Lee K, Youde J, ed. The Oxford Handbook of Global Health Politics. Oxford University Press; 2020. "]}, {"label": ["52"], "mixed-citation": [" St\u00e5hl T, Wismar M, Ollila E, Lahtinen E, Leppo K. Health in All Policies: Prospects and Potentials. The European Observatory on Health Systems and Policies; 2006. "]}, {"label": ["58"], "mixed-citation": [" Attendees of the 9th Global Conference on Health Promotion. Shanghai Declaration on promoting health in the 2030 Agenda for Sustainable Development. 2016. "]}, {"label": ["59"], "mixed-citation": [" Solar O, Irwin A. A Conceptual Framework for Action on the Social Determinants of Health. Geneva: WHO; 2010. "]}, {"label": ["60"], "mixed-citation": [" Ogata S, Sen A. Human Security Now: Commission on Human Security, Final Report. New York: Commission on Human Security; 2003. "]}, {"label": ["62"], "mixed-citation": [" World Health Organization (WHO). Health in All Policies: Helsinki Statement. Framework for Country Action. WHO; 2014. "]}, {"label": ["66"], "mixed-citation": [" Sen A. Inequality Reexamined. Oxford: Clarendon; 1995. "]}, {"label": ["67"], "person-group": ["\n"], "surname": ["Rissel"], "given-names": ["C"], "article-title": ["Empowerment: the holy grail of health promotion?"], "source": ["Health Promot Int"], "year": ["1994"], "volume": ["9"], "issue": ["1"], "fpage": ["39"], "lpage": ["47"], "pub-id": ["10.1093/heapro/9.1.39"]}, {"label": ["68"], "mixed-citation": [" Sen A. Capability and well-being. In: Nussbaum N, Sen A, eds. The Quality of Life. Oxford Scholarship Online; 1993. "]}, {"label": ["69"], "mixed-citation": [" Kawachi I, Subramanian SV, Kim D. Social capital and health: a decade of progress and beyond. In: Kawachi SK, ed. Social Capital and Health. New York, NY: Springer New York; 2008:1-26. "], "pub-id": ["10.1007/978-0-387-71311-3_1"]}, {"label": ["70"], "person-group": ["\n"], "surname": ["Kim"], "given-names": ["H"], "article-title": ["The implicit ideological function of the global health field and its role in maintaining relations of power"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["4"], "fpage": ["e005620"], "pub-id": ["10.1136/bmjgh-2021-005620"]}, {"label": ["71"], "mixed-citation": [" Wilkinson R, Marmot M, Bartley M. Social Determinants of Health: The Solid Facts. 2nd ed. Copenhagen, Denmark: World Health Organization; 2003. "]}, {"label": ["72"], "person-group": ["\n"], "surname": ["de Leeuw", "Harris", "Kim", "Yashadhana"], "given-names": ["E", "P", "J", "A"], "article-title": ["A health political science for health promotion"], "source": ["Glob Health Promot"], "year": ["2021"], "volume": ["28"], "issue": ["4"], "fpage": ["17"], "lpage": ["25"], "pub-id": ["10.1177/17579759211034418"]}, {"label": ["73"], "mixed-citation": [" Newman L, Javanparast S, Baum F, Hutchinson C. Evidence Review: Settings for Addressing the Social Determinants of Health Inequities. Melbourne: VicHealth; 2015. "]}, {"label": ["75"], "mixed-citation": [" Welsh J, Ford L, Strazdins L, Friel S. Evidence Review: Addressing the Social Determinants of Inequities in Mental Wellbeing of Children and Adolescents. VicHealth; 2014. "]}, {"label": ["76"], "mixed-citation": [" Boswell K, Joy I, Lamb C. Keeping Us Well: How Non-Health Charities Address the Social Determinants of Health. The Health Foundation and the Institute of Health Equity, 2017. "]}, {"label": ["77"], "mixed-citation": [" Woolf SH, Aron LY. U.S. Health in International Perspective: Shorter Lives, Poorer Health. Washington, DC: National Academies Press; 2013. "]}, {"label": ["78"], "mixed-citation": [" Dyck M. Social Determinants of M\u00e9tis Health. Canada: M\u00e9tis Centre, National Aboriginal Health Organization; 2008. "]}, {"label": ["79"], "person-group": ["\n"], "surname": ["Greenwood", "Lindsay"], "given-names": ["M", "NM"], "article-title": ["A commentary on land, health, and Indigenous knowledge(s)"], "source": ["Glob Health Promot"], "year": ["2019"], "volume": ["26"], "issue": ["3_suppl"], "fpage": ["82"], "lpage": ["86"], "pub-id": ["10.1177/1757975919831262"]}, {"label": ["80"], "person-group": ["\n"], "surname": ["Chen", "Narasimhan"], "given-names": ["L", "V"], "article-title": ["Human security and global health"], "source": ["J Hum Dev"], "year": ["2003"], "volume": ["4"], "issue": ["2"], "fpage": ["181"], "lpage": ["190"], "pub-id": ["10.1080/1464988032000087532"]}, {"label": ["81"], "mixed-citation": [" Friel S, Hattersley L, Ford L, O\u2019Rourke K. Evidence Review: Addressing the Social Determinants of Inequities in Healthy Eating. The National Centre for Epidemiology and Population Health. Canberra: The Australian National University; 2015. "]}, {"label": ["82"], "mixed-citation": [" Ball K, Carver A, Jackson M, Downing K. Evidence Review: Addressing the Social Determinants of Inequities in Physical Activity and Related Health Outcomes. Carlton South, Victoria: Victorian Health Promotion Foundation; 2015. "]}, {"label": ["85"], "mixed-citation": [" VicHealth. Promoting Equity in Early Childhood Development for Health Equity Through the Life Course. Victorian Health Promotion Foundation; 2015. "]}, {"label": ["86"], "mixed-citation": [" VicHealth. Promoting Equity Through Social Innovation. Victorian Health Promotion Foundation; 2015. "]}, {"label": ["87"], "mixed-citation": [" Board on Population Health Public Health Practice, Division of Behavioral Social Sciences Education IoM, National Research Council, Committee on Population, Panel on Understanding Cross-National Health Differences Among High-Income Countries. U.S. Health in International Perspective: Shorter Lives, Poorer Health. Washington, DC: National Academies Press; 2013. "]}, {"label": ["90"], "mixed-citation": [" Benach J, Muntaner C, Santana V. Employment Conditions Knowledge Network (EMCONET). Final Report. Final Report to the WHO Commission on Social Determinants of Health; 2007. "]}, {"label": ["91"], "person-group": ["\n"], "surname": ["Lacy-Nichols", "Marten"], "given-names": ["J", "R"], "article-title": ["Power and the commercial determinants of health: ideas for a research agenda"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["2"], "fpage": ["e003850"], "pub-id": ["10.1136/bmjgh-2020-003850"]}, {"label": ["101"], "mixed-citation": [" Monbiot G. \u2018Green Growth\u2019 Doesn\u2019t Exist \u2013 Less of Everything is the Only Way to Avert Catastrophe. The Guardian; 2021. "]}, {"label": ["108"], "person-group": ["\n"], "surname": ["Ravikumar", "Larson", "Myers", "Trench"], "given-names": ["A", "AM", "R", "T"], "article-title": ["Inter-sectoral and multilevel coordination alone do not reduce deforestation and advance environmental justice: why bold contestation works when collaboration fails"], "source": ["Environ Plan C"], "year": ["2018"], "volume": ["36"], "issue": ["8"], "fpage": ["1437"], "lpage": ["1457"], "pub-id": ["10.1177/2399654418794025"]}, {"label": ["109"], "person-group": ["\n"], "surname": ["Altman", "Buse"], "given-names": ["D", "K"], "article-title": ["Thinking politically about HIV: political analysis and action in response to AIDS"], "source": ["Contemp Politics"], "year": ["2012"], "volume": ["18"], "issue": ["2"], "fpage": ["127"], "lpage": ["140"], "pub-id": ["10.1080/13569775.2012.674334"]}, {"label": ["110"], "person-group": ["\n"], "surname": ["Patterson", "Stephens"], "given-names": ["AS", "D"], "article-title": ["AIDS mobilisation in Zambia and Vietnam: explaining the differences"], "source": ["Contemp Politics"], "year": ["2012"], "volume": ["18"], "issue": ["2"], "fpage": ["213"], "lpage": ["224"], "pub-id": ["10.1080/13569775.2012.674338"]}, {"label": ["113"], "mixed-citation": [" L\u2019H\u00f4te E, Castellina M, Volmert A, Conklin L, O\u2019Shea P. A Matter of Life and Death: Explaining the Wider Determinants of Health in the UK. The Health Foundation; 2022. "]}, {"label": ["115"], "mixed-citation": [" Wilton Park. Healthy Societies and Healthy Populations: The Pursuit of Collective Action. 2021. "], "uri": ["https://www.wiltonpark.org.uk/event/healthy-societies-and-healthy-populations-the-pursuit-of-collective-action/"]}, {"label": ["116"], "mixed-citation": [" Farrar J, Ahuja A. Spike: The Virus vs. The People - the Inside Story. London: Profile Books; 2021. "]}]	{ "acronym": [], "definition": [] }	117	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Nov 7; 12:7450	oa_package/65/9d/PMC10699824.tar.gz
PMC10699825	0	[]	[]	[]	[]	[]	[ "<p>\n<bold>Citation:</bold> Barthélemy EJ, Lepard J, Hackenberg AEC, et al. Advancing global neurotrauma surveillance through national registries: a response to recent commentaries. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8288. doi:10.34172/ijhpm.2023.8288</p>" ]	[ "<p> We were delighted to read the six commentaries addressing our scoping review<sup>##REF##35021612##1##</sup> and comparative analysis of neurotrauma data dictionaries from the national registries of low- and middle-income countries (LMICs). The correspondents have expanded our consideration of the challenges and opportunities inherent to the use of national trauma registries as a vital tool in advancing neurotrauma surveillance. Herein, we endeavor to respond to the queries raised by the commentators, and highlight common themes raised by their thoughtful correspondences.</p>", "<title>Neurotrauma Surveillance in Latin America</title>", "<p> Rubiano and Clavijo highlight the importance of neurotrauma registry development for advancing organized neurotrauma care worldwide.<sup>##REF##36028976##2##</sup> We thank the authors for sharing their experience with the LATINO-TBI registry, a project that aspires to fill the regional gap in neurotrauma data from the LMICs of Latin America and the Caribbean. The barriers encountered in the implementation of the LATINO-TBI registry, ie, lack of administrative support, incomplete data on prehospital care and outcomes, and inadequate healthcare investment prioritization by governments and institutions committed to the sustainable development of these regions, are commonly encountered in other LMICs. A survey of prehospital and emergency leaders from 13 LMICs in Africa, Asia, and Latin America revealed significant heterogeneity in prehospital care services, general lack of prehospital care service development, and barriers that include inadequate funding, lack of leadership and absence of legislation setting standards.<sup>##REF##22490009##3##</sup> These concerns are echoed in a review by Bommakanti et al, citing lack of resources, insufficient prehospital care and challenges with administrative duties and hospital organization as the most significant barriers to successful trauma registry implementation in LMICs.<sup>##REF##29433888##4##</sup> Collectively, these challenges constitute key advocacy targets for trauma care clinicians and researchers.</p>", "<title>National vs. Institutional Trauma Registries</title>", "<p> Boeck et al offer constructive criticism of our work that highlights challenges to a presumed gold standard of global adaptation of national neurotrauma registries, while promoting the value of institutional registries.<sup>##REF##37579459##5##</sup> We are aligned with the pursuit of, “progress over perfection”; our work was specifically designed to inquire into the current state of national neurotrauma registry development in LMICs, while offering a perspective that neurosurgeons are uniquely positioned to advance in the global health advocacy space.<sup>##REF##30144610##6##,##REF##37579475##7##</sup> We support the development and continued utilization of institutional trauma registries in LMICs, and the inclusion of neurotrauma data elements as possible in these registries to facilitate institutional trauma care quality improvement. Given our explicit interest in neurotrauma care from national healthcare policy standpoint, the use of institutional registries that are not aligned with a national standard was, however, outside of our scope of inquiry.</p>", "<p> We acknowledge the authors’ concern that advocacy for national neurotrauma registries, “…reinforces an obsession with an ideal that prevents instead of augments progress.”<sup>##REF##37579459##5##</sup> Indeed, the challenge of strengthening trauma care systems at the national health policy level is complicated by the heterogeneity of fragmented healthcare systems in many LMICs.<sup>##REF##25458725##8##</sup> Nonetheless, we assert that centering national neurotrauma registry development in LMICs invites their public health leaders to consider how trauma surveillance systems might be (re-)designed and implemented to advance progress in neurotrauma surveillance. The World Health Organization’s (WHO’s) Minimum Data set for Injury is a consensus-based set of core data elements recommended following extensive consultation with members of the international community as a standardized starting point from which individual institutions can add site specific variables at will, while still allowing for participation in a national registry.<sup>##UREF##0##9##</sup> We therefore highlight this dataset as an inclusive, and adaptable data dictionary designed to support national trauma care objectives of healthcare governments in LMICs.</p>", "<title>Approaches to Trauma Registry Development</title>", "<p> Asfaw’s commentary recalls that the successes of global health policy advocacy in infectious diseases provide instructive templates for global surgery, trauma and emergency care.<sup>##REF##37579401##10##</sup> The author cites a Nigerian example of registry development for HIV-associated cancer utilizing the Research Electronic Data Capture system, which offers a ubiquitously available global resource that can readily be adapted by LMICs for trauma registry development.<sup>##REF##37579401##10##</sup> Several commentaries cited here note that the need for trained data management personnel remains a key hurdle to address, even when cost barriers are mitigated by free and open access technologies.<sup>##REF##36028976##2##,##REF##37579401##10##, ####REF##37579434##11##, ##REF##32867675##12####32867675##12##</sup> The opportunities highlighted by successful registry implementation in LMICs, such as the examples in Uganda and Nigeria cited here, can strengthen the advocacy platform for increased government funding to establish these lacking, yet indispensable human resources for trauma registry development and implementation.<sup>##REF##37579401##10##,##REF##37579434##11##</sup></p>", "<p> The commentary by Lecky reflects on the role of grassroots-level public health leadership and social entrepreneurialism.<sup>##REF##37579402##13##</sup> The author asserts that successful examples of national trauma registries are more commonly enterprises that were inspired by the need for data. Moreover, their implementation on a national scale does rely upon the establishment of multiple feedback loops between clinical traumatologists, the (paid) trauma or neurotrauma lead for the registry, hospital trauma audit meetings, and health care governance officers.<sup>##REF##37579402##13##</sup> We appreciate the author’s centering the third key question prioritized by the Global Emergency Care Research Network, an international collaboration composed primarily of representatives from LMICs: <italic toggle=\"yes\">“What are the obstacles to implementing emergency care/trauma registry-based systems in LMICs?”</italic> We appreciate the author’s perspective that despite the limitations of our methods, the rigor and resulting findings of our approach emphasize the need for funding agencies to prioritize this concern.</p>", "<title>National Neurotrauma Surveillance Beyond Registries</title>", "<p> Schenck and Mangat offer recommendations regarding the broader aspects of national neurotrauma surveillance that must complement institutional-level data from hospital-based neurotrauma registries.<sup>##REF##37579475##7##</sup> They highlight many additional prospective sources of neurotrauma surveillance data, such as death records, police reports and various other community records already collected by stakeholders who might synergistically collaborate with their nations’ public health officers. We agree with the authors’ assertion that health care governments are accountable to protecting their citizens from all health threats, including road traffic accidents, violence, and other potential etiologies of neurotrauma. The bottom-up advocacy efforts recommended by the authors build upon our recommendations in a holistic manner that we trust will be useful to health ministries, and stakeholders in community healthcare and global neurotrauma alike.</p>", "<p> Thango et al highlight specific barriers to neurotrauma research capacity in LMICs, including an enormous burden of disease, lack of human and material resources, and contextual factors such as linguistic differences, social disparities, and barriers to data dissemination.<sup>##REF##37579434##11##</sup> However, the authors present an example from Uganda illustrating the feasibility of negotiating these barriers to implement an electronic record-based trauma registry.<sup>##REF##37579434##11##</sup> Recognizing the rapidly approaching 2030 deadline of the Sustainable Development Goals, we thank the authors and join them in renewing the call for clinician-led, data-driven policy advocacy that raises awareness of neurotrauma as a neglected source of national and global morbi-mortality.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["9"], "mixed-citation": [" World Health Organization. WHO Dataset for Injury. "], "uri": ["https://www.who.int/publications/m/item/who-dataset-for-injury"]}]	{ "acronym": [], "definition": [] }	13	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 23; 12:8288	oa_package/6e/f2/PMC10699825.tar.gz
PMC10699826	0	[]	[]	[]	[]	[]	[ "<p>Amidst competing priorities for allocating finite health resources, using evidence-informed priority setting is a valuable tool for achieving population-level health goals. The paper by Baltussen et al comprehensively reports on the development of practical guidance for evidence-informed deliberative processes (EDPs) which will help with sustainability of programs aimed at universal health coverage (UHC). The authors’ experience with the Joint Learning Network for UHC’s (JLN) peer-to-peer learning platform on evidence-informed priority setting offers insights on the practical challenges faced by countries in health benefits package (HBP) design, especially to draw in actors to advocate for the priorities and values across the health system. Lessons harvested from JLN countries that have established such advisory committees can provide practical insights for countries in earlier stages of establishing a systematic process for HBP design. Peer-to-peer learning modalities among countries offer viable and effective approaches to institutionalizing EDPs and systematic priority setting.</p>", "<p>\n<bold>Citation:</bold> Nagpal S, Ahluwalia N, Oliveira Hashiguchi L, McGee K, Lutalo M. Harnessing country experiences for health benefit package design: evidence-informed deliberative processes and experiences from the joint learning network: Comment on \"Evidence-informed deliberative processes for health benefit package design – part II: a practical guide.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7856. doi:10.34172/ijhpm.2023.7856</p>" ]	[ "<p><italic toggle=\"yes\">Public revenues should be directed at health services and interventions that maximize progress toward universal health coverage (UHC)</italic>. How can low- and middle-income countries (LMICs) do more with limited resources for health? Tackling key drivers of inefficiency — such as fragmentation of funding sources, vertical delivery systems, and gaps between investments and results — can help the health sector do more with limited resources. A major cause of health sector inefficiencies stems from decisions about resource allocation at the system, facility or physician level.<sup>##UREF##0##1##</sup> In 2010, the World Health Organization (WHO) estimated that 20%-40% of healthcare expenditure was wasted, and inefficiency was a main driver of this wastage.<sup>##UREF##1##2##</sup> More recently, it was estimated that in Organization for Economic Co-operation and Development countries, between 20% and 50% of health expenditures may be wasted due to inefficiencies.<sup>##UREF##1##2##,##UREF##2##3##</sup> With this understanding, the Joint Learning Network for UHC (JLN) — a global network of practitioners and policy-makers sharing experiences about common challenges to develop and implement knowledge products supporting reforms for UHC, has focused on taking a systematic approach to understanding sources of and contextual factors leading to inefficiency, packaging findings into actionable policy recommendations and achieving efficacy through evidence-informed priority-setting and allocation of health spending.</p>", "<p>\n<italic toggle=\"yes\">In the face of ever-increasing demand for healthcare and competing priorities, using evidence-informed priority setting to allocate finite resources is a valuable tool for achieving population-level health goals. </italic>Evidence-informed priority setting occurs when decision-makers and the processes are explicit and transparent, and priority setting is done in a deliberative manner involving relevant stakeholders, in consideration of best available evidence about clinical and cost-effectiveness and social values.<sup>##REF##31514656##4##,##UREF##3##5##</sup> An evidence-informed health benefits package (HBP) — which defines the coverage of services, the proportion of the costs that are covered, and who can receive these services — is a powerful tool that can guide both the delivery of care and the associated resource allocation. A responsive, evidence-informed HBP is a dynamic policy instrument that is adjusted over time to address emerging challenges in implementation, changing disease burdens, fluctuating budgets, and the emergence of new services. However, a recent review of HBPs in LMICs shows that the majority of packages (14/24) have not been revised substantially – some despite having been in place for over a decade.<sup>##UREF##4##6##</sup></p>", "<p> Health technology assessment (HTA) is a systematic process designed to inform priority setting and decision-making related to the integration of a technology or health intervention in to a HBP. This process can be used to develop and revise HBPs that enhance value for money and minimize opportunity costs associated with less impactful investments. HTA achieves this by facilitating the systematic prioritization of cost-effective health interventions.<sup>##UREF##0##1##,##UREF##5##7##</sup></p>", "<p> The JLN has captured practical lessons from countries in conducting periodic revision of HBPs in a knowledge product titled, “Making Explicit Choices on the Path to UHC: Guide for Health Benefits Package Revision.”<sup>##UREF##6##8##</sup> Guidance in this knowledge product can be used by practitioners in LMICs to support revision of their HBPs while responding to changing disease burdens, fluctuating budgets, and the emergence of new services and health technologies, and to correct for implementation challenges.</p>", "<p>\n<italic toggle=\"yes\">Our experience with the JLN’s engagement in peer-to-peer learning can offer insights on the knowledge gaps at the country level that impact use of evidence-informed processes to determine the HBP design and implementation. </italic>In Cambodia, an evidence-informed deliberative process (EDP) involving a group of key health sector stakeholders, which also included several non-health departments of the government as well as non-governmental entities, was facilitated using prioritization tools from the JLN. This helped inform the country’s prioritization of interventions that were included in the investment case for maternal, reproductive and child health. The consultative, multi-stakeholder process helped build consensus, acceptability and trust among the concerned stakeholders for the prioritized interventions.</p>", "<p> The paper on EDPs by Baltussen et al<sup>##REF##34923808##9##</sup> comprehensively reports on the development of practical guidance for EDPs. It outlines the processes, notably engaging input from stakeholders and the best available evidence that HTA bodies must follow to support legitimate HBP design. Baltussen et al EDP framework can also support the process of developing or revising an HBP while taking into account factors such as disease burden, equity issues, health system goals, and stakeholders’ preferences and values. This resonates very well with a JLN prioritization recommendation in situations of limited fiscal space, to target the poor with health services relevant for their needs. This approach optimizes the use of finite resources while remaining consisitent with societal values.</p>", "<p> National health insurance agencies (NHIAs), that tend to be the main users of the HTA agencies’ work, should have a buy-in into EDPs. However, research shows that in several LMICs, production of HTAs is disconnected from the process by which NHIAs make decisions about reimbursement. HTA methods guides in many JLN member countries do not even mention the NHIA. While such omission may not be deliberate, reasons behind it can vary as the process of priority setting can be very political. While a situational analysis that establishes why attempts to use data and evidence in the past have been successful or unsuccessful can shed light on how elements of the institutional environment and political economy might constrain or support the use of data and evidence in priority setting.<sup>##UREF##3##5##</sup> In this context, EDPs offer a transparent and inclusive process by which legitimate, politically and technically sound recommendations can be made. In Indonesia, guidelines for HTA are being revised, with support from the JLN in helping Indonesia learn from its peers to include EDPs as part of the process, that will enhance credibility, legitimacy and eventual use of the HTA processes, especially by the NHIA.</p>", "<p> A foundational step of priority-setting is drawing in actors who can advocate for the priorities and values across all levels of the health system. Indeed, Baltussen et al<sup>##REF##34923808##9##</sup> advise that the first step in an EDP is installing an advisory committee that has a diverse and sufficient set of perspectives and technical skills, and can play a role in defining priorities. The advisory committee should have the criteria to assess those priorities, and to guide the process of selecting and appraising technologies and interventions through an HTA. One of the areas for practical implementation advice sought by countries and shared in the JLN’s publication on health priority setting<sup>##UREF##3##5##</sup> is on setting up the right institutional mechanisms for EDPs. Lessons from JLN countries that have established such advisory committees — regarding their composition, role and mandate, and the criteria and guidelines used — can be a very useful insight for countries newer to these systematic processes. Such lessons, that can help smoothen the understanding of EDPs and their greater use by countries, could include: the mechanics of these deliberative processes- how to set these up; country learnings on practical aspects of setting up multiple levels of subcommittees if needed; modalities by which countries have provided opportunities to contribute to deliberations that do not depend only on physical participation in meetings – such as providing expert comments; country experiences and practices in compiling relevant evidence in a concise, accessible and standardized format, etc.</p>", "<p>\n<italic toggle=\"yes\">Facilitating country understanding and use of EDPs can encourage periodical revisions of the benefit packages – and thereby the sustainability of health financing programs aimed at supporting progress toward universal health coverage.</italic>If policy-makers have been postponing decisions regarding benefit package revisions due to the complexity of stakeholder dynamics and the potential for debates and resentment, sharing country experiences on the effectiveness of EDPs (Evidence-Based Packages) in fostering trust, credibility, and sustainability can promote their wider adoption. This, in turn, can encourage more frequent revisions of benefit packages. The value of peer learning for policy-makers is that this will help them understand the experiences with use of EDPs and how, if done well, they help build public trust in priority setting processes, and by extension the sustainability of UHC and health insurance programs. The failure to use EDPs in priority setting processes or to clearly communicate the application of such a process to the public can have implications such as patient or public resentment. Backlash against systematic priority setting processes can dampen use of such processes by national health bodies and NHIAs, introducing vulnerabilities to ad-hoc or discretionary decision making. When health budget allocations do not reflect health priorities or align with the prevailing policy and budget cycles, it becomes difficult to link expenditure plans with health objectives, and in turn to justify increases in resources for health. Additionally, when an HBP is underfunded, ill-defined, or has an infeasible scope of services, it can lead to inefficiencies and implicit rationing of health services, creating a ‘broken promise.’<sup>##UREF##7##10##</sup> Given how EDPs offer a transparent and inclusive process to help undertake the necessary revisions in HBPs with legitimacy, we recommend advocacy for EDPs beyond the HTA agencies and the producers of the evidence, to add a focus on the main users of the HTA agencies’ work — the NHIAs, to understand and buy-in into EDPs, as part of their larger buy-in into both using evidence for designing benefit packages and systematic priority setting processes. This can strengthen the resourcing and resolve for using EDPs, and add an additional layer of accountability and transparency for EDPs.</p>", "<p>\n<italic toggle=\"yes\">Peer-to-peer learning modalities among countries can offer a viable and effective mechanism to institutionalize EDPs as well as systematic priority setting itself. </italic>Institutionalizing HTAs can be costly and technically challenging. Building upon the experience of LMICs in understanding the resource and capacity needs, as well as the possible sequencing of efforts, can be invaluable. One such example is the use of adaptive HTA processes in Indonesia during 2022 mentioned above, for which the country has received considerable catalytic inputs from peer countries, and was facilitated by the JLN and the international decision support initiative. As the importance of systematic priority setting (and embedded EDPs within these institutions) becomes better understood, many LMICs may consider introducing these processes. There is an opportunity for countries further along in the institutionalization of EDP to share lessons learned from their own experience, including emerging best practices and how challenges were successfully met.</p>", "<p>\n<italic toggle=\"yes\">We recommend adding a research agenda to this framework, and using peer-to-peer learning to generate new, experience-based knowledge on the relevance of EDPs and how to undertake them better. </italic>This is clearly an area for more exploratory work on a range of themes, which are amenable to both formal research as well as documentation of tacit knowledge held by country practitioners. Questions which could be further investigated include: Why do even established HTA agencies not have EDPs formally instituted? What factors enabled institutionalization of EDPs, especially in LMICs? What strategies have helped convince policy-makers about the importance of EDPs? Would identifying the consequences of decision-making in the absence of an EDP support advocacy for the adoption of EDPs? To better understand how EDPs can be advocated for and institutionalized, it is useful to understand what specifically poses a challenge in setting up and operationalizing EDPs, and what enables it. Exchanges and interactions between practitioners in peer countries can be a valuable approach to capturing experiential knowledge as a complementary modality to formal research, and inspiring and catalyzing policy-makers by distilling knowledge from the successful experiences of their peers.</p>", "<title>Acknowledgements</title>", "<p> The authors would like to thank the facilitators and members of the JLN Efficiency collaborative for the content and examples used in this paper.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> There was no funding received specifically for this paper. This work was supported by respective organizations to which the individual authors are affiliated, to the extent that their time was covered by their employers, where applicable.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["1"], "mixed-citation": [" Tandon A, Bloom D, Oliveira Hashiguchi L, et al. Making the Case for Health: A Messaging Guide for Domestic Resource Mobilization. Joint Learning Network for Universal Health Coverage; 2021. "]}, {"label": ["2"], "mixed-citation": [" World Health Organization (WHO). World Health Report. Geneva: WHO; 2010. "], "uri": ["http://apps.who.int/iris/bitstream/10665/44371/1/9789241564021_eng.pdf"]}, {"label": ["3"], "mixed-citation": [" Organization for Economic Co-operation and Development (OECD). Tackling Wasteful Spending on Health. Paris: OECD Publishing; 2017. "], "uri": ["https://www.oecd.org/els/health-systems/Tackling-Wasteful-Spending-on-Health-Highlights-revised.pdf"]}, {"label": ["5"], "mixed-citation": [" Chi YL, Jeffery M. Health Priority Setting: A Practitioner\u2019s Handbook. Joint Learning Network for Universal Health Coverage; 2019. "]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Regan", "Wilson", "Chalkidou", "Chi"], "given-names": ["L", "D", "K", "YL"], "article-title": ["The journey to UHC: how well are vertical programmes integrated in the health benefits package? A scoping review"], "source": ["BMJ Glob Health"], "year": ["2021"], "volume": ["6"], "issue": ["8"], "fpage": ["e005842"], "pub-id": ["10.1136/bmjgh-2021-005842"]}, {"label": ["7"], "mixed-citation": [" Joint Learning Network for Universal Health Coverage (JLN). Revising Health Benefits Packages\u2014Guidance for Low- and Middle Income Countries (Forthcoming). JLN; 2022. "]}, {"label": ["8"], "mixed-citation": [" Joint Learning Network. Making Explicit Choices on the Path to UHC: Guide for Health Benefits Package Revision. Joint Learning Network; 2022. "]}, {"label": ["10"], "mixed-citation": [" Cotlear D, Nagpal S, Smith O, Tandon A, Cortez R. Going Universal: How 24 Developing Countries Are Implementing Universal Health Coverage from the Bottom Up. Washington, DC: World Bank Publications; 2015. "]}]	{ "acronym": [], "definition": [] }	10	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Oct 28; 12:7856	oa_package/8d/41/PMC10699826.tar.gz
PMC10699827	0	[ "<title>Background</title>", "<p> All countries need to purchase healthcare in ways that ensure resources are used effectively and efficiently; the need for healthcare will always outstrip the finances available with ever improving medical technology and so the more expensive care options that are available.<sup>##UREF##0##1##</sup> Purchasing (the allocation of funds to healthcare providers for services, on behalf of identified groups or a population),<sup>##REF##23940408##2##</sup> requires a continuous search for the best ways to maximise health system performance. It involves deciding which interventions to purchase, how to buy them, and from which providers, how providers will be paid, at what rates and under what contractual arrangements (eg, active or strategic purchasing [SP]).<sup>##UREF##1##3##,##UREF##2##4##</sup></p>", "<p> Given the international call for universal health coverage (UHC), many middle-income countries have started SP initiatives as part of established public insurance schemes.<sup>##REF##23940408##2##,##UREF##3##5##, ####REF##26769987##6##, ##UREF##4##7####4##7##</sup> In this systematic qualitative review, we report on the experiences in nine middle-income countries (both lower- and upper middle-income countries) to understand what extent the activities that constitute SP have been established with public sector insurance schemes, what have been the challenges and facilitators, and to what extent SP is helping countries achieve their UHC goals.</p>", "<title> What Does Strategic Purchasing Involve? </title>", "<p> SP requires the purchaser’s interaction with three key role players: the provider of healthcare services, citizens as the beneficiaries, and government as the regulator of both purchasing and provision of care. ##FIG##0##Figure 1## sets the actions associated with each key actor.</p>", "<title> Universal Healthcare Coverage, Insurance, and Strategic Purchasing </title>", "<p> The aim of universal healthcare coverage is to provide quality healthcare and financial protection to all people in a given country.<sup>##REF##23940408##2##,##UREF##2##4##,##UREF##4##7##,##REF##25378527##8##</sup> Pre-payment, either through taxation or insurance, is necessary to provide financial protection.<sup>##REF##26769987##6##</sup> While SP can be achieved through taxation systems, insurance schemes, with their separation of purchaser and provider roles into different organisations, is where SP is more visible. The core functions of insurance include pooling resources, enrolling members, defining the benefits package, contracting and paying providers and ensuring delivery of quality care that represents value for money. SP is then an essential building block to ensure that an insurance scheme remains financially viable, and that best use is made of available funds.<sup>##REF##23940408##2##,##REF##29502893##9##</sup> Done well, these tasks, in theory, can amount to a virtuous circle, with risk and income cross-subsidisation providing protection from catastrophic expenditure for its members, new members joining as knowledge of the scheme grows, and a benefits package that increases as more resources become available.</p>" ]	[ "<title>Methods</title>", "<p> We conducted a systematic search for literature in the following bibliographic databases: PubMed, CINAHL, Business Source Complete, Econlit, Web of Science, and Scopus (See ##SUPPL##0##Supplementary file 1##, for the search syntax). We included the names of the 110 middle-income countries (as defined by the World Bank).<sup>##UREF##5##10##</sup> Our search start date was 2011 as we found the rate of publications on SP increased at that time and the search was performed in November 2019. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram presents the systematic search and screening process (##FIG##1##Figure 2##). In addition, 38 additional grey literature documents on SP in case study countries, identified through google and google scholar searches, were included (such as conference presentations and reports, from RESYST [Resilient and Responsive health systems] and the World Health Organization [WHO] Global Health Regional websites) to supplement our review.</p>", "<title> Screening Strategy</title>", "<p> Once duplicates had been removed, 691 articles were exported to Covidence (software for managing and streamlining systematic reviews) and screened following the predefined inclusion and exclusion criteria in ##BOX##0##Box 1##. Non-English articles were excluded except Spanish, which ADK is able to read.<sup>##UREF##6##11##</sup> Duplicate screening was conducted at title and abstract stage with differences resolved by a third person. The full-text screening was initially done in batches of 30 in duplicate. Differences were resolved through discussion, and if necessary, the inclusion and exclusion criteria were revised to clarify any uncertainty. We continued screening in batches of 30 until no more differences of opinion arose. A total of 91 articles were found relevant to SP in healthcare in addition to the 38 retrieved from grey literature search. Thus, a total of 129 articles were include in this review.</p>", "<title> Sampling Country Case Studies</title>", "<p> Listing the countries in order of the number of articles on SP, we found 21 countries with one or more articles about SP. We purposively 9 selected countries to include those with the most articles whilst ensuring geographical spread. The countries were: Iran (17 articles), Nigeria (10), China (10), Mexico (7), Ghana (6), Kenya (5), Thailand (3), Vietnam (3), and Indonesia (1).</p>", "<title> Search for Supplementary Articles on Healthcare Financing in Case Study Countries</title>", "<p> We conducted additional searches in August 2020, to find articles on healthcare financing in each case study country. We searched for relevant articles in two main databases: Scopus and PubMed. We also conducted a grey literature search. We used the search terms: ‘healthcare financing’ OR ‘health financing’ AND ‘country’ for each country included. Screening was conducted using the following criteria: the article discussed at least one public healthcare financing mechanism, addressed any element of healthcare financing (eg, benefits package, service delivery platform, reimbursement mechanisms, provider-purchaser relationships, governance systems, etc) in one or more case countries, article was published in a peer-reviewed journal or was policy document that provides details of healthcare financing reforms in the case country. Time limitation was not applied to case study searches. For each case study we identified the following number of articles: Thailand (n = 45), Nigeria (n = 55), Ghana (n = 54), China (n = 91), Iran (n = 58), Mexico (n = 41), Vietnam (n = 42), Kenya (n = 52), and Indonesia (n = 38).</p>", "<title> Data Extraction and Analysis</title>", "<p> A data extraction template was designed and used to extract relevant information. Each team member focused on one or two case study countries. We read the supplementary articles to ensure we understood the healthcare financing system for each case study. We then focused on the SP articles. We extracted all results related to SP and made notes on each paper relating to the results to our understanding of healthcare financing in the country, and questions about SP relevant for our cross-country comparisons. We then reviewed the extractions and notes, and each team member wrote a case study summary covering the structure of healthcare financing, key health system and financing reforms, SP and the associated facilitators and challenges. We held twelve (n = 12) meetings to present the case study summaries to the rest of the team and to identify and discuss key experiences/issues, including the similarities and differences between countries’ and schemes. We used the extracted data, notes and case study summaries to finalise our analysis and write up. Samples of the data extraction files are attached (See ##SUPPL##1##Supplementary file 2##).</p>", "<title> Data Synthesis and Presentation</title>", "<p> While the RESYST framework emphasizes the relationships between the four sets of actors (purchasers, providers, citizens, and government), the detail provided is simply a list of specific tasks that each is responsible for executing. To develop an analytic framework within which to present the synthesis, we kept in mind the core elements of purchasing (deciding what to buy, from whom and how), as well as the importance of activities that maintain relationships between actors, and then organised the available data in the following sections with associated tables: healthcare financing country context; description of schemes (coverage, benefits etc); scheme performance; purchasing arrangements; and, governance of purchasing. (We were constrained by data availability; for example, there was data on reimbursement mechanisms but not the detail of specific contracts).</p>", "<p> Firstly, we compare the structure of healthcare financing in each country based on the relative financial flows (ie, public, and private prepayment spending, external funds, out of pocket, etc) to provide a contextual understanding (##TAB##0##Table 1##).</p>", "<p> Secondly, we provide a description of the insurance schemes, including coverage and the benefits package, in order to compare the benefits packages (which are specified in different ways), we identified whether the packages included three particular treatments — HIV/AIDS treatment (as representative of chronic care), maternal care (including hospital delivery) because its need is widespread, and dialysis (because, its cost has a catastrophic effect on households).<sup>##REF##27737663##12##, ####UREF##7##13##, ##REF##23390079##14##, ##REF##29608610##15##, ##UREF##8##16####8##16##</sup> Three categories were created to represent the extent of the benefits package: (1) full package if it covers all three services, (2) partial package if it covers two of the services, and (3) limited package if only includes one of these services (Further details on membership eligibility criteria and contributions are provided in Table S1 of ##SUPPL##1##Supplementary file 2##).</p>", "<p> Thirdly, we provide an indication of the schemes’ performance using levels of out-of-pocket (OOP) by insured members, whether there were reports of purchases struggling to pay for care, and providers refusing to provide care (##TAB##1##Table 2##).</p>", "<p> Fourthly, we compare key elements of the purchasing arrangements, including reimbursement mechanisms, presence of gate keeping rules, whether there are caps on expenditure, evidence of provider-purchaser negotiations, research capacity, and whether purchasing was decentralised or not (We judged the latter to be important in enabling purchasers to be responsive, particularly in large countries) (##TAB##2##Table 3## and Table S1).</p>", "<p> Fifthly, we described the extent and type of governance because of its impact on SP (##TAB##3##Table 4##). We used the WHO framework on governance for SP to compare the case countries.<sup>##UREF##2##4##</sup> The framework has three key areas: setting directions, coordination and alignment, and legal provisions and regulations. We used the following indicators for comparison: (1) the existence a 5- or 10-year policy/strategy document (setting direction); (2) existence of governance body (coordination and alignment); and (3) a legal framework (legal provisions and regulations). We supplemented this with evidence on accreditation, monitoring of the claims, evidence of corruption and strategies to reduce it, patient engagement and patient feedback channels.</p>" ]	[ "<title>Results</title>", "<title> Healthcare Financing Context in the Case Study Countries</title>", "<p> In ##TAB##0##Table 1## we compare the case study countries’ health financing indicators (in 2017), life expectancy and maternal mortality as indicators of health system performance, as well as their average economic growth rates for the past 40 years (1981-2020) (The order of the countries in ##TAB##1##Table 2## is based on their maternal mortality rate).</p>", "<p> Government expenditure on health was between 2%-3% of gross domestic product (GDP) for five countries (China, Mexico, Thailand, Vietnam, and Kenya) and below 2% in three countries (Indonesia, Ghana, and Nigeria); only in Iran was it above 4% (Evidence suggests that government expenditure needs to be above 5% of GDP to achieve UHC).<sup>##REF##28332456##17##</sup> Public and private expenditure amounted to roughly equal shares of total health expenditure in 6 countries, with the exception of Thailand (76%/23% split), Ghana (33%/52% split), and Nigeria (14%/77%). External donor resources were significant in Ghana, Kenya, and Nigeria (17%-28%). Out of pocket expenditure as percentage of total health expenditure was between 30%-45% of total expenditure in all the case study countries, except for Thailand (11%), Kenya (24%), and Nigeria (77%).<sup>##UREF##9##18##</sup></p>", "<p> Despite a GDP per capita of US$ 3000, and an average growth rate of 2.7% over the last 40 years, Iran had the highest government expenditure on healthcare as percentage of GDP (4.4%) as well as in terms of international dollars (purchasing power parity $); it was also the best performing with the lowest maternal mortality ratio (MMR) of 16/100 000 live births, and a life expectancy of 76 years, although OOP payments are high at 41%.<sup>##UREF##9##18##</sup> Thailand, with its high government share of health expenditure (76.1%), manages to keep out of pocket expenditure low (11%), although its MMR is still double that of Iran. Nigeria is the worst performing country, with MMR of over 900, OOP over 70% and the government share expenditure of total expenditure at 14% (See ##TAB##0##Table 1##).</p>", "<title> Coverage and Benefit Packages Provided by Schemes</title>", "<title> Insurance Coverage</title>", "<p> Five countries had more than 70% population (including rural population) covered by public sector insurance schemes [Thailand (98.5%), China (96.9%), Iran (90%), Vietnam (87%), and Mexico (85%)]<sup>##REF##29608610##15##,##REF##31533710##19##, ####REF##21269682##20##, ##UREF##10##21####10##21##</sup> (Table S1). Indonesia, Ghana, Kenya, and Nigeria had less than 50% of the population covered by state insurance schemes with Nigeria having only 5% coverage of the population by the Formal Sector Social Health Insurance Scheme (FSSHIS).<sup>##REF##28812815##22##, ####REF##30080875##23##, ##REF##22233470##24##, ##REF##28555372##25####28555372##25##</sup> While most schemes’ membership were primarily formal sector employees (Kenya, Indonesia, and Nigeria),<sup>##REF##31234940##26##, ####REF##32516361##27##, ##REF##30579611##28##, ##REF##31535352##29##, ##REF##22232451##30##, ##REF##29282087##31####29282087##31##</sup> some governments provided insurance coverage for the poor in social health insurance (SHI) schemes such as the Universal Coverage Scheme (UCS) in Thailand, Imam Khomeini Relief Foundation (IKRF) in Iran, Urban Employee’s Basic Medical Insurance (UEBMI) in Chine, National Health Insurance Fund (NHIF) in Kenya, and SHI in Vietnam.<sup>##REF##30080875##32##, ####REF##23974406##33##, ##UREF##11##34##, ##UREF##12##35##, ##UREF##13##36##, ##REF##34070687##37##, ##REF##32013955##38####32013955##38##</sup></p>", "<title> Health Benefits Package </title>", "<p> Six of the countries (Iran, Thailand, Indonesia, Ghana, Vietnam, and Kenya) had a comprehensive benefits package by our categorisation, including maternity services with inpatient delivery, HIV/AIDS treatment, and at least part of the costs of dialysis in their benefits package.<sup>##REF##23974406##33##,##REF##31837066##39##, ####REF##27905941##40##, ##REF##30894183##41##, ##UREF##14##42##, ##REF##27178747##43##, ##UREF##15##44##, ##UREF##16##45####16##45##</sup> China, Mexico, and Nigeria’s schemes covered only maternity services, but neither HIV treatment nor dialysis<sup>##REF##23390079##14##,##UREF##16##45##, ####REF##27557551##46##, ##REF##22704914##47##, ##REF##23170770##48####23170770##48##</sup> (See Table S1).</p>", "<title> Performance</title>", "<p> We found evidence of delays in payments of providers in six of the countries (Iran, Mexico, Vietnam, Ghana, Kenya, and Nigeria). We found reports that providers in Nigeria, Vietnam, and Ghana failed to honour essential services contained in the package, often due to delays in payments by the purchaser.<sup>##UREF##11##34##,##REF##31837066##39##,##REF##21071106##49##, ####REF##25494816##50##, ##REF##37383313##51####37383313##51##</sup> Christian Health Association of Ghana returned to full OOPs when national health insurance authority (NHIA) delayed reimbursing their facilities for services provided.<sup>##UREF##17##52##</sup> In Indonesia there was evidence of some hospitals not being able to offer services under the benefits package because of lack of resources.<sup>##REF##31535352##29##,##REF##37383313##51##</sup></p>", "<p> In Thailand of pocket payments (OOPs) were below 15% of total health expenditure, suggesting catastrophic expenditure for households would be minimal.<sup>##REF##32958064##53##</sup> In Indonesia, OOP was also relatively low at 18%; Kenya 29% and Vietnam 30%-39% were the next lowest.</p>", "<p> Only in Thailand, Mexico, Vietnam, and Indonesia was the OOP of members reported to be lower than, or equal, to the national OOP suggesting the scheme was achieving its goal of protecting members to some degree from catastrophic expenditure (##TAB##0##Tables 1## and ##TAB##3##4##). (In Thailand OOP by members and nationally were the same, as coverage is close to 100%). In other countries OOP by members was reported to be higher than the national figure.</p>", "<p> While OOP is complex to measure and therefore there is often considerable variation in its estimates, these figures suggest that the insurance schemes, other than Thailand and Indonesia, were failing to protect members against catastrophic expenditure, and that members were wealthier in comparison to the uninsured and so able to pay out of pocket when the insurance scheme fails them.<sup>##REF##31535352##29##,##REF##31837066##39##,##REF##21071106##49##,##REF##37383313##51##</sup></p>", "<title> Purchasing Arrangements</title>", "<title> Reimbursement Mechanisms</title>", "<p> For primary care, the case study countries predominately used capitation as the reimbursement mechanisms, occasionally with performance-based elements (China and Indonesia),<sup>##REF##31423635##54##,##REF##27538780##55##</sup> and fee for service (FFS) for some specific services, or in specific schemes (Thailand).<sup>##REF##31423635##54##</sup> Indonesia expanded the use of capitation into commitment-based capitation (using indicators to assess health facility staff commitment to work), along with increased monitoring by BPJS (Badan Penyelenggara Jaminan Sosial)-Health. The introduction of capitation and gate-keeping led to a reduction in demand for hospital care.<sup>##REF##31423635##54##</sup> The exceptions were Ghana and Iran where FFS reimbursement is used.<sup>##REF##27178747##43##</sup> Capitation has been piloted in Ghana. As mentioned above, after protests by both providers and members, partly due to inadequate stakeholder engagement, and insufficient preparation and research, the capitation payment mechanism was abandoned.<sup>##REF##27178747##43##,##REF##27557551##46##,##REF##30922298##56##</sup></p>", "<p> Most countries use a case-based payment of varying sophistication for hospital reimbursement, ie, Nigeria, China, Mexico, and Thailand use diagnosis related groups (DRGs),<sup>##REF##25378527##8##,##REF##24735721##57##, ####REF##23339606##58##, ##REF##31519075##59####31519075##59##</sup> while the others used simpler forms, in combination with FFS for medication and for some specific procedures. Only Vietnam used a per-diem payment.<sup>##REF##25514050##60##</sup> China piloted its DRGs before scaling-up, but the implementation was negatively affected by insufficient information system capacity and lack of unified disease classifications. The pilots led to the adoption of mixed provider payment methods,<sup>##REF##27538780##55##,##REF##24735721##57##</sup> with hospitals in some provinces allowed to choose FFS for older patients and those with complications, leading presumably to selection of the more profitable option by providers.<sup>##REF##24735721##57##</sup> Vietnam, Nigeria, and Kenya are using FFS for hospital care and had no process to reform provider payment methods.</p>", "<p> Two countries have attempted to increase the supply of particular services by switching to FFS. Thailand changed the reimbursement methods for HIV and cataracts from capitation to FFS in order to increase supply,<sup>##REF##25378527##8##,##REF##29608610##15##</sup> and China made specific payments for TB services, and paid for patients’ transport and a subsistence allowance in order to ensure better TB outcomes.<sup>##REF##26822583##61##,##REF##31336947##62##</sup></p>", "<p> Governments in all nine countries either paid salaries of staff in public facilities or provided other budgetary support (##TAB##1##Table 2##).</p>", "<title> Gate Keeping</title>", "<p> Gate keeping has been implemented in some countries (ie, Vietnam, Ghana, Iran, Indonesia, and Thailand (except the Civil Servants’ Medical Benefits Scheme [CSMBS]), although implementation varied across countries.<sup>##REF##25378527##8##,##REF##26006186##74##, ####REF##25560361##75##, ##REF##25622127##76####25622127##76##</sup> Ghana, Vietnam, and Thailand had a defined list of health services for which referral was permitted under the gate keeping system.<sup>##UREF##7##13##,##REF##29608610##15##,##REF##25622127##76##</sup> In Indonesia and Mexico, there were no clearly defined services or the cost that are covered during the referral. In the literature reviewed there was no mention of a gate keeping system in Nigeria, Kenya, and China (##TAB##1##Table 2##).</p>", "<title> Budgetary Caps on Expenditure</title>", "<p> Although reimbursement rates for particular services are part of each contract, purchasers need to control overall expenditure, to ensure that it does not exceed the scheme’s income, and so its sustainability. This can be done by setting an overall limit and adjusting the payments rates per service, should the quantity of services push threaten to push expenditure above the limit (for example UCS in Thailand).<sup>##REF##31533710##19##</sup> Alternatively, expenditure limits per person can be set; this is used in China, Indonesia, and for certain services in Kenya.<sup>##REF##31423635##54##,##REF##27357072##77##, ####REF##24107660##78##, ##REF##31571602##79##, ##UREF##21##80##, ##UREF##22##81####22##81##</sup> There is no cap on overall expenditure for the CSMBS in Thailand, and in Iran, Mexico, Vietnam, Ghana, or Nigeria we found no mention of caps on expenditure (##TAB##1##Table 2##).</p>", "<title> Provider-Purchaser Engagement</title>", "<p> Provider-purchaser negotiations are important in determining prices, the affordability of services and the sustainability of a scheme. Purchaser-provider engagement can enable sharing relevant information and building relationships based on trust and collaboration. Lack or limited engagement with providers is more likely to encourage provider opportunism to meet income targets.<sup>##REF##31533710##19##,##REF##23974406##33##,##REF##29657242##82##</sup></p>", "<p> In two countries (Indonesia and Thailand) the purchaser has effective means of engaging with providers,<sup>##REF##25378527##8##,##REF##31603476##83##</sup> with well-structured forums. In Thailand, providers were involved in the national health security board of UCS. The National Health Security Office (NHSO) uses its substantial purchasing power to negotiate for lower prices for some selected high-cost medicines and medical devices, leading to cost savings, increased affordability, and access to essential services.<sup>##REF##29608610##15##,##REF##29800002##84##</sup> For example, when cataract services were on high demand, the NHSO used its central bargaining capacity to negotiate an affordable price for soft lens for providers. Therefore, hospitals could then choose to reimburse on an agreed rate or to use the lens supplied by the NHSO-negotiated vendors.<sup>##REF##25378527##8##,##REF##29608610##15##,##REF##29800002##84##</sup></p>", "<p> Indonesia has reaped substantial benefits from engaging with providers. Performance indicators, on which price revisions and capitation payments were benchmarked, enabled the purchaser to hold primary health providers accountable and minimised opportunistic behaviour (such as using lower cadre of staff despite regulations), despite the administrative burden associated with its execution.<sup>##REF##31603476##83##,##REF##29514283##85##</sup> This was possible through the PPJK agency (Perusahaan Pengurusan Jasa Kepabeanan-health Insurance Directorate) under the Ministry of Health (MoH) to evaluate and calculate prices, simulated with expected revenues.<sup>##REF##31423635##54##</sup></p>", "<p> In six countries (Ghana, Nigeria, Vietnam, Kenya, Mexico, and China), we found limited evidence of active engagement, and prices, benefits, and modes of payments are often fixed by either boards or committees (Kenya, Mexico, and Ghana) and the health ministries (Vietnam). In Kenya, the private sector, represented in the NHIF governing board, had a strong voice, and influence, leading to a ‘purchaser capture,’ demonstrated by the favourable reimbursement rates and terms extended to private health facilities.<sup>##REF##28627085##86##</sup></p>", "<p> Inadequate provider-purchaser engagement and protests have led to Ghana’s capitation policy being suspended; the policy was decided at the level of “elite stakeholders.”<sup>##REF##27178747##43##</sup> However, patients needed to know what interventions were included in the benefits package.<sup>##REF##30894183##41##,##REF##28579626##87##</sup> Health professional associations and providers need to assess the likely effect on service delivery, the services covered in health benefits package, and their income levels.<sup>##REF##27178747##43##</sup> Likewise, in Iran the Ministry of Health and Medical Education (MoHME) independently determined the prices for benefits and the revision of relative value units has faced multiple challenges because of lack of active negotiations with relevant stakeholders.<sup>##REF##31533710##19##,##REF##31256572##88##</sup></p>", "<p> Purchaser-provider tensions were a key contributor to the unravelling of Mexico’s decentralised, SP units within <italic toggle=\"yes\">Seguro Popular</italic> in favour of a centralized system under the Institute for Health and Well-being (INSABI). Decentralised purchasing units struggled to negotiate effectively with centralised and highly influential medical unions. This led to increased contracting which distorted state-level fund allocations (eg, some states were spending nearly 70% of costs on contracts, causing purchasers to introduce a 40% cap). Efforts to “regularise” contracts significantly increased costs (eg, by over 30% in one year). However, better contracts did not produce better performance from providers. This suggests that federal-state coordination was poor, and oversight of purchaser provider negotiations was insufficient.<sup>##REF##27991989##89##,##REF##28209145##90##</sup> However, INSABI, the new centralised purchasing body, emerged without adequate stakeholder consultations<sup>##UREF##23##91##</sup> (##TAB##1##Table 2##).</p>", "<title> Research</title>", "<p> Five countries (Thailand, China, Indonesia, Vietnam, and Mexico) have established health technology assessment (HTA) units, key for deciding what services and technologies to purchase.<sup>##REF##31423635##54##,##REF##19527546##92##, ####REF##34444597##93##, ##REF##30326795##94####30326795##94##</sup> Ghana has some internal capacity within government to conduct research and has initiated the process to establish HTA. In Indonesia the National Basic Health Research Unit, established in 2013, has improved the availability and quality of data on which to make purchasing decisions. The government has also started to collect village level data to guide planning and policy decision-making.<sup>##REF##31603476##83##</sup> Nigeria, Kenya, and Iran had little internal capacity, and relied on publications produced by university academics (##TAB##1##Table 2##).</p>", "<title> Decentralisation</title>", "<p> Although decentralization of healthcare service delivery has been accepted globally as a means to improve the responsiveness of the health system, decentralisation of the purchasing function is less common. In three of our case study countries (Ghana, Iran, and Vietnam), purchasing was carried out at national level.<sup>##REF##31533710##19##,##REF##28812815##22##,##REF##23974406##33##,##REF##31807038##95##, ####REF##18424793##96##, ##REF##30659404##97####30659404##97##</sup> Three countries (Thailand, Indonesia, and China) have decentralised the purchasing function to the local level.<sup>##REF##29800002##84##,##REF##23476091##98##</sup></p>", "<p> Thailand implemented decentralisation by increasing budgetary allocation from 9% to 26% to local governments between 1999 and 2012, to increase their purchasing capacity.<sup>##REF##25378527##8##</sup> However, the government’s action plan has not been fully implemented (such as the involvement of community committees in purchasing) due to a frequent change in governments. The largest public health insurance scheme in China — New Cooperative Medical Scheme has been decentralised to the state level, which give local governments vast autonomy in system design, leading to varying degrees of local government subsidies for premiums, levels of coinsurance and deductibles and reimbursement procedures.<sup>##REF##23476091##98##</sup> Given that Indonesia’s sizeable population, spread over many islands with diverse ethnic and religious groupings, the country has adopted high levels of decentralisation, with district level schemes having considerable autonomy in terms of scheme design and purchasing of healthcare.<sup>##UREF##12##35##,##REF##24966293##99##</sup></p>", "<p> Under the <italic toggle=\"yes\">Seguro Popular</italic> in Mexico, the central government provided funds to state-level autonomous purchasing units called Regimen Estatal de Proteccion Social en Salud (REPSS).<sup>##UREF##25##102##</sup> The REPSS were designed to exist outside of the state health agencies, in order to separate financing from provision, as a mechanism to improve the efficiency and quality of service delivery.<sup>##UREF##25##102##</sup> However, recent reforms have eliminated REPSS, effectively (re)centralising purchasing to a national level under INSABI<sup>##UREF##23##91##,##UREF##25##102##</sup> (##TAB##1##Table 2##).</p>", "<title> Governance of Purchasing</title>", "<title> Policy and Legal Frameworks, Oversight Bodies</title>", "<p> Indonesia, Iran, Vietnam, Kenya, and Thailand had policy frameworks guiding health system and SP reforms. Specifically, Thailand began health reforms in 1942 with an evidence-based National Economic and Social Development Plan (NESDP), which contained six separate reforms.<sup>##REF##31807038##95##</sup> Indonesia had a detailed policy document that provided the sequence for health reforms starting from 1945. Iran transitioned through five sequential reforms from 1964 to the 2014 Health Transformation Plan.<sup>##REF##31533710##19##</sup> Four countries have no explicit policy framework (Ghana, Nigeria, Kenya, and Vietnam).</p>", "<p> Only four countries had independent governance structures to provide oversight. In Kenya, there is a 12-member NHIF board,<sup>##REF##32013955##38##</sup> 31-member UCS board with diverse membership (including non-governmental and civil society organisations in health, and members) in Thailand,<sup>##REF##29608610##15##,##REF##24347713##103##</sup> Ghana’s NHIA has a governing council,<sup>##REF##28812815##22##</sup> and BPJS in Indonesia has a 2-member board of director and commissioner.<sup>##REF##31965166##104##</sup> In Mexico, the General Health Council, a collective decision-making body composed of various stakeholders [representatives from the National Commission for Social Protection in Health (CNPSS), MoH, REPSS], defined and updated the package of high-cost interventions and assists with provider accreditation.<sup>##UREF##25##102##</sup> Many of these boards have patient and private provider representation.<sup>##REF##25378527##8##,##UREF##26##105##</sup> However, the management board members (ie, CSMBS) in Thailand,<sup>##REF##29608610##15##</sup> Ghana and Kenya perform functions that were unrelated to their expertise.<sup>##REF##23974406##33##,##REF##32013955##38##,##UREF##26##105##</sup> Moreover, large boards (eg, 31 for national health security board of UCS in Thailand) can also delay decision-making.<sup>##REF##29608610##15##</sup></p>", "<p> All case study countries had legal and regulatory frameworks establishing the schemes and setting directions for purchasing and service provision, as well as established institutions for implementing SP and associated reforms.<sup>##UREF##10##21##,##REF##23974406##33##,##REF##32013955##38##,##UREF##23##91##,##REF##31807038##95##,##UREF##27##106##, ####REF##28207049##107##, ##REF##32164725##108##, ##UREF##28##109####28##109##</sup> However, diversities exist in how they were constituted and operationalised, for example in Nigeria, although the NHIS was overseeing the activities of health maintenance organizations (HMOs), the activities required of the HMOs were not properly defined, leaving lapses for opportunism.<sup>##UREF##11##34##,##REF##32164725##108##</sup></p>", "<p> Only four countries had functioning/integrated information management system, including e-databases of clients and e-claims/tendering processes (China, Thailand, partly implemented in Ghana, and Mexico).</p>", "<title> Provider Accreditation </title>", "<p> All the case study countries have some form of mechanism for accreditation of health facilities. Three countries use standards provided by international bodies (Thailand, Indonesia, and China), such as the International Society for Quality in Health Care (ISQua) (Thailand, Indonesia) and Joint Commission International Standards (China).<sup>##REF##31965166##104##,##UREF##29##110##,##REF##30408235##111##</sup> For most countries there were reports of either infrequent assessments, with considerable variation in terms of what is done in which province or state (Nigeria, China, Vietnam, Mexico, Ghana, and Iran). Key challenges reported were inadequate and fraudulent assessment and ranking of providers (Iran and Indonesia),<sup>##REF##31965166##104##,##REF##28207049##107##,##REF##30408235##111##</sup> as well as inadequate and non-strict criteria for credentialling providers (Ghana, Kenya, Indonesia, and Iran).<sup>##REF##27905941##40##,##REF##31965166##104##,##REF##30408235##111##, ####REF##25185526##112##, ##REF##30518378##113####30518378##113##</sup> In some countries, public providers are given automatic accreditation (Ghana and Kenya).<sup>##REF##30518378##113##,##REF##29470545##114##</sup></p>", "<title> Monitoring Claims and Services</title>", "<p> Monitoring of claims is important to identify fraud. All case study countries had instituted some strategy for monitoring claims, but they vary in complexity and the extent to which they were implemented. Three countries (Ghana, Vietnam, and Thailand) have implemented e-claim processing to reduce processing time and ensure timely payment of providers (only some health facilities in Ghana). Ghana and Indonesia have established paper-based claim processing units in all health facilities.</p>", "<p> Electronic health records are a significant milestone in being able to check for service over-supply (Ghana, China, Indonesia, and Thailand). An integrated health information management system has been developed in China (One Health Information Management) with unique patient and prescriber identification numbers.<sup>##UREF##30##115##,##UREF##31##116##</sup> Thailand uses its electronic system to track claims of accredited providers.<sup>##REF##29608610##15##</sup> For Ghana, the system allows for auditing of historical claims data.<sup>##REF##28812815##22##,##REF##32497074##117##</sup></p>", "<p> Clinical audits of the services covered in claims were conducted in Ghana, Thailand, China, and Mexico.<sup>##REF##29608610##15##,##REF##28812815##22##,##REF##21733610##118##,##UREF##32##119##</sup> In Mexico, <italic toggle=\"yes\">Instituto Mexicano del Seguro Social</italic> scheme tracks and audits providers for services provided under the SHI.<sup>##UREF##23##91##</sup> Indonesia utilises a taskforce against fraud to clampdown retrospectively on financial wastage, through on-site monitoring of community health centres and district heath offices at given time periods.<sup>##UREF##33##120##</sup> Provider performance is publicly showcased through quarterly hearings. These strategies have identified ‘under the table’ payments from patients, excessive treatment, and fraudulent use of insurance cards by non-members.<sup>##UREF##34##121##</sup></p>", "<p> Although HMOs in Nigeria are mandated by the law to check claims sent from accredited health facilities on a quarterly basis, this is not often done, thereby creating variations in claim amounts versus services provided.<sup>##UREF##11##34##,##REF##32164725##108##</sup> In Iran, the MoHME was responsible for monitoring providers and purchaser organisations for compliance with clinical guidelines and audit regulations,<sup>##REF##32312238##122##</sup> however, this is not done.</p>", "<p> Key explanations for the failure in countries where monitoring was inadequate were limited capacity within NHIF (Kenya),<sup>##REF##29524953##123##</sup> influence of politicians and other beneficiaries of the dysfunctional system (Nigeria).<sup>##UREF##35##124##</sup></p>", "<title> Patient Engagement </title>", "<p> In two countries, patients’ rights are enshrined in law (Mexico, China), and there are channels for patients’ complaints in six countries (Ghana, Thailand, Mexico, Nigeria, China, and Kenya). In five countries, health insurance schemes have hotlines for patients to report complaints (Thailand, Mexico, Ghana, Iran, and Indonesia).<sup>##REF##29608610##15##,##REF##28812815##22##,##UREF##23##91##,##REF##32312238##122##</sup> In Mexico, complaints can be lodged at complaints units or health facility user orientation offices, which are part of the State Health Secretariat.<sup>##UREF##23##91##</sup> In Indonesia there are two mechanisms for patients to voice concerns: patients’ complaints and resolution box (paper-based system) and the customer relations office of the scheme (either in person or by phone), where monthly meetings are held to resolve clients’ issues.<sup>##UREF##33##120##,##UREF##36##125##</sup> However, across countries, the channels functioned poorly, and information gained from patients are not fed back into the system to improve things. Moreover, patients’ awareness of their rights, their entitlements and how to access the benefits was poor.<sup>##UREF##33##120##,##UREF##34##121##</sup></p>", "<title> Corruption and Strategies to Reduce it</title>", "<p> We found reports of corruption in eight countries (Iran, Mexico, Thailand, Vietnam, Indonesia, Ghana, Kenya, and Nigeria). Typical of these were:</p>", "<p>Over prescriptions (Iran, Indonesia), inflation of prices of medicines (Mexico, Ghana),<sup>##UREF##23##91##,##REF##34129630##126##,##REF##28166773##127##</sup> collusion (physicians had certain patients make repeated visits to them within short intervals, and those patients were directed to a particular high-cost pharmacies) between dispensaries and patients (Iran).<sup>##REF##30408235##111##,##REF##32312238##122##,##REF##26927587##128##</sup></p>", "<p>Falsification of DRGs coding (called “DRG-Creep’) (Thailand),<sup>##REF##29608610##15##</sup> inflation of claims (Ghana),<sup>##REF##34129630##126##</sup> inappropriate use of tariffs (Ghana),<sup>##REF##28166773##127##</sup> claiming services that were not provided (Indonesia, Ghana),<sup>##REF##34129630##126##,##REF##28166773##127##</sup> and ‘under table’ payments (Iran).<sup>##REF##31086788##129##</sup></p>", "<p>Falsification of accreditation documents (Kenya),<sup>##REF##25185526##112##,##REF##30518378##113##</sup> or employing unlicensed staff (Indonesia).<sup>##REF##31965166##104##,##UREF##33##120##,##UREF##34##121##</sup></p>", "<p>Conflict of interest where HMOs were owned by political elites who controlled the national health insurance scheme (Nigeria).<sup>##UREF##11##34##,##REF##32164725##108##,##UREF##35##124##</sup></p>", "<p>Misuse or embezzlement of health sector funds (Mexico, Vietnam).<sup>##REF##26017577##100##,##UREF##24##101##,##REF##30207901##130##</sup></p>", "<p> Several measures were introduced in various countries to prevent fraud. Iran granted autonomy to teaching hospitals to manage staff motivation to reduce fraud and introduced new payment reforms to manage clinical services and balance hospital revenues.<sup>##REF##29608610##15##,##REF##30788334##131##</sup> Mexico adjusted its regulatory framework, increasing accountability of the CNPSS and the REPSS through new accounts created at the Federal Treasury and new sanctions.<sup>##UREF##23##91##,##UREF##32##119##</sup> Thailand’s NHSO introduced a global budget to augment the DRG payments and established a rigorous medical audit system.<sup>##REF##29608610##15##</sup></p>", "<p> In Indonesia, the Public Research Anti-Corruption Clearing House and the Corruption Eradication Commission was established to prevent provider fraud.<sup>##REF##31965166##104##,##UREF##34##121##</sup> This was supported by e-tendering for drugs and supplies, introduced to expedite contractual arrangements and reduce corruption.<sup>##UREF##33##120##,##UREF##34##121##</sup> Vietnam introduced an electronic claim management system and provided smart cards for members. Ghana piloted an electronic claim submission and processing system for some providers, provided identity cards for insured members, introduced clinical audit and historical claim auditing of services provided.<sup>##REF##34129630##126##,##REF##28166773##127##</sup> The Kenya’s MoH ensures that adequately trained medical staff conduct clinical reviews/audits in Kenya.<sup>##REF##25185526##112##,##REF##30518378##113##</sup></p>", "<p> While evidence of corruption exists in Nigeria’s healthcare purchasing system, there were no descriptions of efforts to reduce it, in the literature we reviewed (##TAB##2##Table 3##). While there were no reports of corruption in China’s healthcare purchasing system, the National Health and Family Planning Commission introduced laws that prohibited corrupt practices. Providers and pharmaceuticals who were found culpable were blacklisted.</p>" ]	[ "<title>Discussion</title>", "<p> Managed well, public insurance schemes, with risk and income cross-subsidisation, can provide financial protection of their members. In theory, new members join as knowledge of the scheme grows, and the benefits package can be increased as more resources become available. However, for schemes to grow beyond the mandatory enrolment of the formal sector and include the poor, the use of public funds is required; resource constraints and need for care are then at their highest, and the need for ensuring value for money even more important.<sup>##REF##23974406##33##,##UREF##23##91##,##REF##31807038##95##</sup></p>", "<p> As coverage increases, a scheme needs to keep costs at an affordable level, while ensuring that OOP (ie, costs borne by members) do not escalate. Various elements of SP enable control of a schemes’ costs, such as limiting the benefit package, a cap on expenditure, using reimbursement mechanisms that enable cost control (capitation and DRGs), gate-keeping, as well as monitoring claims and minimising corruption. However, containing OOP also requires that appropriate services are provided and paid for an at appropriate rate ie, that the members do not have to seek care elsewhere,<sup>##UREF##37##133##</sup> or the providers do not charge a co-payments or informal fees.<sup>##UREF##4##7##,##UREF##37##133##</sup> Other elements of SP are focused on this task, such as research capacity to ensure the most appropriate services are purchased, the auditing of facilities and quality of care, as well as engagement with providers and members to understand if the scheme is meeting both of their needs.</p>", "<p> The schemes in Thailand and Indonesia have managed to keep OOP relatively low (11% and 18%, respectively). Both have a comprehensive benefit package, a cap on expenditure and some gate-keeping mechanism. They both have forums for systematic engagement between purchaser and providers, HTA research capacity, and have successfully reformed reimbursement mechanisms to change provider incentives. They both use international standards for accrediting facilities and conduct clinical audits of services. In sum, both have effective SP, although Indonesia has not managed to substantially include the poor (coverage is 32%) unlike Thailand (99%) where public funds subsidise membership of the poor.</p>", "<p> In the Vietnamese scheme, coverage is high (87%), and while benefits are limited, there is HTA capacity, a performance capitation mechanism at primary healthcare as well as a gate keeping mechanism, but FFS is used for hospital care and there is no cap on expenditure. As a result, 20% co-payments were introduced. Provider accreditation is inadequate, and there are no clinical audits. OOP are between 30%-39%. More effective cost control through a cap on expenditure and the use of DRGs might have prevented the need to introduce co-payments, and better accreditation and clinical audits might have led to better quality care, reducing the need to seek care elsewhere, both of which would have lowered OOP. Similarly, in Ghana there are limited elements of SP (FFS for hospital care, no cap on expenditure, and limited HTA capacity), and with a comprehensive benefit package, OOP is high at 50%, even though only 60% of the population is covered. In Mexico, moves toward SP that accompanied expanded coverage, did not translate to large reductions in OOPs and raised governance concerns, causing officials to revert to passive purchasing arrangements.</p>", "<p> If SP is to play its role in ensuring the sustainability of an insurance scheme (including fending off politically motivated demands), there needs to be considerable institutional and organisational capacity, both at the purchaser and in government.<sup>##REF##31533710##19##,##REF##30445336##134##</sup> These include research capacity to assess health needs and which services are affordable and best value of money, the capacity to accredit facilities, monitor the quality of care and the claims submitted, and governance capacity to provide stewardship and regulation.<sup>##REF##31965166##104##,##UREF##29##110##,##REF##30408235##111##</sup></p>", "<p> The literature has demonstrated that insufficient regulation leads to lack of trust between providers, purchasers, and service users, and so a failure of financial protection.<sup>##REF##31234940##26##,##REF##27694679##135##</sup> Liu and colleagues reported that unregulated marketization of healthcare provision and inadequate financial protection by purchasers induced unhealthy competition among patients and so “red envelope” payments to secure care.<sup>##REF##32028953##66##</sup> Similar relationships were reported in Iran to skip long queues. Provider opportunism was fuelled by loose/non-existent regulations, disempowerment of patients to make choices,<sup>##REF##32164960##136##</sup> and lack of appropriate incentives for providers. For SP to ensure resources are used wisely, government regulation is also necessary.</p>", "<p> In their realist review of SP, Sanderson et al conclude that SP requires national government purchasers to build close, trusting relationships with providers to facilitate access to local knowledge about needs and priorities.<sup>##REF##30709098##138##</sup> While ‘provider decision autonomy may drive innovation and efficient resource use, it may also create scope for opportunism; interdependence [of purchasers and providers] is likely to be the best power structure to incentivise collaboration needed to drive performance improvement.’<sup>##REF##30709098##138##</sup> Only in two countries did we find evidence of consistent engagement between purchasers and providers.</p>", "<p> Ensuring patients’ rights in doing SP could be achieved through encouraging their participation in committees and boards, creating some awareness, implementing community verification of health benefits packages,<sup>##UREF##38##139##</sup> ascertain population views and values.<sup>##REF##26769987##6##,##REF##29608610##15##,##REF##28812815##22##,##UREF##23##91##,##REF##32312238##122##</sup> These require a degree of decentralisation and institutional purchaser capacity to engage with providers and patients that is not available in most middle-income countries.<sup>##REF##29514283##85##,##REF##30518378##113##</sup></p>", "<p> In a comparison of SP in 10 European countries, Klasa et al<sup>##REF##29502893##9##</sup> argue that SP has not been fully implemented in any one of their case study countries; they conclude that SP is unlikely to work elsewhere and an ‘idea too perfect to exist in reality.’ Similar critiques have been raised by others.<sup>##REF##32677101##140##</sup> The review includes the requirement that there are sufficient providers in any location such that purchaser and patient can choose where to purchase/seek care for SP to be able to occur; we have not included this requirement, because of the idle and so wasted capacity it requires.<sup>##REF##29502893##9##</sup> However, there are a myriad of additional reasons why SP is hard. In practice, purchasers, often lack the data,<sup>##REF##31603476##83##,##UREF##30##115##</sup> expertise,<sup>##UREF##23##91##,##REF##30788334##131##</sup> policy capacity and negotiating power to shape an effective purchasing strategy that is focused on the quality of care and the actual needs of the population,<sup>##UREF##2##4##</sup> instead of historical utilization patterns, prices and volumes.</p>", "<title> Limitations </title>", "<p> One of the limitations of this study is the use of heterogenous information available on the case study countries in published sources. Often information was incomplete and difficult to interpret (for example the details of the contracts and the contracting processes). Some countries may have separate HIV programmes, that are not part of the public insurance scheme, however our focus was the purchasing carried out by the insurance schemes. Interviews with key informants would have provided useful additional information and an opportunity to confirm the published sources, however, this was not possible given the resources available. Two authors were from case study countries (Ghana and Kenya) and so had a greater degree of insight, however, insights from China were sometimes limited due to certain source and government documents being available in Mandarin only.</p>" ]	[ "<title>Conclusion</title>", "<p> In middle income countries, with relatively limited formal employment, managing resources well is particularly important when public funds are needed to provide cover for the poor. Schemes need to control their costs (through, for example, a cap on expenditure, capitation, DRGs, gate keeping, limiting corruption), as well as ensuring appropriate services are available and paid for at an appropriate rate which requires research capacity, audits and engagement, so that OOP do not escalate.</p>", "<p> While SP appears to be working well in both Thailand and Indonesia, it is only Thailand that has managed to provide a comprehensive package, include the poor, and keep OOP low. In Vietnam and Ghana, the combination of partial implementation of SP and relatively high levels of coverage is accompanied by higher levels of OOP.</p>", "<p> We recommend greater investment in purchaser and research capacity, and a focus on strong governance including regular engagement between purchaser, provider and citizens, that enables the building of trusting relationships. Improvements in these areas will allow countries to leverage the potential of SP more fully, thereby progressively expanding financial protection, and furthering movement towards UHC.</p>", "<p> The evidence from nine countries suggests that purchasing reforms, while crucial, remain difficult to enact and sustain.</p>" ]	[ "<p>\n<bold>Background:</bold> Efforts to move towards universal health coverage (UHC) aim to rebalance health financing in ways that increase efficiency, equity, and quality. Resource constraints require a shift from passive to strategic purchasing (SP). In this paper, we report on the experiences of SP in public sector health insurance schemes in nine middle-income countries to understand what extent SP has been established, the challenges and facilitators, and how it is helping countries achieve their UHC goals.\n</p>", "<p><bold>Methods:</bold> We conducted a systematic search to identify papers on SP. Nine countries were selected for case study analysis. We extracted data from 129 articles. We used a common framework to compare the purchasing arrangements and key features in the different schemes. The evidence was synthesised qualitatively.\n</p>", "<p><bold>Results:</bold> Five countries had health technology assessment (HTA) units to research what services to buy. Most schemes had reimbursement mechanisms that enabled some degree of cost control. However, we found evidenced-based changes to the reimbursement mechanisms only in Thailand and China. All countries have some form of mechanism for accreditation of health facilities, although there was considerable variation in what is done. All countries had some strategy for monitoring claims, but they vary in complexity and the extent of implementation; three countries have implemented e-claim processing enabling a greater level of monitoring. Only four countries had independent governance structures to provide oversight. We found delayed reimbursement (six countries), failure to provide services in the benefits package (four countries), and high out-of-pocket (OOP) payments in all countries except Thailand and Indonesia, suggesting the schemes were failing their members.\n</p>", "<p><bold>Conclusion:</bold> We recommend investment in purchaser and research capacity and a focus on strong governance, including regular engagement between the purchaser, provider and citizens, to build trusting relationships to leverage the potential of SP more fully, and expand financial protection and progress towards UHC.</p>", "<p>\n<bold>Citation:</bold> Sumankuuro J, Griffiths F, Koon AD, et al. The experiences of strategic purchasing of healthcare in nine middleincome countries: a systematic qualitative review. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7352. doi:10.34172/ijhpm.2023.7352</p>" ]	[ "<title>Acknowledgements</title>", "<p> Benjo Delarmente (a PhD Candidate) of The John Hopkins University, Baltimore, participated in the article deliberation sessions. We are grateful for his insightful contributions.</p>", "<p> Beryl Maritim was supported by the Consortium for Advanced Research Training in Africa (CARTA). CARTA is jointly led by the African Population and Health Research Center and the University of the Witwatersrand and funded by the Carnegie Corporation of New York (Grant No. G-19-57145), Sida (Grant No:54100113), Uppsala Monitoring Center, Norwegian Agency for Development Cooperation (Norad), and by the Wellcome Trust [reference no. 107768/Z/15/Z] and the UK Foreign, Commonwealth & Development Office, with support from the Developing Excellence in Leadership, Training and Science in Africa (DELTAS Africa) programme. The statements made and views expressed are solely the responsibility of the Fellow.</p>", "<title>Ethical issues</title>", "<p> Ethical approval was not necessary because extracted data from peer-reviewed publications.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This project received funding from South African Chairs Initiative (SARChI) at the Centre for Health Policy (CHP), University of the Witwatersrand, Johannesburg, South Africa.</p>", "<title>Supplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nKey Actors and Their Roles in Strategic Purchasing of Healthcare. Source: From RESYST<sup>##UREF##4##7##</sup> policy brief: What is strategic purchasing for health.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nPapers Identified and Screened: PRISMA Diagram. Abbreviations: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; HTA, Health Technology Assessment.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>Comparison of Key Health Financing Indicators Among Case Study Countries\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Indicators 2017</bold></td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Iran</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>China</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Mexico</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Thailand</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Vietnam</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Indonesia</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ghana</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Kenya</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Nigeria</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">GDP per capita ($) (2021)</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">3000</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">8840</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">9900</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">6600</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">3743</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">4223</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1960</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1500</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">2360</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Economic growth over 40 years (1981-2020)</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.7</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9.2</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.1</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.9</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.6</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.0</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">THE as a % of GDP</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8.7</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5.5</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5.9</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.9</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.3</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.8</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Government health expenditure as % of GDP</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.9</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.9</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.7</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.5</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.1</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.1</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.5</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Government health expenditure as % of THE</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">51.3</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">56.7</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">51.5</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">76.1</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">48.6</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">48.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">33.5</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">42.7</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14.2</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Private health expenditure as % of THE</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">48.7</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">43.3</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">48.5</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">23.6</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">49.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">51.1</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">52.0</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">39.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">77.9</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">External resources on health as % of THE</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.00</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">N/A</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.5</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7.5</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.9</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">21.3</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">28.3</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">17.5</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">OOP expenditure as % of THE</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">41.8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">36.1</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">41.3</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11.1</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">45.3</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">34.6</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">40.3</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">24.0</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">77.2</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Government health expenditure per capita in Int$ </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">901.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">474.8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">552.2</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">525.8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">187.4</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">163..8</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">48.5</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">67.2</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">31.36</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Life expectancy</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">76</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">77</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">75</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">77</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">75</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">72</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">64</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">66</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">54</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Maternal mortality (per 100 000 live births)</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">16</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">29</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">33</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">37</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">43</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">177</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">308</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">342</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">917</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Outcome Measures: Out-Of-Pocket Payments and Whether Members Were Refused Care\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Iran</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>China </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Mexico </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Thailand </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Vietnam </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Indonesia </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ghana </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Kenya</bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Nigeria</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">OOP by subscribers </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">55.0% of OOPs by IHIO, SSO and IKRF members in 2017<sup>##REF##29445699##63##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Cash informal OOPs (called ‘red envelope’) to<break/>physicians ranges between 54.4% (2011)<sup>##UREF##18##64##</sup> to 76.1% (2015)<sup>##UREF##19##65##,##REF##32028953##66##</sup> by UEBMI, URBMI and NCMS</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Segura popular households have a lower proportion of OOP (42.95%) than households without insurance (57.05%)<sup>##REF##29965976##67##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">11% of OOP by UCS, SSS and CSMBS up to 2020<sup>##REF##32958064##53##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Approx. 30.8% of OOP by VSS subscribers in 2020<sup>##REF##32908923##68##</sup><break/>34% OOP at commune health centres/stations <break/>39% OOP at district hospitals<sup>##REF##34093020##69##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">18.0% OOP by JKN subscribers<sup>##UREF##20##70##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">46.9% OOP by NHIS subscribers up to 2020<sup>##REF##33964911##71##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">29.0% OOP by NHIF subscribers up to 2017<sup>##REF##29387800##72##</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">89.8% OOP FSSHIS subscribers<sup>##REF##31837066##73##</sup></td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Problems with payments</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Delays reimbursing of claims</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Selective application of DRGs to selected disease conditions<break/>• No uniformity in application of the 4 payment methods for all hospitals in all provinces\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">• State/REPSS has difficult paying providers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Not reported</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Delayed reimbursing claims</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Delays in reimbursing claims</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Delay in reimbursing claims, which lead to comprised quality of care, and private accredited facilities refusing to provide care for members </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Delays in payments due unavailability of funds </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Delayed payment due to complex payment system<break/>• Failure of NHIS to audit payments</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Providers refusing care to insured</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Insured clients were not refused care</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Yes, if providing care will lead to high cost beyond predefined service rate or cost ceiling </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">No evidence to suggest providers refuse care (The General Health Law prevents this)<break/>*Unclear what will happen under INSABI</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Providers do not refuse to provide health services to subscribers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There is no evidence to suggest that providers refused care to subscribers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• No evidence of providers refusing to provide care<break/>• However, there is evidence of some hospitals not being able to offer services under the benefits package because of lack of resources<sup>a</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Some providers especially the Catholic Health Association of Ghana refused care when NHIS delays in reimbursing claims</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Some members were refused or rationed services because of late payment of capitation and claims by NHIF<break/>• Members of the national scheme faced some discriminatory care compared to other schemes with higher reimbursement rates<sup>##REF##29387800##72##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Patients were sometimes refused timely treatment because of delayed reimbursement of claims for previous services provided</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Cross-country Comparison of Reimbursement Mechanisms and Processes\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Iran </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>China</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Mexico</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Thailand</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Indonesia </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Vietnam </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ghana </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Kenya </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Nigeria </bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">PHC</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\"> FFS </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Central government subsidies PHC through a line budget</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Mix of historical-based funding, capitation, and activity-based funding</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">UCS and SSS: Capitation <break/>CSMBS: FFS</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Capitation </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Performance-based capitation payment at community health centres</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS; Capitation payment method was piloted but suspended</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Capitation </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Capitation, FFS</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Hospital</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS and case-based payments using RVUs<sup>a</sup> or RBRVUs for outpatient and in-patient services, respectively</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Reimbursement mechanisms differ by province<break/>• DRGs in 20 of 32 provinces<break/>• Otherwise scale payment, FFS, capitation (in-patient and out-patient)</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Line budgets, case-based payments, FFS</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• DRGs for in-patient services<break/>• FFS for some services with high levels needs of the population such as cataract surgery, hip replacement therapy, etc</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• DRGs is used in paying in-patient services<break/>• FFS payments<break/>• In-patient “hotel” care funded through a per-diem-payment with co-payments\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Case-based group (a type of DRG) <break/>• FFS payment was applied to only small portions of care</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">DRGs</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Case based payment for bundled care eg, maternity, renal and surgical care<break/>• FFS for radiology (MRI and CT scan capped)</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• FFS based on authorised referrals <break/>• Per case payment</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Medicine</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Outpatient – including in capitation<break/>• Inpatient <break/>• FFS</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">FFS </td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Purchaser-provider negotiation </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• No platform for negotiations among stakeholders<break/>• Government independently determined the tariffs for purchaser organisations\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• No evidence of negotiation<break/>• Pricing was determined by the National Health Development Research Centre\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Fees for physicians are negotiated through short-term contracts <break/>• Drugs are negotiated with suppliers at central level by a commission with diverse representation</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Purchaser, provider, and citizens were engaged in policy initiatives and negotiations, ie, policy-making, design of health benefits package, budgetary processes </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• No evidence of negotiations between purchasers and providers in fixing INA-CBG rates, caps of certain health services, etc<break/>• BJPS and the MoH determined package prices</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• The MoH responsible for setting policy for both public and private providers including benefits package and setting reimbursement prices and co-payments<break/>• No negotiations with beneficiaries</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There were purchaser-provider negotiations. However, these were inadequate which led to stalling of the roll out of the capitation payment methods</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHIF board was mandated by law to determine the rates and claims in consultation with private and public providers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Expert committee with representatives of HMOs, providers, the NHIS, civil society organisations, academia and the Federal MoH defines benefits packages<break/>• Evidence from actuarial study was used to determine rates for capitation and FFS</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Budget support to public providers</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Government allocates funds to public health services, although, inadequate <break/>• Salary and incentives paid to medical university staff based on the medical procedure or speciality</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Government subsidises public healthcare, although the subsidy level varied across the regions<break/></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Under Seguro Popular, providers were issued short-term contracts without benefits <break/></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There are adequate and regular budgetary allocations for public providers</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Budgetary allocations are made to public providers</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• There is annual budgetary support to public providers<break/>• Government pays salaries of public providers<break/></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Annual budgetary allocation to public health providers</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Public facilities are government allocated budgets and salaries <break/>• Casuals and support staff in public facilities are paid from user fees<sup>b</sup></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• The MoH pays staff salaries, mainly for tertiary hospitals <break/>• Budget support is inadequate for primary care\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T4\"><label>Table 4</label><caption><title>Cross-country Comparison of Strategic Purchasing Governance\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Iran </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>China</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Mexico</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Thailand</bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Indonesia </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Vietnam </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Ghana </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Kenya </bold>\n</th><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Nigeria </bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Governance bodies of insurer/purchaser</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">All 3 public insurance organisations (ie, IHIO, SSO, IKRF) and the national health security organisations has structures eg, HCHI</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHC, MoHRSS, and MoH </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">MoH, the COFEPRIS and the GHC, the REPSS, SHS</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">UCS, SSS, and CSMBS have clearly defined governance structures and their interrelationships with providers, NHSO and comptroller and accountant general </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There exist governance structures for JKN, BPJS, and the provider</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• The Department of Health Insurance and the VSS<break/>• There are provincial people’s committees that monitor revenue collection and payments at provincial level</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHIA and NHIS has clearly mapped governance structures</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHIF has a governance structure and is regulated by the National Hospital Insurance Fund Act of 1998</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• The NHIS has formal structures for managing providers and HMOs<break/>• The NHIS runs the FSSHIS and statutorily oversees the HMOs</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Existence of provider governance body</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">MoHME </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHC, MoHRSS, the MoH of China supported by the various local and provincial government department</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Multiple. <break/>• The primary one is Consejo de Salubridad General (GHC). Council has Executive Board made of heads of public institutions <break/>• Other councils, commissions and committees are represented on GHC<sup>a</sup><break/>• MoH<break/>• The COFEPRIS <break/>• The REPSS and SHS</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">MOPH, have clearly defined governance structures and their interrelationships with providers, NHSO and comptroller and accountant general</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Indonesian MoH <break/>• DJSN, the National Social Security Board. DJSN comprises both government officials, community members, and representatives of employee and employer associations</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• MoH, The Department of Health Insurance, VSS Agency, Social Affairs Committee of Vietnam National Assembly<break/>• There are Provincial People’s Committees that monitor revenue collection and payments at provincial level</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">MoH, NHIA</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• MoH, NHIF, Kenya Medical Practitioners and Dentists Board<break/>• NHIF has a governance structure and is regulated by the National Hospital Insurance Fund Act of 1998</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• SMoH, HMOs<break/>• There are laws guiding the activities of government actors (eg, MoH), HMOs and providers<break/>• The NHIS has formal structures for managing providers and HMOs <break/>• The NHIS runs the FSSHIS and statutorily oversees the HMOs</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Accreditation and monitoring of quality of care</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• The MoHME assesses and accredits providers <break/>• No monitoring of providers’ compliance with clinical guidelines\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Local and international bodies accredit health facilities <break/>• Providers are accredited by JCI\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Accreditation is mandatory for Seguro Popular providers, but not IMSS or ISSSTE<break/>• Accredited by Specialty Councils and MoH – COFEPRIS/DGCES to enable funding by CNPSS<sup>b</sup><break/>• ISSSTE has developed a set of 44 quality and efficiency indicators for its hospitals\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Thai HAI provides accreditation to providers using the ISQua</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• The Hospital Accreditation Committee assesses facilities every 3 years using ISQua standards<break/>• BPJS-Health conducts onsite supervision of providers and provides technical support to public providers<break/>• BPJS-Health Office conducts regular public reporting on providers; showcases each provider's performance under the commitment-based capitation<sup>c</sup> payment policy (KBK) payment system and benchmark each provider compared to their peers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The MoH accredits service providers<sup>##REF##26017577##100##</sup></td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Ghana Accreditation Board in collaboration with the MoH assesses and grants accreditation to private providers. However, public providers receive automatic accreditation</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHIF has a benefits and quality assurance management committee for monitoring the quality of services offered by providers. However, this was rarely done to inadequate capacity of NHIF to perform this function</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• HMOs are accredited and registered by the NHIS to purchase healthcare services from providers on behalf of the NHIS.<break/>• NIHS rarely reviews/reaccredits HMOs and providers (lack of resources) <break/>• HMOs conducts quarterly review of providers to ensure provision of quality care</td></tr><tr><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Monitoring claims</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">No clearly established monitoring systems in place for monitoring claims </td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Have introduced electronic health records and e-claim processing</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There are information systems for tracking monitoring quality of care</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• NHSO had a thorough system of medical audits to prevent fraud. Use of global budgets prevented ‘DRG-Creep’<break/>• Created unique identification number for each medicine to enable monitoring of use by prescribers\n</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• The district health offices conduct monthly monitoring of providers to track targets<break/>• However, on-site monitoring and technical support to providers is inconsistent<break/>• Evidence of fraud in provider claims processing<break/>• Although evidence of active monitoring and enforcement of capitation payment rules (eg, a private primary provider’s contract was retracted/terminated for violation of terms)</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• In 2015, VSS set up electronic claims management system and this provided insured persons with a smart card <break/>• In 2017 – 97% of service providers had access via a portal to the VSS claims management system, and 60% connected daily</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• There are provider monitoring units in all NHIS offices<break/>• Claim processing units are established in all health facilities to ensure proper completion of claims and adherence of providers to defined costing guidelines<break/>• Auditing of historical claims data to identify fraud <break/>• Claims centre has been able to detect fraud in claim processing</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHIF responded to the rise of fraudulent claims by employing medically trained personnel to review medical claims before payment</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• HMOs compile and send patient encounter data quarterly to NHIS<break/>• Facilities do not always send the data to HMO<break/>• No systematic approach and large variations in what is done and how often<break/>• NHIS is meant to audit payments to ensure timely reimbursement of claims, however, this is not done<sup>##UREF##11##34##</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Evidence of corruption</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• “Under table” payments for health services<break/>• Evidence of repeated visits to particular physicians in a short time<break/>• Dispensing prescriptions at a particular pharmacy suggests collusion between physician and pharmacy over prescriptions, inflates prescription claims by over 25%\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">No evidence identified</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Mostly tied to state-level purchases of medicines and human resources<break/>• There is also a political side to corruption. For example, a former governor of Tabasco State was sent to jail in 2013 for mishandling funds for Seguro Popular. Other states have faced similar allegations</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Providers falsified DRGs called “DRG-Creep” where up-coding of diagnosis in favour of higher DRG weights</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Over prescriptions or clients lying to prescribers on specific health conditions, and afterwards go to sell those medicines at “underground market” <break/>• Professionals falsifying services that were never provided <break/>• Repeated submission of claims for a similar service<break/>• Changing the dates/medicinal records on patient records <break/>• Utilisation of unlicensed staff to provide substandard care</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Civic organisations have documented corruption in Vietnam <break/>Besides documented inequalities due to misuse of resources and differences in services provided in provinces,<sup>##UREF##24##101##</sup> there was no further evidence of corruption</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There were cases of corruption such as inflation of claims, overbilling of medicines, inappropriate use of tariff, duplication of claims, lack of diagnostic evidence to back claims, absence of linkage between treatment and diagnosis, and treatment outside benefits package </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There were reports of corruption in the accreditation process and the processing of claims</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Many HMOs are owned by financially and politically affluent citizens, some of whom serve as members of the NHIS governing council<break/>• Currently no legislation that prohibit this arrangement\n</td></tr><tr><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Strategies to reduce corruption</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• In the fifth development plan (2011-2015), teaching hospitals were granted autonomy to ensure staff satisfaction and decrease in provider fraud<break/>• A new payment system was introduced, to change the costs of clinical services and balance hospitals’ revenues and expenses</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The National Health and Family Planning Commission promulgated circulars that established “prohibitions” on corrupt practices among providers, and “blacklisted\" system on pharmaceutical and medical device providers</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Adjustment of regulatory framework with CNPSS managing resources and times of transfer of resources throughout the different levels (Federal, state, REPSS)<break/>• The CNPSS and the REPSS had increased accountability for Segura Popular through new accounts created at the Federal Treasury, and new sanctions established\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHSO manages malpractice by applying a global budget on top of the DRG system and a thorough system of medical audit administered </td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Public Research Anti-Corruption Clearing House and the Corruption Eradication Commission established in 2015 to prevent provider fraud <break/>• An e-tendering policy for drugs and supplies was introduced in 2014 to expedite contractual arrangements and reduce corruption</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• In 2015, the government embarked on a project to enable electronic claims management<break/>• Provided insured persons with a smart card <break/>• By 2017 – 97% of service providers had access via a portal to the VSS claims management system, and 60% connected daily\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Implementation of e-claim submission/processing platform<break/>• Introduction of clinical audit and historical auditing of claims through the claim processing centres</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• NHIF employed staff with medical training to review claims made by providers<break/>• There are also recent plans to cede the function of accreditation to the MoH\n</td><td style=\"text-align:left;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">No evidence of any</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Channels for feedback from members</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">There is a hotline “1690” to report informal payments and report patient complaints about providers</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Patients can lodge complaints at the respective hospitals, or through complaint letters</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• Members can lodge complaints through the CONAMED<break/>• The CNDH intervenes in high-profile cases<break/>• A Patient’s Charter was published by the CONAMED and replicated in human rights guidelines\n</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• A 24-hour call centre service (code “1330”) was established to create public awareness about members entitlements and for patients’ complaints and resolutions<break/>• The call centre was established for all three schemes, although, evaluations showed underutilisation</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• BPJN Kesehatan also mandates all providers to have a patient complaints and resolution box<break/>• Complaints were received through the box and monthly meetings by facility management to resolve the issues <break/>• Customers could also make complaints through the customer relations office\n</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">The MoH has a dedicated division within the Department of Health Insurance that deals with issues reported by members</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">NHIS member complaints hotline was established to monitor provider-patient behaviours/relationships<break/></td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">A toll-free line and email address is indicated in their NHIF website and publicity materials but there were reports that the phone number is not functioning</td><td style=\"text-align:left;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n• HMOS are mandated to conduct quarterly seminars with beneficiaries; few people engage as communication channels are not clear <break/>• HMOs hold forums to inform people of their benefits and entitlements, but there is limited awareness amongst users of the forums <break/>• A complaints system exists but is not fully implemented\n</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>\n<bold>Box 1.</bold> Inclusion and Exclusion Criteria</title><p>\n<bold> Inclusion Criteria</bold>\n</p><list list-type=\"bullet\"><list-item><p>Describe a purchasing function (either in a public national health system or specific private insurance scheme) that aims to have characteristics associated with SP, ie, desires to obtain value for money through contracts or reimbursement mechanisms. </p></list-item><list-item><p>Includes evidence from a middle-income country as defined by the World Bank. </p></list-item><list-item><p>Evidence reviews if they include middle-income countries. </p></list-item></list><p>\n<bold> Exclusion Criteria</bold>\n</p><list list-type=\"bullet\"><list-item><p>Those presenting evidence from either high- or low-income countries. </p></list-item><list-item><p>Those that describe reforms that aim to improve value for money without discussing contracts or reimbursement mechanisms. </p></list-item><list-item><p>Studies that discussed performance-based financing or results-based financing, or payment for performance. </p></list-item><list-item><p>If studies were conference abstract, opinion piece, systematic literature reviews or grey literature. </p></list-item><list-item><p>Studies published before 2011. </p></list-item><list-item><p>If they discussed only revenue mobilisation, contracting, health financing or health insurance other than SP functions. </p></list-item><list-item><p>We excluded opinion pieces and commentaries. </p></list-item></list><p>-------------------</p><p> Abbreviation: SP, strategic purchasing.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 1. Search Strategy.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>Supplementary file 2 contains Table S1.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: THE, total health expenditure; GDP, gross domestic product; N/A, not available; OOP, out-of-pocket.</p><p> Source: The World Bank and WHO (2021): World Development Indicators, last updated on July 30, 2021.<sup>##UREF##9##18##</sup></p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: UEBMI, Urban Employee’s Basic Medical Insurance; URBMI, Urban Resident’s Basic Medical Insurance; OOP, out-of-pocket payment; IHIO, Iran Health Insurance Organisation; SSO, Social Security Organisation; IKRF, Imam Khomeini Relief Foundation; NHIS, National Health Insurance Scheme; FSSHIS, Formal Sector Social Health Insurance Scheme; NHIF, National Health Insurance Fund; UCS, Universal Coverage Scheme; JKN, Jaminan Kesehatan Nasional; CSMBS, Civil Servants’ Medical Benefits Scheme; NCMS, New Cooperative Medical Scheme; INSABI, Institute for Health and Well-being; SSS, Social Security Scheme; DRGs, diagnosis related groups; REPSS, Regimen Estatal de Proteccion Social en Salud; VSS, Vietnam Social Security.</p><p>\n<sup>a</sup> The World Bank. Implementation completion and results report on a credit in the amount of special drawing right (SDR) 41.5 million (US$ 65.0 million equivalent) to the socialist republic of Vietnam for a central north region health support project. Hanoi: The World Bank; 2017.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: FFS, fee for service; DRG, diagnosis related groups; UCS, Universal coverage scheme; SSS, social security scheme; CSMBS, Civil Servants’ Medical Benefits Scheme; MoH, Ministry of health; BJPS, Badan Penyelenggara Jaminan Sosial; PHC, primary healthcare; RVUs, relative value units; RBRVUs, resource-based relative value units; MRI, magnetic resonance imaging; CT, computerized tomography; INA-CBG, Indonesian-Case Based Group; NHIF, National Health Insurance Fund; HMOs, health maintenance organizations; NHIS, National Health Insurance Scheme.</p><p>\n<sup>a</sup>RVUs is the real monetary value for health services.</p><p>\n<sup>b</sup>“user fees” is a charge imposed by the government for the primary purpose of covering the cost of providing a service, directly raising funds from the people who benefit from the care or service being provided.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: IHIO, Iran Health Insurance Organisation; SSO, Social Security Organisation; IKRF, Imam Khomeini Relief Foundation; NHSO, National Health Security Office; HCHI, High Council of Health Insurance; NHC, National Health Commission; MoHRSS, Ministry of Human Resources and Social Security; MoHME, Ministry of Health and Medical Education; COFEPRIS, Federal Commission for the Protection Against Sanitary Risks; REPSS, Regimen Estatal de Proteccion Social en Salud; CSMBS, Civil Servants’ Medical Benefits Scheme; SSS, Social Security Scheme; UCS, Universal Coverage Scheme; BPJS, Badan Penyelenggara Jaminan Sosial; JKN, Jaminan Kesehatan Nasional; VSS, Vietnam Social Security; NHIA, National Health Insurance Authority; NHIF, National Health Insurance Fund; HMO, health maintenance organization; FSSHIS, Formal Sector Social Health Insurance Scheme; GHC, General Health Council; DJSN, Dewan Jaminan Sosial Nasional; SMoH, State Ministry of Health; JCI, Joint Commission International; IMSS, Instituto Mexicano del Seguro Social; ISSSTE, Institute for Social Security and Services for State Employees; DGCES, General Directorate for Health Quality and Education; CNPSS, National Commission for Social Protection in Health; ISQua, International Standards for Quality in Healthcare; HAI, Health Accreditation Institute; KBK, Kapitasi Berbasis Komitmen; CNDH, National Commission for Human Rights; DRGs, diagnosis related groups; REPSS, Regimen Estatal de Proteccion Social en Salud; MoH, Ministry of Health; SHS, State Health Secretariats.</p><p>\n<sup>a</sup>Councils (against Addictions, for Accident Prevention, and for the Prevention and Control of HIV/AIDS), Commissions (Bioethics, Human Genome, Occupational Health and Safety, Human Resources Development, and Health Research), Committees (Oral Health, Care for the Aging, and Epidemiological Surveillance) and the Reproductive Health Group.</p><p>\n<sup>b</sup>Under INSABI, plans are underway to transfer accreditation to the GHC.</p><p>\n<sup>c</sup>Under the commitment-based capitation policy (2016) BPJS-Health employs indicators of staff commitment to decide on the capitation grant percentage to allocate to primary health provider.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7352-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7352-g002\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7352-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7352-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" World Health Organization (WHO). The World Health Report 2000: Health Systems: Improving Performance. WHO; 2000. "]}, {"label": ["3"], "mixed-citation": [" McIntyre D. Learning from Experience: Health Care Financing in Low-and Middle-Income Countries. Geneva: Global Forum for Health Research; 2007. "]}, {"label": ["4"], "mixed-citation": [" World Health Organization (WHO). Governance for Strategic Purchasing: An Analytical Framework to Guide a Country Assessment. WHO; 2019. "]}, {"label": ["5"], "mixed-citation": [" Honda A, Hanson K, Tangcharoensathien V, Huntington D, McIntyre D. Strategic purchasing\u2019\u2013definition and analytical framework used in the multi-country study. In: Strategic Purchasing in China, Indonesia and the Philippines. Geneva: World Health Organization; 2016:2. "]}, {"label": ["7"], "mixed-citation": [" RESYST. What is strategic purchasing for health? Resarchonline website. "], "uri": ["https://researchonline.lshtm.ac.uk/id/eprint/2760470/2/Purchasing%20brief.pdf"]}, {"label": ["10"], "mixed-citation": [" Hamadeh N, Van Rompaey C, Metreau E. New World Bank Country Classifications by Income Level: 2021-2022. World Bank Blogs; 2021. "]}, {"label": ["11"], "mixed-citation": [" Serajuddin U, Hamadeh N. New World Bank Country Classifications by Income Level: 2020-2021. World Bank Blogs; 2020. "], "uri": ["https://blogs.worldbank.org/opendata/new-world-bank-country-classifications-income-level-2020-2021"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Nguyen", "Ivers", "Jan", "Pham"], "given-names": ["H", "R", "S", "C"], "article-title": ["Analysis of out-of-pocket costs associated with hospitalised injuries in Vietnam"], "source": ["BMJ Glob Health"], "year": ["2017"], "volume": ["2"], "issue": ["1"], "fpage": ["e000082"], "pub-id": ["10.1136/bmjgh-2016-000082"]}, {"label": ["16"], "mixed-citation": [" World Health Organization (WHO). The World Health Report 2003: Shaping the Future. WHO; 2003. "]}, {"label": ["18"], "mixed-citation": [" World Bank. World Development Indicators. DataBank; 2021. "]}, {"label": ["21"], "person-group": ["\n"], "surname": ["Gu", "Page-Jarrett"], "given-names": ["E", "I"], "article-title": ["The top-level design of social health insurance reforms in China: towards universal coverage, improved benefit design, and smart payment methods"], "source": ["J Chin Gov"], "year": ["2018"], "volume": ["3"], "issue": ["3"], "fpage": ["331"], "lpage": ["350"], "pub-id": ["10.1080/23812346.2018.1491112"]}, {"label": ["34"], "person-group": ["\n"], "surname": ["Etiaba", "Onwujekwe", "Honda", "Ibe", "Uzochukwu", "Hanson"], "given-names": ["E", "O", "A", "O", "B", "K"], "article-title": ["Strategic purchasing for universal health coverage: examining the purchaser-provider relationship within a social health insurance scheme in Nigeria"], "source": ["BMJ Glob Health"], "year": ["2018"], "volume": ["3"], "issue": ["5"], "fpage": ["e000917"], "pub-id": ["10.1136/bmjgh-2018-000917"]}, {"label": ["35"], "person-group": ["\n"], "surname": ["Maharani", "Tampubolon"], "given-names": ["A", "G"], "article-title": ["Does corporatisation improve organisational commitment? Evidence from public hospitals in Indonesia"], "source": ["Int J Hum ResourManag"], "year": ["2018"], "volume": ["29"], "issue": ["13"], "fpage": ["1999"], "lpage": ["2026"], "pub-id": ["10.1080/09585192.2016.1239121"]}, {"label": ["36"], "person-group": ["\n"], "surname": ["Meemon", "Paek"], "given-names": ["N", "SC"], "article-title": ["The impact of Thailand\u2019s Universal Coverage Scheme on household catastrophic health expenditure"], "source": ["Asia-Pac Soc Sci Rev"], "year": ["2019"], "volume": ["19"], "issue": ["3"], "fpage": ["144"], "lpage": ["154"]}, {"label": ["42"], "person-group": ["\n"], "surname": ["Le Tuan", "Nam", "Dung"], "given-names": ["P", "VT", "TC"], "article-title": ["Adopting Thai Diagnosis Related Group for Vietnam universal health coverage: a case of Ba Vi district hospital"], "source": ["Siriraj Med J"], "year": ["2015"], "volume": ["67"], "issue": ["5"], "fpage": ["227"], "lpage": ["234"]}, {"label": ["44"], "person-group": ["\n"], "surname": ["Prakongsai", "Palmer", "Uay-Trakul", "Tangcharoensathien", "Mills"], "given-names": ["P", "N", "P", "V", "A"], "article-title": ["The implications of benefit package design: the impact on poor Thai households of excluding renal replacement therapy"], "source": ["J Int Dev"], "year": ["2009"], "volume": ["21"], "issue": ["2"], "fpage": ["291"], "lpage": ["308"], "pub-id": ["10.1002/jid.1553"]}, {"label": ["45"], "person-group": ["\n"], "surname": ["Zhang", "Zhang", "Zhu", "Zhu", "Wen"], "given-names": ["H", "C", "S", "F", "Y"], "article-title": ["Costs of hospitalization for chronic kidney disease in Guangzhou, China"], "source": ["Public Adm Policy"], "year": ["2019"], "volume": ["22"], "issue": ["2"], "fpage": ["138"], "lpage": ["151"], "pub-id": ["10.1108/PAP-09-2019-0018"]}, {"label": ["52"], "person-group": ["\n"], "surname": ["Adu-Gyamfi", "Brenya", "Amoah"], "given-names": ["S", "E", "A"], "article-title": ["National Health Insurance Scheme of Ejisu-Juaben and matters arising"], "source": ["Int J Soc Sci Stud"], "year": ["2015"], "volume": ["3"], "issue": ["5"], "fpage": ["40"], "lpage": ["60"], "pub-id": ["10.11114/ijsss.v3i5.962"]}, {"label": ["64"], "person-group": ["\n"], "surname": ["Kong", "Du", "Zhao", "Yang", "Qin"], "given-names": ["XJ", "Z", "M", "Y", "Y"], "article-title": ["Red envelope and doctor-patient trust: report of research on national questionnaire survey of 4000 inpatients in 10 cities (VII)"], "source": ["Med PhilosHumanis Social Med Edit"], "year": ["2011"], "volume": ["32"], "issue": ["5"], "fpage": ["34"], "lpage": ["37"]}, {"label": ["65"], "person-group": ["\n"], "surname": ["Guo"], "given-names": ["Y"], "article-title": ["Personal relationships with the physicians, impression on the physicians and the urban residents\u2019 residents\u2019 behavior of sending the red envelopes"], "source": ["Chinese Health Service Management"], "year": ["2015"], "volume": ["2"], "fpage": ["124"], "lpage": ["126"]}, {"label": ["70"], "mixed-citation": [" Hidayat B. Out-of-Pocket Payments in the National Health Insurance of Indonesia: A First Year Review: Policy Brief. German National Library; 2015. "]}, {"label": ["80"], "person-group": ["\n"], "surname": ["Zhao", "Wang", "Shen", "Wang"], "given-names": ["C", "C", "C", "Q"], "article-title": ["China\u2019s achievements and challenges in improving health insurance coverage"], "source": ["Drug DiscovTher"], "year": ["2018"], "volume": ["12"], "issue": ["1"], "fpage": ["1"], "lpage": ["6"], "pub-id": ["10.5582/ddt.2017.01064"]}, {"label": ["81"], "person-group": ["\n"], "surname": ["Sunarti", "Ghozali", "Haris", "Rahman", "Rahman"], "given-names": ["S", "MT", "F", "FF", "RA"], "article-title": ["Preventing fraud and deficit through the optimization of health insurance in Indonesia"], "source": ["Syst Rev Pharm"], "year": ["2020"], "volume": ["11"], "issue": ["7"], "fpage": ["228"], "lpage": ["231"]}, {"label": ["91"], "person-group": ["\n"], "surname": ["Gonz\u00e1lez Block", "Reyes Morales", "Hurtado", "Balandr\u00e1n", "M\u00e9ndez"], "given-names": ["M", "H", "LC", "A", "E"], "article-title": ["Mexico: health system review"], "source": ["Health Syst Transit"], "year": ["2020"], "volume": ["22"], "issue": ["2"], "fpage": ["1"], "lpage": ["222"]}, {"label": ["101"], "person-group": ["\n"], "surname": ["Palmer"], "given-names": ["MG"], "article-title": ["Inequalities in universal health coverage: evidence from Vietnam"], "source": ["World Dev"], "year": ["2014"], "volume": ["64"], "fpage": ["384"], "lpage": ["394"], "pub-id": ["10.1016/j.worlddev.2014.06.008"]}, {"label": ["102"], "mixed-citation": [" Gonz\u00e1lez Block M, Reyes H, Cahuana Hurtado L, Balandr\u00e1n A, M\u00e9ndez E. Mexico\u2019s health system: in longstanding pursuit of universal coverage and integration. Eur J Public Health 2020;30(Suppl 5):ckaa165.782. "], "pub-id": ["10.1093/eurpub/ckaa165.782"]}, {"label": ["105"], "person-group": ["\n"], "surname": ["Kazungu", "Kabia", "Munge", "Barasa"], "given-names": ["J", "E", "K", "E"], "article-title": ["Assessing the progress and gaps in strategic health purchasing in Kenya"], "source": ["Wellcome Open Res"], "year": ["2021"], "volume": ["6"], "fpage": ["81"], "pub-id": ["10.12688/wellcomeopenres.16606.1"]}, {"label": ["106"], "person-group": ["\n"], "surname": ["Mukhlisa", "Pujiyanto"], "given-names": ["MN", "P"], "article-title": ["The effect of health insurance on institutional delivery in Indonesia"], "source": ["Kesmas"], "year": ["2018"], "volume": ["12"], "issue": ["3"], "fpage": ["148"], "lpage": ["152"], "pub-id": ["10.21109/kesmas.v12i3.1099"]}, {"label": ["109"], "person-group": ["\n"], "surname": ["Tangcharoensathien", "Suphanchaimat", "Thammatacharee", "Patcharanarumol"], "given-names": ["V", "R", "N", "W"], "article-title": ["Thailand\u2019s universal health coverage scheme"], "source": ["Econ Polit Wkly"], "year": ["2012"], "volume": ["47"], "issue": ["8"], "fpage": ["53"], "lpage": ["57"]}, {"label": ["110"], "mixed-citation": [" Liu J. Healthcare Quality and HIT-International Standards, China Practices. CRC Press; 2019. "]}, {"label": ["115"], "person-group": ["\n"], "surname": ["Luo", "Zhang", "Li"], "given-names": ["S", "K", "B"], "article-title": ["Medical informatics in China: healthcare IT trends, academic and research developments"], "source": ["Yearb Med Inform"], "year": ["2010"], "volume": ["19"], "issue": ["1"], "fpage": ["109"], "lpage": ["115"], "pub-id": ["10.1055/s-0038-1638700"]}, {"label": ["116"], "person-group": ["\n"], "surname": ["Youthao", "Amornsiriphong"], "given-names": ["S", "S"], "article-title": ["One Health information management: health system reforms to support social well-being in Thailand"], "source": ["Int J One Health"], "year": ["2021"], "volume": ["7"], "issue": ["1"], "fpage": ["96"], "lpage": ["103"]}, {"label": ["119"], "mixed-citation": [" Gonz\u00e1lez-Block M, Alarc\u00f3n Irigoyen J, Figueroa Lara A, Ibarra Espinosa I, Cort\u00e9s Llamas N. [The strategic purchasing of health services: a big opportunity for the National Universal Health System]. Gac Med Mex 2015;151(2):278-280. [Spanish]. "]}, {"label": ["120"], "person-group": ["\n"], "surname": ["Tan"], "given-names": ["SY"], "article-title": ["Bureaucratic autonomy and policy capacity in the implementation of capitation payment systems in primary healthcare: comparative case studies of three districts in Central Java, Indonesia"], "source": ["J Asian Public Policy"], "year": ["2019"], "volume": ["12"], "issue": ["3"], "fpage": ["330"], "lpage": ["350"], "pub-id": ["10.1080/17516234.2018.1459150"]}, {"label": ["121"], "person-group": ["\n"], "surname": ["Khoiri", "Hidayat", "Chalidyanto", "Suhariadi"], "given-names": ["A", "W", "D", "F"], "article-title": ["Potential of hospital fraud in the Indonesia national health insurance era (a descriptive phenomenological research)"], "source": ["Indian J Forensic Med Toxicol"], "year": ["2020"], "volume": ["14"], "issue": ["3"], "fpage": ["1132"], "lpage": ["1136"], "pub-id": ["10.37506/ijfmt.v14i3.10527"]}, {"label": ["124"], "person-group": ["\n"], "surname": ["Lawan", "Iliyasu", "Daso"], "given-names": ["UM", "Z", "AM"], "article-title": ["Challenges to the scale-up of the Nigerian National Health Insurance Scheme: public knowledge and opinions in urban Kano, Nigeria"], "source": ["Ann Trop Med Public Health"], "year": ["2012"], "volume": ["5"], "issue": ["1"], "fpage": ["34"], "lpage": ["39"], "pub-id": ["10.4103/1755-6783.92878"]}, {"label": ["125"], "mixed-citation": [" Hariyanto H, Denison T, Stillman L. Understanding Health Information System Implementation in an Indonesian Primary Health Centre: A Sociotechnical Perspective. 2018. "], "uri": ["https://aisel.aisnet.org/pacis2018/219"]}, {"label": ["133"], "mixed-citation": [" World Health Organization (WHO). Designing Health Financing Systems to Reduce Catastrophic Health Expenditure. WHO; 2005. "]}, {"label": ["139"], "person-group": ["\n"], "surname": ["Witter", "Bertone", "Namakula"], "given-names": ["S", "MP", "J"], "article-title": ["(How) does RBF strengthen strategic purchasing of health care? Comparing the experience of Uganda, Zimbabwe and the Democratic Republic of the Congo"], "source": ["Glob Health Res Policy"], "year": ["2019"], "volume": ["4"], "fpage": ["3"], "pub-id": ["10.1186/s41256-019-0094-2"]}]	{ "acronym": [], "definition": [] }	140	CC BY	no	2024-01-13 00:02:17	Int J Health Policy Manag. 2023 Nov 6; 12:7352	oa_package/e7/f1/PMC10699827.tar.gz
PMC10699828	0	[]	[ "<title>Mixing Methods – Moving Beyond Modelling Methods</title>", "<p> The paper notes that one of its contributions lies in its integration of SD modelling with AR noting that this constitutes a mixed methods approach. This assertion raises two important considerations. The first is that the mix moves beyond the established concept of mixed methods referred to. For example, the paper cites Mingers and Gill<sup>##UREF##11##14##</sup> noting that ‘no single methodology can offer a complete view of the complexities facing organisations’ however, Mingers and Gill focus on mixing MS/OR methods whereas the paper views mixing methods as combining modelling techniques with research approaches. As such further reflection on this form of mixing of methods would be worthwhile, both from a conceptual perspective as well as a practical one.</p>", "<p> Furthermore, the combination touches on the second consideration which is the assertion that using a modelling technique alongside AR is new. This is not the case as illustrated by Peter Checkland’s work where AR is explicitly mentioned as being a key component. For example, it is noted by Rose<sup>##UREF##12##15##</sup> that “Soft systems methodology is well established as a vehicle for action research, particularly in programmes initiated at Lancaster University.” Other work in the PSM field also operates within the AR approach. How then is the approach presented in the paper adding to our knowledge of using models within an AR approach? For example, what activities/approaches worked well in healthcare where there are multiple stakeholders with vastly different knowledge bases and power hierarchies?</p>", "<p> Another area where further exploration would provide value is how the research avoided crossing the fine line between consultancy and AR.<sup>##UREF##13##16##</sup> It has been argued that to ensure robust AR it is necessary to have a detailed pre-understanding of the methods and tools, allowing for operationalisation and subsequently reflection. Given that this study centres on a re-analysis of cases it is not clear whether a clear design had been produced in advance and subsequently reflected upon. More detail here would help further our understanding of the use of AR from a retrospective stance and enhance our understanding of where, when, and how AR can be undertaken. Given that the research is based on an analysis of 5 cases, how do the insights elicited from the scrutiny of these cases map onto the AR cycle for increased robustness? For example, were there any lessons from the first case study employed when undertaking the subsequent studies? Finally, given the authors used James and colleagues’<sup>##UREF##14##17##</sup> work to understand the cases, and centres on how to use and choose a management consultant (and is in the business literature rather than academic literature) what impact might this have had on the outcomes?</p>" ]	[]	[ "<title>Discussion</title>", "<p> The paper presents further evidence for the use of modelling <italic toggle=\"yes\">with</italic> groups – seeking to develop solutions that are both procedurally rational as well as procedurally just – extending our knowledge and bringing the integration further into the health discipline. As such it provides valuable insights. However, it appears to take a slightly myopic view as it does not consider related literature that would help both in terms of extending our knowledge of visual interactive modelling and bringing disparate disciplines together. That said, it is recognised that this is a challenge for any researcher. Extrapolating into the future, it might also be worth considering how developments in artificial intelligence (for example generative artificial intelligence) could not only help in the development of models (for example, ChatGTP is able to produce excellent software code) but also in the sourcing of relevant information – both as an input into the SD model but also as a means of integrating the SD modelling with other complementary models (potentially giving rise to further insights and deeper understanding). This could be augmented with the improvements being made in online processes enabling (<italic toggle=\"yes\">a</italic>) appropriate (in terms of being able to access all the right people) engagement, and (<italic toggle=\"yes\">b</italic>) potentially bringing together the backroom work and workshops facilitating learning. To conclude, the research provides an alternative way of considering mixing methods from that presented within the MS/OR world and encompasses the mixing of OR methods, to one that integrates modelling techniques with research methods broadening the concept of mixing methods and opening avenues for further research into wider combinations.</p>" ]	[]	[ "<p>This commentary reflects upon the insights for improvement cases reported by Holmström et al where they consider the integration of action research (AR)—a research methodology—and system dynamics (SD)—a modelling technique—to manage the complexity of patient care pathways. Whilst this combination can be effective, recognising that SD is a simulation model whereas AR is a research approach is important for both practical and conceptual reasons. In addition, some of the benefits noted can also be achieved through taking a wider examination of modelling techniques, particularly problem structuring methods (PSMs) as SD has been considered a PSM and PSMs are designed to effectively engage multi-disciplinary group members in the search for solutions as this will provide further avenues for both engagement and learning.</p>", "<p>\n<bold>Citation:</bold> Ackermann F. Widening the lens: reflecting on the mixing of system dynamics with action research alongside work within the problem structuring methods field: Comment on \"Insights gained from a re-analysis of five improvement cases in healthcare integrating system dynamics into action research.\"<italic toggle=\"yes\"> Int J Health Policy Manag</italic>. 2023;12:7620. doi:10.34172/ijhpm.2023.7620</p>" ]	[ "<p> Holmström and colleagues<sup>##REF##35247937##1##</sup> present a strong case for using system dynamics (a continuous simulation modelling approach) within an action research (AR) setting to enable healthcare workers to develop more effective solutions. Building on a retrospective analysis of 5 case studies, the paper identifies that (<italic toggle=\"yes\">a</italic>) groups move between convergence and divergence phases, (<italic toggle=\"yes\">b</italic>) there is an increase in the likelihood of implementation, and (<italic toggle=\"yes\">c</italic>) learning takes place through deep engagement and co-creation of action. This is clearly a valuable study.</p>", "<p> As such, this work builds on an existing body of extant work, particularly in the management science/operational research (MS/OR) arena. The need for, and use of, qualitative and quantitative modelling to support groups in tackling complex messy problems is well established. Models provide the opportunity to take a systemic approach (increasing the likelihood of sustainable outcomes), exploring how different views interconnect and how a shared language/understanding is created. In addition, models can take the form of a ‘negotiative device’<sup>##UREF##0##2##,##UREF##1##3##</sup> facilitating socio-political considerations. Consequently, models can enhance the chances of implementation. System dynamics (SD) using causal loop diagrams (CLDs) provides the means for negotiating what the ‘problem’ is, and complemented by computer-based simulation for assessing the impact of actions on the system, realises these benefits. Moreover, using an AR approach when modelling has been seen to be an important part of the Operational Research world, both from a decision-making quality perspective as well as from a social-behavioural perspective.<sup>##UREF##2##4##</sup> This commentary seeks to explore in more detail both aspects extending the contribution of the paper.</p>", "<title>Models for Learning, Negotiation, and Ownership</title>", "<p> The authors note early on that there are considerable challenges when bringing multi-professional staff together due to there being different knowledge bases and different power bases. Whilst the first of these is predominantly a content consideration, the second focuses on process issues. As such designing approaches that consider both process and content modelling can increase the likelihood of success. SD modelling, both through the construction of CLDs and the running of the simulation model not only enables the range of different views to be accommodated but also ensures that all participants are on the ‘same page.’ As such the CLD and/or simulation model can act as a transitional object<sup>##REF##13061115##5##</sup> and/or boundary object<sup>##UREF##3##6##</sup> enabling the group to navigate both the process and content challenges. For example, models, whether they be SD-oriented or some other form, provide the means of separating the proponent from the contribution further helping to manage some of the socio-political considerations. Attending to both process and content is important as one can usefully inform the other acting as a ‘multiplier’ effect<sup>##UREF##4##7##</sup> and understanding how best to embed this within decision-making in any realm is a worthy activity.</p>", "<p> The authors also touch on the role of learning when embracing SD modelling augmented with AR. Whilst this is not new as a range of authors for example Thompson et al<sup>##UREF##5##8##</sup> and Peck<sup>##UREF##6##9##</sup> report on this phenomenon, it adds to our understanding of how models can facilitate sense-making – a necessary requirement when working with complex problems such as healthcare provision. It would be interesting and useful to compare how the models built in the healthcare situations facilitated learning as compared with the experiences of other researchers. What new insights were there, and what lessons were to be learnt? This is particularly of interest given that the study focused on work that combined group discussion through workshops with backroom modelling – a practice used by researchers and consultants typically seeking to balance the complexity of SD modelling with time efficiency (recognising that the participants were time-poor). It would be interesting to consider whether this separation enables the most effective learning or whether a different balance would better enable those participating to learn and negotiate successful outcomes. This consideration is stimulated by the fact that Figure 1 shows different balances between facilitated group work and modeller backroom development throughout the cases with the beginning and end being dominated by facilitated group work, suggesting that it is not only the <italic toggle=\"yes\">balance</italic> between the two modes of working but <italic toggle=\"yes\">where</italic> in the intervention one mode appears to take precedence over another. It would also be interesting to consider whether the gaps between workshops allowed for participants to sound out some of the insights emerging from the workshops with others in their workplace – checking both the content considerations (for example was anything missing or erroneous) along with the process considerations (ensuring political feasibility for emergent outcomes) – a feature that has been noted by Ackermann et al.<sup>##UREF##7##10##</sup></p>", "<p> The paper additionally raises the value of co-creation increasing the likelihood of implementation. This benefit has been noted in strategy research whereby co-created models enable participants to gain both emotional and cognitive commitment to the outcomes as well as enhance their understanding of the problematic situation.<sup>##UREF##8##11##</sup> Understanding better how to facilitate co-creation is important as it attends to both process and content management and thus teases out the activities that prove to be particularly efficacious adding to the extant knowledge. Augmenting this would be considering explicitly how best to ensure that the process embedded principles of procedural justice.<sup>##UREF##9##12##</sup> The paper notes the value of engagement and explanation – two of the 3 principles proposed by Kim and Mauborgne<sup>##UREF##9##12##</sup> and potentially touches on the third expectation, clarity, adding further flesh to the principles. Moreover, through further reflection on the cases, it might be possible to identify which activities contributed to attending to the principles taking note of whether there were any healthcare particularities – recognising that in some instances, context matters.</p>", "<p> One of the aspects I found challenging was that there was little recognition of the work done in the field of problem structuring methods (PSMs).<sup>##UREF##10##13##</sup> PSMs explicitly address situations where there is not an agreed problem definition, where the ‘problem’ is disputed – a characteristic that was noted as being present in the case studies. PSMs also support the identification of cause and effect seeking the root causes as does CLD. They attend to both the process and content considerations and strongly advocate for facilitation. Finally, they too attend to sense-making and shared mental models. Some consideration as to how this study builds, elaborates, or contradicts findings in the PSM literature would extend our knowledge of how best to tackle complex problems in healthcare and beyond.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that she has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "person-group": ["\n"], "surname": ["Eden"], "given-names": ["C"], "article-title": ["A framework for thinking about group decision support systems (GDSS)"], "source": ["Group Decis Negot"], "year": ["1992"], "volume": ["1"], "issue": ["3"], "fpage": ["199"], "lpage": ["218"], "pub-id": ["10.1007/bf00126263"]}, {"label": ["3"], "mixed-citation": [" Eden C, Ackermann F. Use of \u2018soft-OR\u2019 models by clients: what do they want from them? In: Pidd M, ed. Systems Modelling: Theory & Practice. Chichester: Wiley; 2004. "]}, {"label": ["4"], "person-group": ["\n"], "surname": ["Franco", "H\u00e4m\u00e4l\u00e4inen", "Rouwette", "Lepp\u00e4nen"], "given-names": ["LA", "RP", "EAJA", "I"], "article-title": ["Taking stock of behavioural OR: a review of behavioural studies with an intervention focus"], "source": ["Eur J Ope Res"], "year": ["2021"], "volume": ["293"], "issue": ["2"], "fpage": ["401"], "lpage": ["418"], "pub-id": ["10.1016/j.ejor.2020.11.031"]}, {"label": ["6"], "mixed-citation": [" Zagonel AA. Model conceptualization in group model building: a review of the literature exploring the tension between representing reality and negotiating a social order. In: Proceedings of the 2002 International Conference of the System Dynamics Society. Palermo, Italy: System Dynamics Society; 2002. "]}, {"label": ["7"], "mixed-citation": [" Eden C. The unfolding nature of group decision support. In: Eden C, Radford J, eds. Tackling Strategic Problems: The Role of Group Decision Support. London: SAGE Publications; 1990. "]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Thompson", "Howick", "Belton"], "given-names": ["JP", "S", "V"], "article-title": ["Critical Learning Incidents in system dynamics modelling engagements"], "source": ["Eur J Oper Res"], "year": ["2016"], "volume": ["249"], "issue": ["3"], "fpage": ["945"], "lpage": ["958"], "pub-id": ["10.1016/j.ejor.2015.09.048"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Peck"], "given-names": ["S"], "article-title": ["Group model building: facilitating team learning using system dynamics"], "source": ["J Oper Res Soc"], "year": ["1998"], "volume": ["49"], "issue": ["7"], "fpage": ["766"], "lpage": ["767"], "pub-id": ["10.1057/palgrave.jors.2600567"]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Ackermann", "Franco", "Gallupe", "Parent"], "given-names": ["F", "LA", "B", "M"], "article-title": ["GSS for multi-organizational collaboration: reflections on process and content"], "source": ["Group Decis Negot"], "year": ["2005"], "volume": ["14"], "issue": ["4"], "fpage": ["307"], "lpage": ["331"], "pub-id": ["10.1007/s10726-005-0317-4"]}, {"label": ["11"], "mixed-citation": [" Ackermann F, Eden C. Mapping out Strategic Success. London: SAGE Publications; 2008. "]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Kim", "Mauborgne"], "given-names": ["WC", "RA"], "article-title": ["A procedural justice model of strategic decision making: strategy content implications in the multinational"], "source": ["Organ Sci"], "year": ["1995"], "volume": ["6"], "issue": ["1"], "fpage": ["44"], "lpage": ["61"], "pub-id": ["10.1287/orsc.6.1.44"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Mingers", "Rosenhead"], "given-names": ["J", "J"], "article-title": ["Problem structuring methods in action"], "source": ["Eur J Oper Res"], "year": ["2004"], "volume": ["152"], "issue": ["3"], "fpage": ["530"], "lpage": ["554"], "pub-id": ["10.1016/s0377-2217(03)00056-0"]}, {"label": ["14"], "mixed-citation": [" Mingers J, Gill A. Multimethodology: The Theory and Practice of Combining Management Science Methodologies. Chichester: John Wiley& Sons; 1997. "]}, {"label": ["15"], "person-group": ["\n"], "surname": ["Rose"], "given-names": ["J"], "article-title": ["Soft systems methodology as a social science research tool"], "source": ["Syst Res Behav Sci"], "year": ["1997"], "volume": ["14"], "issue": ["4"], "fpage": ["249"], "lpage": ["258"], "pub-id": ["10.1002/(sici)1099-1743(199707/08)14:4<249::aid-sres119>3.0.co;2-s"]}, {"label": ["16"], "person-group": ["\n"], "surname": ["Eden", "Ackermann"], "given-names": ["C", "F"], "article-title": ["Theory into practice, practice to theory: action research in method development"], "source": ["Eur J Oper Res"], "year": ["2018"], "volume": ["271"], "issue": ["3"], "fpage": ["1145"], "lpage": ["1155"], "pub-id": ["10.1016/j.ejor.2018.05.061"]}, {"label": ["17"], "mixed-citation": [" James M, Cotter S, Fairley A, Payne A. How to Use and Choose a Management Consultant. London: The Economist; 1989. "]}]	{ "acronym": [], "definition": [] }	17	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Oct 8; 12:7620	oa_package/6d/c3/PMC10699828.tar.gz
PMC10702003	38062505	[]	[]	[]	[]	[]	[ "<title>Keywords</title>" ]	[ "<p id=\"Par4\">We read the meta-analysis by Messina et al. [##REF##37940953##1##] on the effectiveness of pulse pressure variation (PPV) and stroke volume variation (SVV) in predicting fluid responsiveness with both interest and skepticism.</p>", "<p id=\"Par5\">This meta-analysis included studies involving patients with an open chest, ventilated with a low tidal volume, or undergoing laparoscopic surgery (with increased abdominal pressure due to pneumoperitoneum). In these conditions, PPV and SVV are known to be unreliable to predict fluid responsiveness [##REF##25887325##2##]. Including studies where these limitations are not respected inevitably leads to an overall moderate predictive value. In other words, it is entirely foreseeable that the performance of a diagnostic tool will be moderate when one fails to consider the well-known limitations associated with its use.</p>", "<p id=\"Par6\">We appreciate the fact that the predictive value of PPV and SVV was assessed in various subgroups. Regrettably, it was not evaluated in the subgroup of patients meeting all the conditions conducive to the reliable use of PPV and SVV. What was the area under the curve (AUC) in the subgroup of patients undergoing non-laparoscopic surgery with a closed chest and a tidal volume of 7–9 ml/kg? Would it support the conclusion that PPV and SVV are only moderately accurate to predict fluid responsiveness?</p>", "<p id=\"Par7\">We firmly believe that both PPV and SVV serve as reliable predictors of fluid responsiveness, provided that physiologic limitations to their use are respected [##REF##16052125##3##, ##REF##30138573##4##]. Since the initial description of PPV almost 25 yrs ago [##REF##10051276##5##], these limitations have been extensively discussed in numerous articles, including in this journal [##REF##25887325##2##], and are summarized once more in the “PPV-meter” shown in Fig. ##FIG##0##1##. Many of these limitations (e.g. atrial fibrillation, spontaneous breathing activity, low tidal volume) are encountered less frequently in patients undergoing major surgery with general anesthesia than in critically ill patients. Of note, a tidal volume of 7–9 ml/kg, commonly used during surgery [##REF##28633157##6##], has been deemed safe [##REF##24623057##7##]. For patients ventilated with a tidal volume < 7 ml/kg, the assessment of changes in PPV during a mini-fluid challenge [##REF##26152341##8##] or a transient rise in tidal volume (aka tidal volume challenge) [##REF##28320434##9##] has proved useful to predict fluid responsiveness. Unfortunately, these points were not addressed in the paper by Messina et al. [##REF##37940953##1##].</p>", "<p id=\"Par8\">Finally, unlike SVV monitoring, PPV monitoring does not require any cardiac output monitoring device. In a meta-analysis assessing the respective performance of PPV and SVV, it would have been wise to highlight this practical advantage as well.</p>", "<p id=\"Par9\">In summary, physiologic limitations to the use of PPV and SVV should be respected not only in clinical practice but also in meta-analyses; otherwise, they may lead to misleading conclusions. When these limitations are respected, we believe that both PPV and SVV are valuable variables for predicting fluid responsiveness and personalizing hemodynamic management, potentially leading to improved patient outcomes [##REF##25348900##10##].</p>" ]	[ "<title>Author contributions</title>", "<p>FM drafted the manuscript, and all authors revised the manuscript and approved the final version.</p>", "<title>Funding</title>", "<p>The authors did not receive any funding for this article.</p>", "<title>Availability of data and material</title>", "<p>Not applicable.</p>", "<title>Declarations</title>", "<title>Ethics approval and consent to participate</title>", "<p id=\"Par10\">Not applicable.</p>", "<title>Competing interests</title>", "<p id=\"Par11\">None in relation with this article.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><p>Pulse pressure variation (PPV)-meter summarizing the clinical meaning of PPV (right) and main limitations to its clinical use (left)</p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[]	[ "<fn-group><fn><p>This comment refers to the article available online at 10.1186/s13054-023-04706-0.</p></fn><fn><p><bold>Publisher's Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"13054_2023_4765_Fig1_HTML\" id=\"MO1\"/>" ]	[]	[]	{ "acronym": [ "PPV", "SVV", "AUC" ], "definition": [ "Pulse pressure variation", "Stroke volume variation", "Area under the curve" ] }	10	CC BY	no	2024-01-13 23:36:46	Crit Care. 2023 Dec 7; 27:482	oa_package/bf/59/PMC10702003.tar.gz
PMC10702367	0	[]	[]	[]	[]	[]	[ "<p>\n<bold>Citation:</bold> Abbasi K, Ali P, Barbour V, et al. Reducing the risks of nuclear war—the role of health professionals. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8208. doi:10.34172/ijhpm.2023.8208</p>" ]	[ "<p> In January 2023, the Science and Security Board of the Bulletin of the Atomic Scientists moved the hands of the Doomsday Clock forward to 90s before midnight, reflecting the growing risk of nuclear war.<sup>##UREF##0##1##</sup> In August, 2022, the United Nation Secretary-General António Guterres warned that the world is now in a time of nuclear danger not seen since the height of the Cold War.<sup>##UREF##1##2##</sup> The danger has been underlined by growing tensions between many nuclear armed states.<sup>##UREF##0##1##,##REF##36882544##3##</sup> As editors of health and medical journals worldwide, we call on health professionals to alert the public and our leaders to this major danger to public health and the essential life support systems of the planet—and urge action to prevent it.</p>", "<p> Current nuclear arms control and non-proliferation efforts are inadequate to protect the world’s population against the threat of nuclear war by design, error, or miscalculation. The Treaty on the Non-Proliferation of Nuclear Weapons (NPT) commits each of the 190 participating nations “to pursue negotiations in good faith on effective measures relating to cessation of the nuclear arms race at an early date and to nuclear disarmament, and on a treaty on general and complete disarmament under strict and effective international control.”<sup>##UREF##2##4##</sup> Progress has been disappointingly slow and the most recent NPT review conference in 2022 ended without an agreed statement.<sup>##UREF##3##5##</sup> There are many examples of near disasters that have exposed the risks of depending on nuclear deterrence for the indefinite future.<sup>##UREF##4##6##</sup> Modernisation of nuclear arsenals could increase risks: for example, hypersonic missiles decrease the time available to distinguish between an attack and a false alarm, increasing the likelihood of rapid escalation.</p>", "<p> Any use of nuclear weapons would be catastrophic for humanity. Even a “limited” nuclear war involving only 250 of the 13 000 nuclear weapons in the world could kill 120 million people outright and cause global climate disruption leading to a nuclear famine, putting 2 billion people at risk.<sup>##UREF##5##7##,##REF##37118594##8##</sup> A large-scale nuclear war between the United States and Russia could kill 200 million people or more in the near term, and potentially cause a global “nuclear winter” that could kill 5–6 billion people, threatening the survival of humanity.<sup>##UREF##5##7##,##REF##37118594##8##</sup> Once a nuclear weapon is detonated, escalation to all-out nuclear war could occur rapidly. The prevention of any use of nuclear weapons is therefore an urgent public health priority and fundamental steps must also be taken to address the root cause of the problem—by abolishing nuclear weapons.</p>", "<p> The health community has had a crucial role in efforts to reduce the risk of nuclear war and must continue to do so in the future.<sup>##REF##35255264##9##</sup> In the 1980s the efforts of health professionals, led by the International Physicians for the Prevention of Nuclear War (IPPNW), helped to end the Cold War arms race by educating policy-makers and the public on both sides of the Iron Curtain about the medical consequences of nuclear war. This was recognised when the 1985 Nobel Peace Prize was awarded to the IPPNW<sup>##UREF##6##10##</sup> (<uri xlink:href=\"https://www.ippnw.org\">https://www.ippnw.org</uri>).</p>", "<p> In 2007, the IPPNW launched the International Campaign to Abolish Nuclear Weapons, which grew into a global civil society campaign with hundreds of partner organisations. A pathway to nuclear abolition was created with the adoption of the Treaty on the Prohibition of Nuclear Weapons in 2017, for which the International Campaign to Abolish Nuclear Weapons was awarded the 2017 Nobel Peace Prize. International medical organisations, including the International Committee of the Red Cross, the IPPNW, the World Medical Association, the World Federation of Public Health Associations, and the International Council of Nurses, had key roles in the process leading up to the negotiations, and in the negotiations themselves, presenting the scientific evidence about the catastrophic health and environmental consequences of nuclear weapons and nuclear war. They continued this important collaboration during the First Meeting of the States Parties to the Treaty on the Prohibition of Nuclear Weapons, which currently has 92 signatories, including 68 member states.<sup>##UREF##7##11##</sup></p>", "<p> We now call on health professional associations to inform their members worldwide about the threat to human survival and to join with the IPPNW to support efforts to reduce the near-term risks of nuclear war, including three immediate steps on the part of nuclear-armed states and their allies: first, adopt a no first use policy<sup>##UREF##8##12##</sup>; second, take their nuclear weapons off hair-trigger alert; and, third, urge all states involved in current conflicts to pledge publicly and unequivocally that they will not use nuclear weapons in these conflicts. We further ask them to work for a definitive end to the nuclear threat by supporting the urgent commencement of negotiations among the nuclear-armed states for a verifiable, timebound agreement to eliminate their nuclear weapons in accordance with commitments in the NPT, opening the way for all nations to join the Treaty on the Prohibition of Nuclear Weapons.</p>", "<p> The danger is great and growing. The nuclear armed states must eliminate their nuclear arsenals before they eliminate us. The health community played a decisive part during the Cold War and more recently in the development of the Treaty on the Prohibition of Nuclear Weapons. We must take up this challenge again as an urgent priority, working with renewed energy to reduce the risks of nuclear war and to eliminate nuclear weapons.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["1"], "mixed-citation": [" Science and Security Board, Bulletin of the Atomic Scientists. A Time of Unprecedented Danger: It is 90 Seconds to Midnight. 2023 Doomsday Clock Statement. January 24, 2023. "], "uri": ["https://thebulletin.org/doomsday-clock/current-time/"]}, {"label": ["2"], "mixed-citation": [" United Nations. Future Generations Counting on Our Commitment to Step Back from Abyss, Lift Cloud of Nuclear Annihilation for Good, Secretary-General Tells Review Conference. SG/SM/21394. August 1, 2022. "], "uri": ["https://press.un.org/en/2022/sgsm21394.doc.htm"]}, {"label": ["4"], "mixed-citation": [" United Nations. 2005 Review Conference of the Parties to the Treaty on the Non-Proliferation of Nuclear Weapons (NPT). May 2-27, 2005. "], "uri": ["https://www.un.org/en/conf/npt/2005/npttreaty.html"]}, {"label": ["5"], "mixed-citation": [" Mukhatzhanova G. 10th NPT Review Conference: Why it Was Doomed and How it Almost Succeeded. Arms Control Association. October 2022. "], "uri": ["https://www.armscontrol.org/act/2022-10/features/10th-npt-review-conference-why-doomed-almost-succeeded"]}, {"label": ["6"], "mixed-citation": [" Lewis P, Williams H, Pelopidas B, Aghlani S. Too Close for Comfort: Cases of Near Nuclear Use and Options for Policy. Chatham House Report. April 2014. "], "uri": ["https://www.chathamhouse.org/2014/04/too-close-comfort-cases-near-nuclear-use-and-options-policy"]}, {"label": ["7"], "mixed-citation": [" Bivens M. Nuclear Famine. IPPNW. August 2022. "], "uri": ["https://www.ippnw.org/wp-content/uploads/2022/09/ENGLISH-Nuclear-Famine-Report-Final-bleed-marks.pdf"]}, {"label": ["10"], "mixed-citation": [" Nobel Prize Outreach AB. International Physicians for the Prevention of Nuclear War\u2014Facts. 1985. "], "uri": ["https://www.nobelprize.org/prizes/peace/1985/physicians/facts/"]}, {"label": ["11"], "mixed-citation": [" UN Office for Disarmament Affairs. Treaty on the Prohibition of Nuclear Weapons. 2023. "], "uri": ["https://treaties.unoda.org/t/tpnw"]}, {"label": ["12"], "mixed-citation": [" Center for Arms Control and Non-Proliferation. No First Use: Frequently Asked Questions. 2023. "], "uri": ["https://armscontrolcenter.org/issues/no-first-use/no-first-use-frequently-asked-questions/"]}]	{ "acronym": [], "definition": [] }	12	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Aug 2; 12:8208	oa_package/38/45/PMC10702367.tar.gz
PMC10702368	37579355	[ "<title>Introduction</title>", "<p> Powell and Mannion<sup>##REF##37579456##1##</sup> explore the extent to which ‘health policy process’ research can and should draw more insights from ‘the wider policy process literature.’ Their review of reviews finds that very few health studies provide an awareness of that wider field or a clear indication of how and why they use policy theories. While health research could continue to develop and apply health policy-specific models, they recommend the greater appreciation and application of the wider literature, which tends to be ‘conceptually stronger’ and based on far more empirical studies.</p>", "<p> In that context, I explore the potential obstacles to, and payoffs from, the greater use of policy theories in health policy research. First, I ask: what would health researchers be trying to do, and why? For example, do they simply seek better explanations for the sake of their scholarly understanding? Or, do they want to use that knowledge to improve health policy and policy-making? Key sources in Powell and Mannion’s review suggest that both aims may be conflated with reference to the term ‘policy analysis.’ Second, I describe what the combination of theoretical and normative aims may look like by drawing on a review by Cairney et al of the use of policy theories in public health research (studies of ‘Health in All Policies,’ HiAP).<sup>##REF##37645203##2##</sup> This review identifies similarly low engagement with policy theories, but also the attempt by some scholars to translate theoretical insights into strategies to influence policy processes. A focus on this search for ‘practical lessons from policy theories’ helps to identify what they can and cannot tell us, and to raise dilemmas regarding the trade-offs between the aims of health researchers.</p>" ]	[]	[]	[]	[ "<title>Conclusion</title>", "<p> I agree with Powell and Mannion: the study of health policy processes should be informed routinely by insights from ‘the wider policy process literature,’ including the mainstream policy theories that they describe. However, health researchers need to be clear on what they are using these theories for. In other words, to maximise the value of this endeavour, researchers need to know what exactly policy theories are and are not, how and why they seek to use these insights, and if policy theories were designed for this purpose. First, the most direct value of theories comes from their ability to help explain health policy processes. Policy theories provide abstract insights that can be applied empirically in different ways to specific contexts Examples include to identify how and why policy-makers pay attention to and interpret policy relevant evidence in particular ways (such as through a ‘neoliberal’ lens), the extent to which policy-making environments are conducive to the implementation of specific health strategies, and if one strategy (such as for public health) may be undermined by another (such as when healthcare commands far more attention and resources). Second, policy theories can aid the pursuit of policy analysis, such as to encourage the designers of policy instruments to consider how (<italic toggle=\"yes\">a</italic>) they would interact with the existing policy mix, and (<italic toggle=\"yes\">b</italic>) the extent to which their success depends on collaboration across multiple policy-making centres. Third, however, they do not offer simple practical lessons on how to respond, such as to improve the use of some evidence or help to produce more coherent policy or joined-up policy-making. Rather, they may help to provoke more critical reflection on the dilemmas and trade-offs associated with policy-making.</p>" ]	[ "<p>Powell and Mannion suggest that ‘health policy process’ research should draw more lessons from ‘the wider policy process literature.’ While health research could continue with sector specific models, the wider literature is ‘conceptually stronger.’ In that context, I clarify how and why health researchers should use policy theories. I describe a review of the use of policy theories in public health research to show that many researchers use them to not only understand policy-making but also influence policy and policy-making. Most policy theories are not designed for that purpose, but it is still possible to produce practical lessons. I outline the issues that arise when repurposing theory-informed insights, such as that policy change takes a long time, and the scale of policy-making is potentially overwhelming. I then highlight the valuable role of theories in raising dilemmas in relation to modes of governance and evidence production.</p>", "<p>\n<bold>Citation:</bold> Cairney P. Why should health researchers use policy theories? Comment on \"Modelling the health policy process: one size fits all or horses for courses?\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7977. doi:10.34172/ijhpm.2023.7977</p>" ]	[ "<title>If Using Policy Theories, What Would Health Researchers be Trying to Do, and Why?</title>", "<p> To answer this question, it is essential to clarify (1) what using policy theories means, and indeed (2) what policy theories are. First, using policy theories can relate to two distinct aims:</p>", "<p>To understand policy-making by describing and explaining policy processes. </p>", "<p>To understand policy-making, then use that knowledge to evaluate or seek to influence policy change. </p>", "<p> Powell and Mannion focus primarily on the former, to describe a collection of ‘theories of the policy process’ that inform a programme of empirical studies. However, they also cite the ‘pioneering work of Walt and Gilson’<sup>##REF##10139469##3##</sup> which focuses primarily on the latter. Walt and Gilson relate this task to damaging reforms in ‘developing countries’: (<italic toggle=\"yes\">a</italic>) economic crisis and ‘shifts towards neo-liberal values’ prompted many countries to reduce public health spending, increase healthcare charges, and subject the health sector to new public management reforms (while relying more on the private sector); and (<italic toggle=\"yes\">b</italic>) ‘negative effects of health reforms on health status, especially on the vulnerable.’ In that context, they criticize a sole focus on the technical content of policy reforms (as if policy could be designed in a vacuum), in favour of a greater understanding of how reforms will fare during implementation (including the power of the actors involved). This understanding is essential to efforts to improve health, since — for example — a vague global commitment to public health principles or strategies (now summed up by the phrase ‘Health in All Policies’) will be futile unless its advocates understand how those commitments will be enacted or undermined by the politics and policy processes of each country.</p>", "<p> Second, in the ‘policy sciences,’<sup>##UREF##0##4##</sup> policy theory is not synonymous with ‘policy analysis.’ Instead, there are two distinct but – hopefully – mutually informative types of study:</p>", "<p>‘Policy analysis’ describes the (research informed but clearly political) act of defining a problem, generating feasible solutions, using values and goals to compare them, predicting their effects, and making recommendations. </p>", "<p>‘Policy process research’ describes the study of policy-making, such as to identify the environment or context in which policy analysis and choice takes place.<sup>##UREF##1##5##</sup></p>", "<p> Advocates of the ‘new policy sciences’<sup>##UREF##2##6##</sup> recommend a return to treating both concerns as symbiotic, to reverse a long-term trend towards the ‘unnecessary split between basic and applied research.’ In other words, for the most part, most of the policy theories listed by Powell and Mannion tend not to be applied to ‘policy analysis.’</p>", "<p> Therefore, disambiguation matters because the use of policy theories in ‘health policy analysis’ can range in meaning, from (<italic toggle=\"yes\">a</italic>) a sole focus on the scientific study of processes, to (<italic toggle=\"yes\">b</italic>) the combination of scientific and applied research. Further, the latter role can include attempts to (<italic toggle=\"yes\">a</italic>) inform policy analysis, (<italic toggle=\"yes\">b</italic>) evaluate the progress or success of a policy strategy or instrument, and/or (<italic toggle=\"yes\">c</italic>) influence policy and policy-making.</p>", "<title>What Practical Lessons Can Policy Theories Provide and not Provide?</title>", "<p> It is straightforward to use elements of policy theories to <italic toggle=\"yes\">describe</italic> or <italic toggle=\"yes\">explain</italic> key concerns in health research. First, for example, we can address classic questions — such as why is there such an absence of ‘evidence-based policy-making’? — to the concept of ‘bounded rationality,’<sup>##UREF##3##7##</sup> in which policy-makers do not have the ability to gather and process all policy relevant evidence or to relate it to a coherent set of policy preferences. Rather, they use cognitive shortcuts to make efficient choices.<sup>##UREF##4##8##</sup> Health researchers often describe a technocratic solution, to produce more high-quality evidence to reduce policy-maker <italic toggle=\"yes\">uncertainty</italic>, which is incomplete without a political solution based on how policy actors exercise power to reduce <italic toggle=\"yes\">ambiguity</italic> (in other words, the multiple ways to interpret the same problem).<sup>##UREF##5##9##</sup> Indeed, the latter concern is a routine feature of HiAP research, in which researchers contrast a damaging ‘neoliberal’ framing of health at the expense of a proper focus on the ‘social determinants of health.’<sup>##REF##37645203##2##</sup></p>", "<p> Second, a collection of concepts to describe the ‘policy-making environment’ or ‘system’<sup>##UREF##6##10##</sup> helps to explain why the adoption of a new policy <italic toggle=\"yes\">strategy</italic> would not lead to the desired policy <italic toggle=\"yes\">outcomes</italic>. They suggest that there is no such thing as a linear and orderly ‘policy cycle’ in which a single powerful central government can simply define a problem, adopt a solution, then guarantee implementation. Rather, there are many policy-makers spread across many levels and types of government (polycentric or multi-centric policy-making), and each venue or ‘centre’ has its own: formal and informal rules (institutions), relationships between policy makers and influencers (networks), dominant ways to understand policy problems and establish the feasibility of solutions (beliefs, ideas, and paradigms), and responses to social and economic conditions or events. Therefore, a decision reached in one centre may be amplified or dampened in others.</p>", "<p> It is far less straightforward to use this knowledge to <italic toggle=\"yes\">respond</italic> to these dynamics. There are some notable attempts to translate theoretical insights into practical lessons in HiAP research,<sup>##UREF##7##11##,##UREF##8##12##</sup> to produce recommendations including:</p>", "<p>Reframe the health and health inequalities problem (as socially determined, not the fault of individuals) and seek audiences in government that are relatively sympathetic to policy change. </p>", "<p>Form alliances, coalitions, or networks of actors who support the social determinants frame and can oppose advocates of neoliberal approaches. </p>", "<p>Support policy entrepreneurs who can exploit windows of opportunity for policy change. </p>", "<p> However, in each case, policy theories inform cautionary tales regarding:</p>", "<p>\n<italic toggle=\"yes\">The time it takes to reframe problems or adopt new solutions</italic>. Classic accounts of multiple streams analysis<sup>##UREF##9##13##</sup> and punctuated equilibrium theory<sup>##UREF##10##14##</sup> describe such changes as taking place over decades (if at all). </p>", "<p>\n<italic toggle=\"yes\">The scale of required activity</italic>. A key aim of HiAP advocates is to foster intersectoral action across (and outside of) government. Approaches such as the advocacy coalition framework<sup>##UREF##11##15##</sup> describe the spread of policy-making across a huge number of subsystems, each with their own actors, rules, and relationships. </p>", "<p>\n<italic toggle=\"yes\">The limited role of exceptional actors</italic>. While Kingdon<sup>##UREF##9##13##</sup> signalled the important role of policy entrepreneurs, they were akin to surfers waiting for the big wave. In other words, their environments provided most of the explanation of policy change opportunities.</p>", "<p> In many ways, policy theories are better suited to more reflective lessons, such as to highlight the dilemmas and trade-offs that emerge from contradictory aims. For example, Cairney and colleagues’ review<sup>##REF##37645203##2##</sup> identifies two evergreen issues: (1) a <italic toggle=\"yes\">governance dilemma</italic>, when actors seek the benefits of policy-making centralisation (to institutionalise a strategic plan and oblige change) <italic toggle=\"yes\">and</italic> decentralisation (to foster local creativity and collaboration); and, (2) an <italic toggle=\"yes\">evidence dilemma</italic>, when actors seek the benefits of high quality scientific evidence (restricting participation to experts and technocrats) <italic toggle=\"yes\">and</italic> the experiential knowledge of professionals, citizens, and communities (maximising participation and rejecting hierarchies of knowledge).</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that he has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["4"], "mixed-citation": [" Lasswell HD. The policy orientation. In: Lerner D, Lasswell HD, eds. The Policy Sciences: Recent Developments in Scope and Methods. Stanford, CA: Stanford University Press; 1951. "]}, {"label": ["5"], "mixed-citation": [" Cairney P. The Politics of Policy Analysis. London: Palgrave; 2021. "]}, {"label": ["6"], "person-group": ["\n"], "surname": ["Cairney", "Weible"], "given-names": ["P", "CM"], "article-title": ["The new policy sciences: combining the cognitive science of choice, multiple theories of context, and basic and applied analysis"], "source": ["Policy Sci"], "year": ["2017"], "volume": ["50"], "issue": ["4"], "fpage": ["619"], "lpage": ["627"], "pub-id": ["10.1007/s11077-017-9304-2"]}, {"label": ["7"], "mixed-citation": [" Simon HA. Models of Man; Social and Rational. New York, NY: Wiley; 1957. "]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Cairney", "Kwiatkowski"], "given-names": ["P", "R"], "article-title": ["How to communicate effectively with policymakers: combine insights from psychology and policy studies"], "source": ["Palgrave Commun"], "year": ["2017"], "volume": ["3"], "issue": ["1"], "fpage": ["37"], "pub-id": ["10.1057/s41599-017-0046-8"]}, {"label": ["9"], "mixed-citation": [" Cairney P. The Politics of Evidence-Based Policy Making. London: Palgrave; 2016. "]}, {"label": ["10"], "mixed-citation": [" Cairney P. Understanding Public Policy. 2nd ed. London: Red Globe; 2010. "]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Townsend", "Friel", "Baker", "Baum", "Strazdins"], "given-names": ["B", "S", "P", "F", "L"], "article-title": ["How can multiple frames enable action on social determinants? Lessons from Australia\u2019s paid parental leave"], "source": ["Health Promot Int"], "year": ["2019"], "volume": ["35"], "issue": ["5"], "fpage": ["973"], "lpage": ["983"], "pub-id": ["10.1093/heapro/daz086"]}, {"label": ["12"], "person-group": ["\n"], "surname": ["Harris", "Kent", "Sainsbury"], "given-names": ["P", "J", "P"], "article-title": ["Creating \u2018healthy built environment\u2019 legislation in Australia; a policy analysis"], "source": ["Health Promot Int"], "year": ["2017"], "volume": ["33"], "issue": ["6"], "fpage": ["1090"], "lpage": ["1100"], "pub-id": ["10.1093/heapro/dax055"]}, {"label": ["13"], "mixed-citation": [" Kingdon J. Agendas, Alternatives and Public Policies. New York, NY: Harper Collins; 1984. "]}, {"label": ["14"], "mixed-citation": [" Baumgartner FR, Jones BD. Agendas and Instability in American Politics. Chicago, IL: University of Chicago Press; 1993. "]}, {"label": ["15"], "mixed-citation": [" Jenkins-Smith HC, Nohrstedt D, Weible CM, Ingold K. The advocacy coalition framework: an overview of the research program. In: Theories of the Policy Process. London: Routledge; 2018:135-171. "]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Jul 24; 12:7977	oa_package/a0/be/PMC10702368.tar.gz
PMC10702369	37579356	[]	[]	[]	[]	[]	[ "<p>The authors wholeheartedly agree with Labonté: global health equity needs radical changes in economic thinking and policies, including degrowth and reducing consumption in parts of the world. But to mobilize sufficient people for radical change, reducing overconsumption and for degrowth, we may need to stop calling it that. Language is important and using the same frames and words as our opponents do can be counterproductive. Global health advocates need to be strategic about framing, use hope-based communication and develop attractive and convincing narratives. By doing so, hopefully we can bring these messages across to larger groups of people and increase the push for social change.</p>", "<p>\n<bold>Citation:</bold> Meurs M, Koutsoumpa M, Huisman V. Ensuring global health equity in a post-pandemic economy: words count! Comment on \"Ensuring global health equity in a post-pandemic economy.\" Int <italic toggle=\"yes\">J Health Policy Manag</italic>. 2023;12:7794. doi:10.34172/ijhpm.2023.7794</p>" ]	[ "<p> In his editorial “Ensuring Global Health Equity in a Post-pandemic Economy,”<sup>##REF##35942959##1##</sup> Labonté hits the nail on the head: socio-economic inequality and our unsustainable economic growth model are main drivers of health inequity and they require solutions that many consider to be radical. As Labonté describes, the policy tools to implement several of those solutions are already there. Some more and others less elaborated, but still, they are there: a larger role for states in the economy, progressive tax systems — including fair international taxation —, monetary policy reforms and a reform of international financial institutions. Academics have thought them through, activists have been calling for them, and in some cases, politicians are implementing them. What we need, Labonté says, is an activist public health movement to mobilize the political will for implementing these policies. While we wholeheartedly agree, we believe that we need to use different framing, language and words to reach larger groups of people and grow such an activist public health movement that can push for change.</p>", "<p> After hopeful calls for a “green recovery” and “building back better” from many countries and international organisations, as Labonté observes, ambition levels are already declining. In many regions of the world, populist and far-right political groups are gaining votes by electoral promises to continue business as usual. Moreover, civic space is under authoritarian attack in many countries. Meanwhile, in others, ruled by liberal democracy, large groups of voters support political parties whose policy promises do not serve their well-being. Not in the long run and in many cases not even in the short run. Why? And, more importantly, how can we persuade people to support the change we want to see?</p>", "<p> Not by calling for degrowth, for reducing overconsumption or for a radical overhaul — even if we agree with it. The prospect of change, especially radical change, instils feelings of uncertainty and therewith resistance in many people. Even though high-income countries will need to change, a lot, using these terms fosters a feeling that people need to give up something valuable. As Labonté quoted from Walden Bello: <italic toggle=\"yes\">“…there will need to be political and social psychological transformations from societies that have been weaned on overconsumption.” </italic>As activists and part of a social movement, we know that changing the public opinion, is a very complex and multifactorial process.</p>", "<p> To create socio-economic equality and a sustainable economic growth model we need more than an activist public health movement. We need a much more widespread public push for change. To get such a widespread push, we need to weigh our words with care. As global health advocates, we are keenly aware that the framing of a message is often more powerful than its content to convince people and persuade them into behaviour change. However, language, framing and using the words that ‘make people tick’ remains uncharted territory for many of us. While it is exactly the language, framing and words that have the potential to take people to the streets, push for change and possibly change their voting preferences.</p>", "<p> As Anat Shenker-Osorio says: <italic toggle=\"yes\">“A great message doesn’t say what’s already popular; a great message makes popular what needs to be said.”</italic><sup>##UREF##0##2##</sup></p>", "<p> Therefore, we are making a case for using convincing framing and hope-based communication. Research shows that framing is essential to convince people of your message. Cognitive scientist George Lakoff explains it like this: <italic toggle=\"yes\">“facts matter enormously, but to be meaningful they must be framed in terms of their moral importance. […] If the facts don’t fit the frames in your brain, the frames in your brain will stay and the facts are ignored or challenged or belittled.”</italic><sup>##UREF##1##3##</sup> So, people’s brains take shortcuts to interpret what you are saying, and those shortcuts are based on the ideas they already have.</p>", "<p> Often, advocates try to counter a narrative by using the same words as their opponents. Think of the ‘Brexit’ versus ‘No Brexit’ campaign. This is counterproductive. When using words that strongly link to the opposite frame, you activate that frame, undermining your own views. It is important to use your own frames, choose your own words, not those of the ones holding a different view. According to Lakoff, effective reframing is more than presenting the facts in an effective way. It is about ingraining certain ideas, developed over time, consistently and precisely enough to create an accurate frame for our understanding.<sup>##UREF##1##3##</sup></p>", "<p> Hope-based communication builds on that idea. It emphasizes the importance of creating strong, positive narratives (frames) based on our shared values. At a high level, our values are quite similar; we all want to be as healthy as possible; we want the best for our children; and we desire to be loved and treated with respect. As Bonanno et al say: <italic toggle=\"yes\">“[These] shared values are widely held beliefs among the population of interest.” </italic>and<italic toggle=\"yes\"> “[serve] to build a connection between the speaker and the audience, creating a willingness to listen to further information.”</italic><sup>##UREF##2##4##</sup> A telling example to illustrate this point is given by Anat Shenker-Osorio: <italic toggle=\"yes\">“Marriage equality won out precisely because LGBT people made the debate about values of commitment and family. When they stopped talking ‘rights’ and started talking ‘love,’ the tide turned.”</italic><sup>##UREF##0##2##</sup></p>", "<p> Next, we must paint a clear and appealing picture of what our ideal world looks like. If people recognize themselves in that view, it becomes easier for them to follow ideas and call for or adopt policies that will help realize this world. Thomas Coombes, communication strategist and hope-based communication champion, explains that hope-based communication does not ignore the problems, but instead it puts them into the context of how things should be.<sup>##UREF##3##5##</sup> So, rather than reacting to our opponents’ ideas — merely focusing on what we are against —, we must show that it is possible to make the changes, offering a hopeful perspective that is activating.<sup>##UREF##4##6##</sup> For example, research in the environmental field shows that people are more likely to change their intentions when they receive a positive framing of an issue, whereas fear can leave them overwhelmed and not action oriented.<sup>##UREF##5##7##, ####UREF##6##8##, ##UREF##7##9####7##9##</sup></p>", "<p> We recognize that there is no silver bullet when it comes to effecting social change. However, we do think, and evidence supports, that creating a positive perspective is more activating than focusing only on the problems.<sup>##UREF##8##10##</sup> And thus, worth exploring in our quest to realize global health equity.</p>", "<title>Redirecting the Growth Narrative</title>", "<p> Let’s look at the framing around economic growth and degrowth. People often relate growth with something positive, like improvements in health and well-being. And when we think about economic growth, the shortcut in our brains usually leads us to the most common, most used indicator for it: gross domestic product (GDP). We quickly link GDP with positive outcomes, not leaving room to reflect that focusing on GDP growth without taking measures to equitably distribute wealth and invest in the social sectors, will not be beneficial for all of us. Or that GDP also grows as a result of activities that are downright harmful, to the environment, to health, to the well-being of many. The United States, for example, stands out as a country with one of the highest GDP growth rates and GDP per capita in the world. Nevertheless, among other GDP-high countries, it also has the highest economic inequality and poverty, and lack of universal access to healthcare, heavily influencing the life expectancy and well-being of the population.</p>", "<p> In fact, economic equality correlates far more closely with happiness, longevity and well-being of the population than GDP. According to the World Health Organization (WHO),<sup>##UREF##9##11##</sup> evidence shows that even a modest redistribution of wealth has considerably greater impact on poverty reduction than economic growth alone. And according to Wilkinson and Pickett, it is not so much the growth of an economy that matters, but rather how wealth is distributed within it.<sup>##UREF##10##12##</sup> Economic growth does not, in itself, improve well-being. Tax revenues may indeed increase with GDP growth, but what matters is whether and how governments invest those revenues in good quality and universally accessible health and education, infrastructure and other public services.</p>", "<p> Unfortunately, the Sustainable Development Goals (SDGs) have legitimized the use of GDP as the most appropriate economic indicator. It has become and continues to be part of our vocabulary as civil society and in the global discourse, as we often refer to the SDGs as ‘the world we want.’ But if the world we want is fair and just, with well-being for everyone, we need to measure different things.</p>", "<p> Alternatives exist and have for many years. They can be very useful for building a new narrative of what our ideal world looks like. The Genuine Progress Indicator (GPI) is one. It starts with a measurement of GDP but then considers positive externalities like household and volunteer work, and subtracts negative externalities, such as pollution, resource depletion and crime; and it adjusts for inequality.<sup>##UREF##11##13##</sup> So, it basically tries to net the positive and negative outcomes of economic growth to evaluate whether or not it has benefited society. Another alternative is Bhutan’s Gross National Happiness indicator (GNH). The central concept of GNH is that sustainable development should give equal importance to non-economic aspects of well-being, like sustainable and equitable socio-economic development. We need to move away from the eternal chase of GDP and growth as we know it.</p>", "<p> If governments and the global community would shift their policies and approach towards maximising the GPI or GNH or any other sustainable indicator instead of GDP, then they would adopt policies that improve social well-being and allow for a fairer distribution of wealth, and health and well-being, across the world.</p>", "<p> How do we get them to do that, when economic and GDP growth continues to dominate the headlines of major news channels and to drive decision-making? Well-framed information is only one piece of the puzzle of change, which is a wide and complex territory that social movements, including the global health community, are still trying to fully grasp. Knowledge is important, but change is a dynamic, iterative process that also differs across contexts and time.</p>", "<p> To garner the widespread public support that is needed, we must create strong and convincing framing. Let’s be deliberate and creative with words. Terms like “no Brexit,” or even “degrowth,” do not convey a vision of the world you want to create, instead it activates and strengthens the opposite view. Do not assume people think from the same starting point as you do. Keep emphasizing what you want the world to look like and why – linking to our shared values. Once people share your frame, your ideas for change will stick much better. We must find the right words and the right frames to help make that happen.</p>", "<p> Rather than calling for ‘degrowth,’ let’s call for growing a care economy, as suggested by one of the interviewees of Labonté in his article. Instead of emphasizing the need to reduce consumption, we can focus on the need for increased consumption of what is essential for well-being, such as clean air and universal health coverage. If we can paint a picture – in our own words – of a world in which all can flourish, then hopefully we can activate people at the grassroots level to bring change from below and sufficient people to vote into office those political leaders that will raise and maintain ambition levels for a green, caring and inclusive economy.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Disclaimers</title>", "<p> The views expressed in this commentary are those of the authors and do not constitute an official position of Wemos.</p>", "<title>Funding</title>", "<p> All authors are employees of Wemos, a non-profit organization. Wemos’ sources of funding can be found at <uri xlink:href=\"https://www.wemos.org/\">https://www.wemos.org/</uri>.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "mixed-citation": [" Shenker-Osorio A. Messaging This Moment: A Handbook for Progressive Communicators. Centre for Community Change; 2017. "], "uri": ["https://communitychange.org/wp-content/uploads/2017/08/C3-Messaging-This-Moment-Handbook.pdf"]}, {"label": ["3"], "mixed-citation": [" Lakoff G. The All New Don\u2019t Think of an Elephant!: Know Your Values and Frame the Debate. Chelsea Green Publishing; 2014. "]}, {"label": ["4"], "person-group": ["\n"], "surname": ["Bonanno", "Ennes", "Hoey"], "given-names": ["A", "M", "JA"], "article-title": ["Empowering hope-based climate change communication techniques for the Gulf of Maine"], "source": ["Elementa (Wash D C)"], "year": ["2021"], "volume": ["9"], "issue": ["1"], "fpage": ["00051"], "pub-id": ["10.1525/elementa.2020.00051"]}, {"label": ["5"], "mixed-citation": [" ENNHRI. Hope-Based Communication: From Problem to Solution. "], "uri": ["https://www.youtube.com/watch?v=xZk5ldgtsng"]}, {"label": ["6"], "mixed-citation": [" Hope-Based Comms: A Strategy for Change. "], "uri": ["https://www.hope-based.com/"]}, {"label": ["7"], "person-group": ["\n"], "surname": ["Geiger", "Swim", "Fraser"], "given-names": ["N", "JK", "J"], "article-title": ["Creating a climate for change: Interventions, efficacy and public discussion about climate change"], "source": ["J Environ Psychol"], "year": ["2017"], "volume": ["51"], "fpage": ["104"], "lpage": ["116"], "pub-id": ["10.1016/j.jenvp.2017.03.010"]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Morton", "Rabinovich", "Marshall", "Bretschneider"], "given-names": ["TA", "A", "D", "P"], "article-title": ["The future that may (or may not) come: how framing changes responses to uncertainty in climate change communications"], "source": ["Glob Environ Change"], "year": ["2011"], "volume": ["21"], "issue": ["1"], "fpage": ["103"], "lpage": ["109"], "pub-id": ["10.1016/j.gloenvcha.2010.09.013"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Bilandzic", "Kalch", "Soentgen"], "given-names": ["H", "A", "J"], "article-title": ["Effects of goal framing and emotions on perceived threat and willingness to sacrifice for climate change"], "source": ["Sci Commun"], "year": ["2017"], "volume": ["39"], "issue": ["4"], "fpage": ["466"], "lpage": ["491"], "pub-id": ["10.1177/1075547017718553"]}, {"label": ["10"], "person-group": ["\n"], "surname": ["Marlon", "Bloodhart", "Ballew"], "given-names": ["JR", "B", "MT"], "article-title": ["How hope and doubt affect climate change mobilization"], "source": ["Front Commun (Lausanne)"], "year": ["2019"], "volume": ["4"], "fpage": ["20"], "pub-id": ["10.3389/fcomm.2019.00020"]}, {"label": ["11"], "mixed-citation": [" World Health Organization (WHO). Closing the Gap in a Generation. WHO; 2008. "]}, {"label": ["12"], "mixed-citation": [" van Woerden W, de Groot T, van de Pas R, Bloemen S. Living Well on a Finite Planet. Building a Caring World Beyond Growth. Amsterdam: Commons Network; 2021. "]}, {"label": ["13"], "mixed-citation": [" Talbarth J, Webb J. Genuine progress indicator. Vol. 2022. In: GGBP Case Study Series, Green Growth in Practice: 2014. "]}]	{ "acronym": [], "definition": [] }	13	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Jul 24; 12:7794	oa_package/3f/a2/PMC10702369.tar.gz
PMC10702370	37579359	[ "<title>Background</title>", "<p> A vital mechanism for assuring safety and performance of high-risk medical devices in patients is that they are subject to systematic post-market surveillance, which includes the collection of high-quality clinical data by registries. For regulatory purposes, such post-market clinical follow-up (PMCF) is mandatory for cardiovascular devices like stents and valves and for orthopaedic devices like hip and knee implants.</p>", "<p> The International Medical Device Regulators Forum (IMDRF) defines a medical device registry as “an organized system with a primary aim to increase the knowledge on medical devices contributing to improve the quality of patient care that continuously collects relevant data, evaluates meaningful outcomes and comprehensively covers the population defined by exposure to particular device(s) at a reasonably generalizable scale (eg, international, national, regional, and health system).”<sup>##UREF##0##1##</sup> A medical device registry is thus an unselected population-based health information system collecting large numbers of real-world data regarding safety and performance of specific devices over time, with the aim to improve the quality of patient care,<sup>##UREF##0##1##, ####UREF##1##2##, ##UREF##2##3##, ##REF##31210971##4####31210971##4##</sup> and therefore well suited to provide clinical evidence on PMCF of devices for regulatory purposes.</p>", "<p> The European Medical Device Regulation (MDR) requires manufacturers to plan and conduct surveillance of their devices (see Article 83 of (EU) 2017/745<sup>##UREF##3##5##</sup>), but the list of sources of available information that can be used for this purpose includes “relevant specialist or technical literature, databases and/or registers” and “information, including feedbacks and complaints, provided by users, distributors and importers” (see Annex III, clause 1.1(a)).<sup>##UREF##3##5##</sup> Real-world data collected by medical device registries are particularly useful as they enable continuous benchmarking across longer follow-up in many more patients than enrolled in clinical trials.<sup>##REF##30943790##6##, ####REF##27581825##7##, ##REF##23992139##8##, ##UREF##4##9##, ##REF##31312522##10####31312522##10##</sup></p>", "<p> The utility of medical device registries organized by medical professional associations is exemplified by the case of the ‘‘Metal on Metal’’ (MoM) hip implants. Originally developed as a more durable alternative to implants with ceramic or polyethylene components, mid-term follow-up registry data of patients with MoM showed far higher revision rates when compared with other implants.<sup>##REF##31210979##11##</sup> The Australian Orthopaedic Association National Joint Replacement Registry identified these implants as having an outlier performance, three years before their withdrawal from the market in 2010.<sup>##REF##22258775##12##, ####UREF##5##13##, ##UREF##6##14####6##14##</sup> For cardiovascular diseases, device registries have provided important insights on the safety of coronary stents, by documenting increased rates of low-frequency events such as stent thrombosis with specific stent platforms.<sup>##REF##20031749##15##,##REF##25042421##16##</sup></p>", "<p> Principles have been proposed by regulators to evaluate whether the quality of clinical data on medical devices meets the scientific standards to be used for PMCF. They include coverage (ie, extent of participation in data collection), completeness (ie, data used in analyses are consistently captured), accuracy (ie, data recorded is an accurate reflection of the healthcare event), consistency (ie, uniformity in following the same procedures for data capture), integrity (ie, consistent recording of unique identification of medical devices), and reliability (ie, reproducibility of data elements).<sup>##UREF##0##1##</sup> Specific criteria have not been proposed, however, and it is therefore unknown if existing medical device registries in Europe would allow manufacturers to meet the MDR requirements to an acceptable standard. As part of the Coordinating Research and Evidence for Medical Devices (CORE-MD) project, this systematic review therefore aims to: (1) identify current European cardiovascular and orthopaedic medical device registries, and (2) review these registries by 33 items that related to their structures, methodologies, and quality of data.</p>" ]	[ "<title>Methods</title>", "<p> This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines,<sup>##REF##33782057##17##</sup> and it was registered in the Center for Open Science in October 2021 (<uri xlink:href=\"https://osf.io/7yuwx/\">https://osf.io/7yuwx/</uri>) prior to data collection.</p>", "<title> Search Strategy </title>", "<p> A previous study identified European registries on implantable medical devices<sup>##REF##24075007##18##</sup> from which we adapted and updated its search strategy in order to identify new registries and expand the list of registries for this systematic review. Eight literature libraries (Centre for Reviews and Dissemination York, Cochrane library, Embase, Emcare, Google Scholar, Medline, PubMed, and Web of Science) were searched for publications between January 1, 2013 and July 7, 2021, using a systematic search strategy (##SUPPL##0##Supplementary file 1##) created by a librarian (JWS). References were imported to EndNote (Version X9, Clarivate Analytics, Philadelphia, the USA) which was used to remove duplicate publications, and subsequently exported to the web application Rayyan (Doha, Qatar)<sup>##REF##27919275##19##</sup> which was used for study selection.</p>", "<title> Study Selection </title>", "<p> Two reviewers (LAH and THG) independently screened titles and abstracts and then independently assessed eligibility of full texts. Discrepancies were resolved by discussion. If consensus could not be reached, the senior researcher (PJMvdM) was consulted for a decisive vote. Studies were included firstly if they described a European regional, national, or multi-country cardiovascular medical device registry in which data were captured on coronary stents and/or on percutaneous or surgical valve repair or replacement. We focused on coronary artery stents as they are commonly used high-risk devices with a low frequency of adverse events so that a large number of patients is needed to detect safety issues, and on valve prostheses because there are many new devices for which guidance is needed on benchmarking safety and performance. Secondly, we also included European registries capturing data on hip and/or knee prostheses since they are the most common orthopaedic high-risk devices. By applying these criteria and by excluding multicenter studies, we complied with the IMDRF definition of a registry,<sup>##UREF##0##1##</sup> which is particularly relevant to evaluate implant performance in the entire population receiving such a device in daily practice, rather than in selected (high-performing) centers. Additional inclusion criteria were: (<italic toggle=\"yes\">i</italic>) an active/accessible website at the time of study collection; or (<italic toggle=\"yes\">ii</italic>) at least one publication and/or annual report containing registries’ data between 2013 and 2021. We defined an “active registry” as a registry that published at least one annual report and/or peer-reviewed paper containing registries’ data, during or later than 2018. The reason for making a distinction between “active” and “non-active” registries is to give a better estimate regarding the number of registries able to contribute evidence for regulatory purposes in practice. In addition, “active” registries may also report the structural and methodological characteristics determining the quality of the data more consistently. No language restriction was applied. Data were extracted from any peer-reviewed publication(s) that described the registries’ structure and methodology, and combined with data from the most recent published annual report(s) (if available) and/or registries’ website (if available). To identify any more registries that were not yet included in this review, the references in publications and annual reports were checked, and clinical experts were consulted (five for the cardiovascular and eight for the orthopaedic field). For orthopaedic registries, we also checked the list on the EFORT — Network of Orthopaedic Registries of Europe (NORE) —website (<uri xlink:href=\"https://efortnet.efort.org/nore-map/#/nore/map-all\">https://efortnet.efort.org/nore-map/#/nore/map-all</uri>).</p>", "<title> Data Extraction and Analysis</title>", "<p> Based on the literature including a study reporting best-practice recommendations,<sup>##REF##27997813##20##</sup> LAH and PJMvdM developed a list of items that could be used to assess registries’ structures and methodological characteristics, reflecting the previously mentioned principles<sup>##UREF##0##1##</sup> and therefore relevant to judge the quality of registry data for regulatory purposes as required by the MDR. These were sent to 13 experts in the cardiovascular (n = 7) and/or orthopaedic (n = 6) fields, for feedback and suggestions of relevant additional items. Consensus was reached on a total of 33 quality items covering six domains: (1) Identification (6 items) to understand which population the registry intends to describe; (2) Maturity (3 items) to contextualize the numbers of procedures and extent to which longer-term outcomes may already be captured; (3) Governance (5 items) to enable assessment of the integrity of data; (4) Coverage, design & organisation (8 items) to reflect the aforementioned principles of coverage and consistency; (5) Data quality & completeness (4 items) to reflect the aforementioned principles of completeness and accuracy, and (6) Safety & performance (7 items) to capture reliability of data in using standard definitions to assess safety; details of each item are given in ##BOX##0##Box 1##. Data were also collected on: (<italic toggle=\"yes\">i</italic>) the number of peer-reviewed publications since foundation of the registry, as an indicator of scientific utility; (<italic toggle=\"yes\">ii</italic>) the number of included manufacturers and the total number of patients/procedures, to indicate the average experience with a specific device, that would potentially be relevant when assessing the performance based on a minimum sample size to obtain reliable estimates, and (<italic toggle=\"yes\">iii</italic>) reported outcomes, including definitions and durations of follow-up.</p>", "<p> Using a prespecified format, publicly available data were extracted independently by LAH and THG for each registry and each item. Otherwise, items were recorded as ‘‘Not reported” (N/R). Median values (given the skewed distributions) and interquartile ranges (IQRs) were calculated for the percentage of items reported per domain and across all domains, for both cardiovascular and orthopaedic registries. Analyses were performed using Microsoft Excel (Excel version 2012, Microsoft, Redmond, the USA).</p>" ]	[ "<title>Results</title>", "<title> Literature Search</title>", "<p> The searches identified 4538 cardiovascular and 4485 orthopaedic publications, of which 1727 cardiovascular and 1360 orthopaedic publications remained after removing duplicates. Title and abstract screening identified a total of 81 cardiovascular and 27 orthopaedic registries, mentioned in publications from January 2013 to July 2021 (##FIG##0##Figure 1##). Twelve cardiovascular registries were excluded because they focused on other cardiovascular devices (eg, pacemakers) (n = 11) or no devices (n = 1) and a further 51 cardiovascular and seven orthopaedic registries were excluded during full-text screening, mostly because of reporting on a single or multicenter study, or due to registry mergers (##FIG##0##Figure 1##). Manual search identified two additional cardiovascular<sup>##UREF##7##21##,##UREF##11##25##</sup> and six orthopaedic registries,<sup>##UREF##33##47##,##UREF##37##51##,##UREF##39##53##,##UREF##43##57##,##UREF##46##60##,##UREF##52##66##</sup> that did not publish any peer-reviewed papers and therefore were not found in the literature search. Thus, a total of 20 cardiovascular<sup>##UREF##7##21##, ####UREF##8##22##, ##UREF##9##23##, ##UREF##10##24##, ##UREF##11##25##, ##UREF##12##26##, ##UREF##13##27##, ##UREF##14##28##, ##UREF##15##29##, ##UREF##16##30##, ##UREF##17##31##, ##UREF##18##32##, ##UREF##19##33##, ##UREF##20##34##, ##UREF##21##35##, ##UREF##22##36##, ##UREF##23##37##, ##UREF##24##38##, ##UREF##25##39##, ##UREF##26##40####26##40##</sup> and 26 orthopaedic registries<sup>##UREF##27##41##, ####UREF##28##42##, ##UREF##29##43##, ##UREF##30##44##, ##UREF##31##45##, ##UREF##32##46##, ##UREF##33##47##, ##UREF##34##48##, ##UREF##35##49##, ##UREF##36##50##, ##UREF##37##51##, ##UREF##38##52##, ##UREF##39##53##, ##UREF##40##54##, ##UREF##41##55##, ##UREF##42##56##, ##UREF##43##57##, ##UREF##44##58##, ##UREF##45##59##, ##UREF##46##60##, ##UREF##47##61##, ##UREF##48##62##, ##UREF##49##63##, ##UREF##50##64##, ##UREF##51##65##, ##UREF##52##66####52##66##</sup> were selected for data extraction.</p>", "<title> Overall Findings</title>", "<p> Across all domains, a median of 33% (IQR 14%-71%) of the predefined 33 quality items were reported by cardiovascular registries and 60% (IQR 28%-100%) by orthopaedic registries. The highest median value was reached for the domain ‘Identification’ since almost all registries reported information on eg, the type of registry: 75% (IQR 69%-100%) for cardiovascular and 100% (IQR 100%-100%) for orthopaedic registries (##FIG##1##Figure 2##). The lowest percentages were observed for the domains ‘Data quality & completeness’ and ‘Safety & performance’; for cardiovascular registries these were respectively 25% (IQR 0%-25%) and 0% (IQR 0%-4%) and for orthopaedic registries they were 38% (IQR 0%-69%) and 50% (IQR 0%-71%) (##FIG##1##Figure 2##).</p>", "<title> Domains “Identification” and “Maturity” </title>", "<p> The majority of included registries (41 out of 46; 89%) were national registries,<sup>##UREF##7##21##, ####UREF##8##22##, ##UREF##9##23##, ##UREF##10##24##, ##UREF##11##25##, ##UREF##12##26####12##26##,##UREF##14##28##, ####UREF##15##29##, ##UREF##16##30##, ##UREF##17##31##, ##UREF##18##32##, ##UREF##19##33##, ##UREF##20##34##, ##UREF##21##35##, ##UREF##22##36##, ##UREF##23##37##, ##UREF##24##38##, ##UREF##25##39##, ##UREF##26##40##, ##UREF##27##41##, ##UREF##28##42##, ##UREF##29##43##, ##UREF##30##44##, ##UREF##31##45##, ##UREF##32##46##, ##UREF##33##47##, ##UREF##34##48####34##48##,##UREF##37##51##,##UREF##39##53##,##UREF##40##54##,##UREF##42##56##, ####UREF##43##57##, ##UREF##44##58##, ##UREF##45##59##, ##UREF##46##60##, ##UREF##47##61##, ##UREF##48##62##, ##UREF##49##63##, ##UREF##50##64##, ##UREF##51##65##, ##UREF##52##66####52##66##</sup> with only 3 (7%) regional registries<sup>##UREF##13##27##,##UREF##38##52##,##UREF##41##55##</sup> and 2 (4%) multi-country registries<sup>##UREF##35##49##,##UREF##36##50##</sup> (Table S1A and S1B, ##SUPPL##1##Supplementary files 2## and ##SUPPL##2##3##). The first cardiovascular registry was founded in 1978<sup>##UREF##9##23##</sup> and the two most recent in 2013,<sup>##UREF##21##35##,##UREF##23##37##</sup> while the first orthopaedic registry was established in 1975<sup>##UREF##51##65##</sup> and the most recent in 2019.<sup>##UREF##39##53##</sup> Initial motivations to set up a registry were mostly reported (by 60% of cardiovascular<sup>##UREF##7##21##,##UREF##9##23##,##UREF##11##25##, ####UREF##12##26##, ##UREF##13##27####13##27##,##UREF##15##29##,##UREF##19##33##,##UREF##21##35##, ####UREF##22##36##, ##UREF##23##37####23##37##,##UREF##25##39##,##UREF##26##40##</sup> and 92% of orthopaedic registries<sup>##UREF##28##42##, ####UREF##29##43##, ##UREF##30##44####30##44##,##UREF##32##46##, ####UREF##33##47##, ##UREF##34##48##, ##UREF##35##49##, ##UREF##36##50##, ##UREF##37##51##, ##UREF##38##52##, ##UREF##39##53##, ##UREF##40##54##, ##UREF##41##55##, ##UREF##42##56##, ##UREF##43##57##, ##UREF##44##58##, ##UREF##45##59##, ##UREF##46##60##, ##UREF##47##61##, ##UREF##48##62##, ##UREF##49##63##, ##UREF##50##64##, ##UREF##51##65##, ##UREF##52##66####52##66##</sup>) and often involved ensuring patients’ safety. More orthopaedic than cardiovascular registries publish annual reports (77% versus30%), although for some registries (35%) data were last reported more than four years ago and therefore labelled as ‘‘non-active’’ (##TAB##0##Table##). Of the active registries (65%), a median of 43% (IQR 25%-80%) of the 33 quality items were reported by cardiovascular registries and 75% (IQR 41%-100%) by orthopaedic registries (##FIG##2##Figure 3##).</p>", "<title> Domains “Governance” and “Coverage, Design & Organisation ”</title>", "<p> Mandatory enrolment of eligible patients was implemented in 8 (40%) cardiovascular<sup>##UREF##8##22##,##UREF##10##24##,##UREF##13##27##,##UREF##15##29##,##UREF##16##30##,##UREF##23##37##,##UREF##25##39##,##UREF##26##40##</sup> and 12 (46%) orthopaedic registries<sup>##UREF##28##42##,##UREF##29##43##,##UREF##32##46##,##UREF##34##48##,##UREF##36##50##,##UREF##37##51##,##UREF##41##55##,##UREF##42##56##,##UREF##45##59##,##UREF##46##60##,##UREF##48##62##,##UREF##50##64##</sup> (Table S2A and S2B). Few cardiovascular<sup>##UREF##7##21##,##UREF##10##24##,##UREF##13##27##,##UREF##15##29##,##UREF##21##35##, ####UREF##22##36##, ##UREF##23##37####23##37##,##UREF##25##39##,##UREF##26##40##</sup> and orthopaedic<sup>##UREF##28##42##, ####UREF##29##43##, ##UREF##30##44####30##44##,##UREF##32##46##,##UREF##39##53##,##UREF##40##54##,##UREF##47##61##, ####UREF##48##62##, ##UREF##49##63####49##63##,##UREF##51##65##</sup> registries have reported on their funding and few report on the patient informed consent process<sup>##UREF##10##24##,##UREF##11##25##,##UREF##13##27##,##UREF##15##29##,##UREF##17##31##,##UREF##19##33##, ####UREF##20##34##, ##UREF##21##35##, ##UREF##22##36##, ##UREF##23##37####23##37##,##UREF##25##39##,##UREF##26##40##,##UREF##28##42##,##UREF##30##44##,##UREF##32##46##,##UREF##34##48##,##UREF##36##50##,##UREF##40##54##,##UREF##46##60##,##UREF##49##63##,##UREF##50##64##</sup> (Table S3A and S3B). The number of participating hospitals per registry varied largely, with a median of 28 (IQR 17-89) hospitals for cardiovascular registries and 71 (IQR 42-116) hospitals for orthopaedic registries (Table S4A and S4B). The proportion of all eligible hospitals that participated in the registry (ie, hospital-level coverage) was only reported by 6 (30%) cardiovascular registries,<sup>##UREF##10##24##,##UREF##12##26##, ####UREF##13##27##, ##UREF##14##28####14##28##,##UREF##17##31##,##UREF##20##34##</sup> with a median hospital-level coverage of 100% (IQR 98%-100%) and by 9 (35%) orthopaedic registries,<sup>##UREF##30##44##, ####UREF##31##45##, ##UREF##32##46####32##46##,##UREF##34##48##,##UREF##38##52##,##UREF##40##54##,##UREF##46##60##,##UREF##50##64##,##UREF##51##65##</sup> also with a median hospital-level coverage of 100% (IQR 95%-100%) (Table S4A and S4B).</p>", "<p> In general, cardiovascular registries report on studies for which selected patient groups are included, so data on the total number of patients receiving an implant were reported by only 4 (20%) registries.<sup>##UREF##7##21##,##UREF##11##25##,##UREF##15##29##,##UREF##20##34##</sup> The median for stents was 12 395 (IQR 3985-201 647) and the median for valves was 2325 (IQR 861-10 479) (Table S4A and S4B). Given the regular publication of annual reports, the total and annual volume of implant procedures in orthopaedic registries was mostly reported; details were on both items was not available for 7 (27%) registries.<sup>##UREF##27##41##,##UREF##31##45##,##UREF##33##47##,##UREF##35##49##,##UREF##39##53##,##UREF##40##54##,##UREF##47##61##</sup> Overall, orthopaedic registries reported on a median of 120 408 (IQR 52 391-218 445) hip implants and a median of 102 649 (IQR 51 700-194 076) knee implants (Table S4A and S4B). Data linkage with other sources — mostly national clinical databases — was reported by 8 (40%) cardiovascular<sup>##UREF##7##21##,##UREF##10##24##,##UREF##13##27##,##UREF##15##29##,##UREF##20##34##,##UREF##22##36##,##UREF##23##37##,##UREF##25##39##</sup> and 14 (54%) orthopaedic registries.<sup>##UREF##28##42##,##UREF##30##44##, ####UREF##31##45##, ##UREF##32##46####32##46##,##UREF##34##48##,##UREF##36##50##,##UREF##38##52##,##UREF##40##54##,##UREF##41##55##,##UREF##46##60##,##UREF##48##62##, ####UREF##49##63##, ##UREF##50##64##, ##UREF##51##65####51##65##</sup></p>", "<p> Information was mostly provided on hospital and/or device-level, while in some cases also surgeon-level information was provided. There were more different types of implants in orthopaedic than in cardiovascular registries, shown by totals of 37 different manufacturers for knee implants and 63 for hip implants compared with 13 different manufacturers of valves and 11 of stents (Table S5A and S5B).</p>", "<title> Domain “Data Quality & Completeness”</title>", "<p> None of the cardiovascular registries reported patient/procedure-level data completeness (Table S6A and S6B). Techniques to handle missing data were described in only 1 cardiovascular registry (5%),<sup>##UREF##7##21##</sup> which applied a data completeness threshold (ie, a certain variable will only be analyzed if its completeness is ≥95%). Most (55%) cardiovascular registries<sup>##UREF##7##21##,##UREF##9##23##,##UREF##12##26##,##UREF##13##27##,##UREF##15##29##,##UREF##16##30##,##UREF##20##34##, ####UREF##21##35##, ##UREF##22##36##, ##UREF##23##37####23##37##,##UREF##26##40##</sup> reported on procedures to check the quality of their data, such as checking on the range and consistency of entries, and verification by audits or an external electronic tool.</p>", "<p> Patient/procedure-level completeness was reported by 16 (62%) orthopaedic registries,<sup>##UREF##28##42##, ####UREF##29##43##, ##UREF##30##44##, ##UREF##31##45##, ##UREF##32##46####32##46##,##UREF##34##48##,##UREF##36##50##,##UREF##38##52##, ####UREF##39##53##, ##UREF##40##54##, ##UREF##41##55####41##55##,##UREF##46##60##,##UREF##48##62##, ####UREF##49##63##, ##UREF##50##64##, ##UREF##51##65####51##65##</sup> which varied from 19% for hip prostheses in the Irish National Orthopaedic Register to 98%-99% for knee prostheses in the Danish Knee Arthroplasty Register. Both registries used data linkage with national patient databases to determine patient/procedure-level completeness (Table S6A and S6B). Techniques to handle missing data were clearly described by only 1 orthopaedic registry (4%),<sup>##UREF##36##50##</sup> which sent requests for missing data to each orthopaedic department once every three months. Almost half (46%) of the orthopaedic registries,<sup>##UREF##28##42##,##UREF##29##43##,##UREF##32##46##,##UREF##36##50##,##UREF##38##52##, ####UREF##39##53##, ##UREF##40##54##, ##UREF##41##55####41##55##,##UREF##46##60##,##UREF##49##63##, ####UREF##50##64##, ##UREF##51##65####51##65##</sup> reported that they implemented techniques for quality assurance of the data, which in the majority consisted of comparing registry data with national patient databases or implant databases.</p>", "<title> Reported Outcomes, Definitions, and Duration of Follow-up </title>", "<p> The number of peer-reviewed publications per registry in the period January 2013 – July 2021 varied, with a median of 11 (IQR 3-33) published articles among cardiovascular registries and 9 (IQR 2-45) among orthopaedic registries. A wide variety of outcomes as well as their definitions and durations of follow-up were reported by both cardiovascular and orthopaedic registries (Table S7A and S7B).</p>", "<p> The most frequently reported outcome in cardiovascular registries was mortality; reported by 18 (90%) registries.<sup>##UREF##7##21##, ####UREF##8##22##, ##UREF##9##23##, ##UREF##10##24####10##24##,##UREF##12##26##, ####UREF##13##27##, ##UREF##14##28##, ##UREF##15##29##, ##UREF##16##30##, ##UREF##17##31##, ##UREF##18##32##, ##UREF##19##33##, ##UREF##20##34##, ##UREF##21##35##, ##UREF##22##36##, ##UREF##23##37####23##37##,##UREF##25##39##,##UREF##26##40##</sup> Mortality was reported using 70 different time-points, from in-hospital mortality to mortality at 21 years, the majority of registries (80%) reported on 30-day mortality.<sup>##UREF##7##21##,##UREF##8##22##,##UREF##10##24##,##UREF##13##27##, ####UREF##14##28##, ##UREF##15##29##, ##UREF##16##30##, ##UREF##17##31##, ##UREF##18##32##, ##UREF##19##33##, ##UREF##20##34##, ##UREF##21##35##, ##UREF##22##36##, ##UREF##23##37####23##37##,##UREF##25##39##,##UREF##26##40##</sup> Major cardiovascular events (MACE) were reported as combined end-points by 8 (40%) registries,<sup>##UREF##7##21##,##UREF##13##27##, ####UREF##14##28##, ##UREF##15##29####15##29##,##UREF##18##32##,##UREF##22##36##,##UREF##23##37##,##UREF##26##40##</sup> but with 7 different combinations of complications included in this endpoint and 7 different time intervals with most (50%) registries reporting on 1-year MACE.<sup>##UREF##14##28##,##UREF##15##29##,##UREF##22##36##,##UREF##26##40##</sup> Reporting on other single outcomes also showed large variability, ranging from 3 to 40 outcome variables per registry (Table S7A and S7B).</p>", "<p> In orthopaedic registries, revision surgery (for any cause) was the most frequently reported outcome, reported by 20 (77%) registries.<sup>##UREF##28##42##, ####UREF##29##43##, ##UREF##30##44####30##44##,##UREF##32##46##,##UREF##34##48##,##UREF##36##50##, ####UREF##37##51##, ##UREF##38##52##, ##UREF##39##53##, ##UREF##40##54##, ##UREF##41##55##, ##UREF##42##56##, ##UREF##43##57##, ##UREF##44##58##, ##UREF##45##59##, ##UREF##46##60####46##60##,##UREF##48##62##,##UREF##49##63##,##UREF##51##65##</sup> It was mostly reported as the revision rate or cumulative revision risk but at 30 different time-points up to 25 years, with the most common end-point being the 1-year revision rate which was reported by 10 registries (38%).<sup>##UREF##28##42##,##UREF##29##43##,##UREF##32##46##,##UREF##36##50##, ####UREF##37##51##, ##UREF##38##52####38##52##,##UREF##42##56##,##UREF##45##59##,##UREF##46##60##,##UREF##52##66##</sup> Specific reasons for revision were reported by 19 (73%) registries,<sup>##UREF##28##42##, ####UREF##29##43##, ##UREF##30##44####30##44##,##UREF##32##46##,##UREF##34##48##,##UREF##36##50##, ####UREF##37##51##, ##UREF##38##52##, ##UREF##39##53##, ##UREF##40##54##, ##UREF##41##55##, ##UREF##42##56##, ##UREF##43##57####43##57##,##UREF##45##59##,##UREF##46##60##,##UREF##48##62##,##UREF##49##63##,##UREF##51##65##,##UREF##52##66##</sup> but these reasons for revision varied between registries (eg, infection, loosening, component failure, etc). Patient-reported outcome measurements (PROMs) were reported by 5 (19%) orthopaedic registries,<sup>##UREF##30##44##,##UREF##32##46##,##UREF##34##48##,##UREF##49##63##,##UREF##51##65##</sup> with a total of 8 different scores for knee surgery patients and 11 scores for hip surgery patients. All registries measuring PROMs reported pre-operative PROMs, but post-operative PROMs were measured at different time-points up to 10-years post-operatively. Other outcomes (eg, renal failure, hip dislocation, deep venous thrombosis, etc) were inconsistently reported by 13 (50%) registries,<sup>##UREF##30##44##,##UREF##32##46##,##UREF##34##48##,##UREF##36##50##,##UREF##37##51##,##UREF##40##54##, ####UREF##41##55##, ##UREF##42##56####42##56##,##UREF##44##58##,##UREF##46##60##,##UREF##48##62##,##UREF##49##63##,##UREF##51##65##</sup> the majority (77%) reported on mortality<sup>##UREF##30##44##,##UREF##36##50##,##UREF##37##51##,##UREF##41##55##,##UREF##42##56##,##UREF##44##58##,##UREF##46##60##,##UREF##48##62##,##UREF##49##63##,##UREF##51##65##</sup> (Table S7A and S7B).</p>", "<title> Domain “Safety & Performance”</title>", "<p> Public reporting on how feedback on eg, devices, hospitals, and surgeons is provided was reported by 3 (15%) cardiovascular registries<sup>##UREF##7##21##,##UREF##15##29##,##UREF##22##36##</sup> (Table S8A and S8B). Managerial procedures to detect individual hospitals or specific devices using an outlier performance analysis based on benchmark thresholds was reported by 1 (5%) cardiovascular registry, the British Cardiovascular Intervention Society registry (BCIS). The outlier was defined using funnel plots, with 2 and 3 standard deviations. Outlier results regarding the timing of treatment (to assess any delay before treatment is delivered) compared between hospitals, as well as adverse outcomes per hospital, were publicly available. However, outlier reports on patients’ survival data per hospital were only disclosed confidentially to each hospital. No outlier reports for specific implants were reported by cardiovascular registries.</p>", "<p> Public reporting on the frequency of feedback provided was reported by 14 (54%) orthopaedic registries.<sup>##UREF##28##42##, ####UREF##29##43##, ##UREF##30##44####30##44##,##UREF##32##46##,##UREF##34##48##,##UREF##36##50##,##UREF##39##53##,##UREF##41##55##,##UREF##44##58##,##UREF##46##60##,##UREF##48##62##,##UREF##49##63##,##UREF##51##65##,##UREF##52##66##</sup> Most registries report that they provide annual feedback, while 2 registries (the Irish National Orthopaedic Register and the Swiss national registry for hip and knee replacement) do so both annually and quarterly. The majority provided feedback both at the hospital level and for individual devices. Details of outlier procedures including statistical testing were reported by 8 (31%) registries, of which 3 reported solely on outlier devices,<sup>##UREF##45##59##,##UREF##46##60##,##UREF##52##66##</sup> 2 solely on outlier hospitals,<sup>##UREF##44##58##,##UREF##48##62##</sup> 1 on outlier devices and hospitals,<sup>##UREF##51##65##</sup> and 2 on outlier devices, hospitals, and surgeons.<sup>##UREF##36##50##,##UREF##49##63##</sup> Outlier procedures were mostly publicly available. No registries shared the same definition of an outlier (eg, above the 95% control limit in the funnel plot <italic toggle=\"yes\">versus </italic>revision rates of more than twice compared to the relevant group). Overall, in all annual reports, a total of 95 total hip arthroplasty (THA) component combinations, 3 THA cups, 2 THA stems, and 24 total knee arthroplasty (TKA) implants were identified by these 8 registries as outlier implants. Overall, registries all identified different outlier implants, with only 1 outlier implant (a THA component combination) identified by more than 1 registry.</p>" ]	[ "<title>Discussion</title>", "<p> In this systematic review we have evaluated structural and methodological characteristics as well as the data quality of 46 European cardiovascular and orthopaedic medical device registries, in an attempt to gain insight into the usability of these data sources for regulatory purposes. Medical device registries are potentially well suited for post-market surveillance as they may collect data from unselected patient populations and monitor safety and performance throughout the lifetime of specific devices. However, we found heterogeneity and incomplete transparency in quality items related to their structure and methodology, implying that it would be difficult currently for registries to agree upon common principles, to report the information needed by regulators to judge the quality of their data, and to collect and report comparable information across Europe.</p>", "<p> The European Union (EU) has regulatory requirements relating to the PMCF of medical devices.<sup>##UREF##53##67##, ####UREF##54##68##, ##UREF##55##69####55##69##</sup> As stated by the MDR in Article 83, manufacturers have to set up, document, maintain, and update a post-market surveillance system for each device, in which relevant data on the quality, performance, and safety of an implant are evaluated, directly after Conformité Européenne (CE) approval and throughout the entire expected lifetime of a device.<sup>##UREF##54##68##</sup> To allow for lifetime evaluation and benchmarking of implants, registries need clearly defined methods to detect outliers and to report safety concerns for specific implants, but these were reported by only 5% of the cardiovascular and 31% of the orthopaedic registries that were included in this systematic review. Even more, none of the registries used the same definition, making it difficult for manufacturers, regulators, but also patients to assess whether the device performs worse in all or only in some settings. Furthermore, four orthopaedic registries identified >100 components and combinations of implants as outliers, with only one outlier implant identified by more than one registry, which may partly result from the different definitions used from the fact that and that not all implants are used in all countries and/or regions and thereby included in the registry.</p>", "<p> Another way to enable benchmarking of implants across registries is to implement objective performance classification systems such as the Orthopaedic Data Evaluation Panel (ODEP). The ODEP rating provides benchmarks for orthopaedic prostheses (hip, knee, and shoulder implants) based on the number of years for which the product has been monitored and on the strength of the evidence provided by different data sources, including registry data, randomized controlled trials, peer-reviewed publications, podium presentations, and manufacturers’ in-house data sources.<sup>##UREF##56##70##,##UREF##57##71##</sup> The ODEP rating can be considered as an absolute benchmark to identify if implants meet the benchmark criteria, whereas others have suggested relative benchmark approaches within a given registry eg, comparing with the best implant construct<sup>##UREF##58##72##, ####UREF##59##73##, ##REF##25520423##74##, ##UREF##60##75####60##75##</sup> or with all other similar implants.<sup>##REF##23992139##8##</sup></p>", "<p> The MDR in Article 108 states that registries need to establish common principles, so that they can collect comparable information and thereby contribute to the independent evaluation of the long-term safety and performance of devices.<sup>##UREF##55##69##</sup> They need to capture the same outcomes, based on the same definitions and the same durations of follow-up, before they can be used to benchmark devices and pool data for early detection of safety concerns. Current European device registries do not meet these recommended principles, however, since our systematic review showed large heterogeneity between recorded outcomes, definitions of outcome variables, and time-points for follow-up. Comparable findings were reported by a recent study of the quality of cardiac registries across all subspecialties of cardiac care, in which several registries gave explicit definitions for only a low percentage of variables.<sup>##REF##34517724##76##</sup> Similar findings were also observed for orthopaedic registries, with considerable heterogeneity in captured outcomes and definitions used for revision procedures.<sup>##UREF##61##77##, ####REF##35446260##78##, ##REF##29598886##79####29598886##79##</sup> Another aspect to consider before outcomes across registries can be pooled, is whether registries use the same implant library to classify implants by relevant device characteristics.<sup>##REF##31312521##80##</sup> The European Medical Device nomenclature is a generic classification intended for this purpose, but more detailed libraries are used by registries to capture their specialty-specific characteristics as well. For orthopaedic devices for instance, the International Society of Arthroplasty Registers (ISAR) has proposed a global registry library in 2019 to ensure the same classification of orthopaedic devices across registries.<sup>##REF##31312521##80##</sup> Also, this problem of using different implant libraries can be solved if registries document the unique device identifier for each implant.</p>", "<p> In combination, these findings highlight the importance of international agreement on definitions of data and outcomes, as well as time-points used for measuring outcomes within registries. This might be reached by developing consensus frameworks to achieve common datasets that must be captured by registries<sup>##REF##34351420##81##</sup> such as the clinical outcome endpoints in heart failure trials created by the European Society of Cardiology Heart Failure Association, the common dataset for acute coronary syndromes and percutaneous coronary interventions created by the EuroHeart data science group, the benchmarking document for hip and knee arthroplasties by the ISAR, and the common dataset for demographics and implant survival following THA by the Nordic Arthroplasty Register Association.<sup>##REF##23787718##82##, ####REF##35380662##83##, ##REF##19513887##84##, ##UREF##62##85####62##85##</sup></p>", "<p> In addition to these common data specifications, the IMDRF states that registries should include at least 95% of all patients receiving a device, to have sufficiently robust high-quality data to inform regulatory decisions.<sup>##UREF##0##1##</sup> As shown in our systematic review, patient/procedure-level completeness was not reported publicly by any of the cardiovascular registries, but it was available for the majority (65%) of orthopaedic registries. Of the latter only 11 of 13 orthopaedic registries reported recent data (2018 and beyond) that reached a patient/procedure-level completeness of 95% or above. Similar findings were shown for European THA and TKA registries by Lübbeke et al, with 67% reporting patient-level completeness,<sup>##REF##29598886##79##</sup> and for cardiovascular registries, of which the majority had data completeness below 50% or not available.<sup>##REF##34517724##76##</sup></p>", "<p> Making it mandatory to enroll all patients in a registry would help to increase patient/procedure-level completeness.<sup>##REF##30269654##86##</sup> In this systematic review, however, none of the mandatory cardiovascular registries and only 75% of the mandatory orthopaedic registries reported patient/procedure-level completeness. Since completeness of patients is often checked against electronic medical records, it could also help to automatically populate certain data fields regarding patient and implant characteristics from the electronic medical records, so that less information needs to be entered by medical professionals, thereby preventing data loss as well as double data entry. However, rather than considering single items that on their own will contribute to higher quality data, the quality of the evidence provided by registry data is ultimately determined by the combination of multiple factors.</p>", "<p> The strength of this systematic review is its’ comprehensiveness. We updated the search strategy used by Niederländer et al,<sup>##REF##24075007##18##</sup> and expanded it with support from an experienced librarian. In addition, experts in the field (cardiologists and orthopaedic surgeons) were consulted, resulting in the addition of two cardiovascular registries. Furthermore, European orthopaedic registries listed on the EFORT – NORE-website were checked for their eligibility, resulting in an additional six orthopaedic registries and the completeness of included European cardiovascular registries as well as orthopaedic registries was checked by experts in the relevant field. Thus the likelihood of missing relevant registries is very low. However, some limitations remain. Firstly, we relied on publicly available information regarding registries’ structure and methodological characteristics as well as outcomes, which means that some items that we did not find may have been available if we had approached each registry directly. Therefore, the regulatory utility of the data generated by some registries may be higher than that found by this analysis. Secondly, this systematic review only focuses on cardiovascular and orthopaedic registries, because they represent the most commonly used high-risk medical devices aiming to reduce patients’ mortality and morbidity.<sup>##REF##34760284##87##</sup> However, the items used to determine the regulatory utility of these registries would also be applicable to other (high-risk) medical device registries.</p>", "<p> An overview of publicly available information, as summarized in this systematic review, demonstrates the transparency of European cardiovascular and orthopaedic medical device registries and what information could already be available for regulators. We have proposed characteristics that can be used to interpret whether the data provided by registries are of sufficient quality, and we have identified registries that had an active/accessible website at the time of study selection and/or that published at least one paper or annual report between 2013 and 2021. No data were collected since 2018 were available for 35% of these registries (shown in Table), and so there is a chance that some are no longer active and thereby would not be able to contribute evidence for regulatory purposes. However, the cut-off point to define an active registry was arbitrary and we therefore highlighted that the median of items reported across all domains among active registries was higher than items reported across all registries combined (ie, both “active” and “in-active” labelled registries).</p>" ]	[ "<title>Conclusion</title>", "<p> This systematic review showed large heterogeneity and incomplete public transparency related to structure and methodological characteristics of the registries that were reviewed, which implies that it would be difficult to combine and judge the regulatory utility of data reported by registries. Effort is needed from registries to agree upon a minimum set of quality criteria that all registries should publicly report to provide information needed by regulators to judge the quality of registry data and use them for medical device safety surveillance. Developing comprehensive and trustworthy medical device registries will be tremendously valuable, not only for manufacturers to meet the requirements of the MDR for PMCF of their devices, but also for healthcare professionals and patients to support evidence-based choices of devices and contribute to their long-term safety and efficacy.</p>" ]	[ "<p>\n<bold>Background:</bold> The European Union Medical Device Regulation (MDR) requires manufacturers to undertake post-market clinical follow-up (PMCF) to assess the safety and performance of their devices following approval and Conformité Européenne (CE) marking. The quality and reliability of device registries for this Regulation have not been reported. As part of the Coordinating Research and Evidence for Medical Devices (CORE-MD) project, we identified and reviewed European cardiovascular and orthopaedic registries to assess their structures, methods, and suitability as data sources for regulatory purposes.\n</p>", "<p>\n<bold>Methods:</bold> Regional, national and multi-country European cardiovascular (coronary stents and valve repair/replacement) and orthopaedic (hip/knee prostheses) registries were identified using a systematic literature search. Annual reports, peer-reviewed publications, and websites were reviewed to extract publicly available information for 33 items related to structure and methodology in six domains and also for reported outcomes. </p>", "<p>\n<bold>Results:</bold> Of the 20 cardiovascular and 26 orthopaedic registries fulfilling eligibility criteria, a median of 33% (IQR: 14%-71%) items for cardiovascular and 60% (IQR: 28%-100%) items for orthopaedic registries were reported, with large variation across domains. For instance, no cardiovascular and 16 (62%) orthopaedic registries reported patient/ procedure-level completeness. No cardiovascular and 5 (19%) orthopaedic registries reported outlier performances of devices, but each with a different outlier definition. There was large heterogeneity in reporting on items, outcomes, definitions of outcomes, and follow-up durations. </p>", "<p>\n<bold>Conclusion:</bold> European cardiovascular and orthopaedic device registries could improve their potential as data sources for regulatory purposes by reaching consensus on standardised reporting of structural and methodological characteristics to judge the quality of the evidence as well as outcomes.</p>", "<p>\n<bold>Citation:</bold> Hoogervorst LA, Geurkink TH, Lübbeke A, et al. Quality and utility of European cardiovascular and orthopaedic registries for the regulatory evaluation of medical device safety and performance across the implant lifecycle: a systematic review. <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7648. doi:10.34172/ijhpm.2023.7648</p>" ]	[ "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>", "<title>Funding</title>", "<p> This work was supported by the by the European Union’s Horizon 2020 Research and Innovation Programme (grant number 965246) and was part of the CORE-MD project.</p>", "<title>Disclaimers</title>", "<p> For Paul Piscoi: the information and views set out in this article are those of the authors and do not necessarily reflect the official opinion of the European Commission.</p>", "<title>\nSupplementary files\n</title>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><statement><p>\nPRISMA Flowchart – (A) Cardiovascular and (B) Orthopaedic registries. Abbreviations: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; N/A, not reported.</p></statement></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><statement><p>\nReported Items by Cardiovascular (A) and Orthopaedic (B) Registries in Each Domain Indicating the Variation in Reporting Across Registries (with the lower end of the boxes representing the first quartile and the higher upper end the third quartile; the solid lines in the boxes representing the median values (if not visible the solid lines are at the same level as the 1st or 3rd quartile); the T-shaped whiskers the maximum or minimum values (without outliers); the individual points representing outlier values).</p></statement></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><statement><p>\nReported Items by the Active Labelled Cardiovascular (A) and Orthopaedic (B) Registries in Each Domain Indicating the Variation in Reporting Across Registries (with the lower end of the boxes representing the 1st quartile and the higher upper end the 3rd quartile; the solid lines in the boxes representing the median values (if not visible the solid lines are at the same level as the first or third quartile); the T-shaped whiskers the maximum or minimum values (without outliers); the individual points representing outlier values).</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table</label><caption><title>Recent Activity of Included Registries\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\"> </td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Published Paper(s) Containing Registries’ Data (2018 and Beyond) </bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Published Annual Report(s) Containing Registries’ Data (2018 and Beyond)</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Active Registry</bold>\n</td></tr><tr style=\"background-color:#c3c3c3\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Cardiovascular registries – combined </td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">5 out of 7 (71%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">BCIS</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">East Denmark Heart Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">German Society for Thoracic and Cardiovascular Surgery</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Polish National Database of Cardiac Surgery Procedures</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Portuguese National Registry of Intervention Cardiology</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Spanish Cardiac Catheterization and Coronary Intervention Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Western Denmark Heart Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#c3c3c3\"><td colspan=\"3\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">Cardiovascular registries – stents</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2 out of 2 (100%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Polish National Percutaneous Coronary Intervention Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Swedish Coronary Angiography and Angioplasty Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#c3c3c3\"><td colspan=\"3\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">Cardiovascular registries – valves </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4 out of 11 (36%)</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Quality Assurance Registry on Aortic Valve Replacement</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Austrian-TAVI Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Belgian TAVI Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Czech TAVI Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">FinnValve Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">FRANCE-TAVI Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">German Aortic Valve Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Polish Registry of TAVI</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Spanish Registry of Heart Valves Repair</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Swedish Transcatheter Cardiac Intervention Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Swiss TAVI Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#c3c3c3\"><td colspan=\"3\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">Orthopaedic arthroplasty registries – combined </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14 out of 20 (70%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Croatian Register of Endoprothesis</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">German Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Finnish Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Irish National Orthopaedic Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Lithuanian Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Dutch Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Hungarian Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Norwegian Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Nordic Arthroplasty Register Association</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National Joint Registry for England, Wales, Northern Ireland, the Isle of Man, and the States of Guernsey</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Belgian National Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Catalan Arthroplasty Register </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">National Arthroplasty Registry of Slovenia </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Italian Arthroplasty Registry</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Emilia-Romagna Region Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Romanian National Arthroplasty Register </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Portuguese National Arthroplasty Register </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Scottish Arthroplasty Project Joint Registry </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Slovakian National Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Swiss Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#c3c3c3\"><td colspan=\"3\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">Orthopaedic arthroplasty registries – hips </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3 out of 4 (75%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Czech Republic Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">French Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Danish Hip Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Swedish Hip Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr style=\"background-color:#c3c3c3\"><td colspan=\"3\" style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\">Orthopaedic arthroplasty registries – knees </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2 out of 2 (100%)</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Danish Knee Arthroplasty Register</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Swedish Knee Arthroplasty Register </td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Yes</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>\n<bold>Box 1.</bold> Description of the Items in Each Domain That Were Extracted for Each Registry\n</title><p>\n<bold>Identification</bold>\n</p><p> 1. Class of device (cardiovascular registries – stents/cardiovascular registries – valves/cardiovascular registries – combined)/(orthopaedic arthroplasty registries – combined/orthopaedic arthroplasty registries – hips/orthopaedic arthroplasty registries – knees)</p><p> 2. Name of registry</p><p> 3. Initial motivation/goal to set up the registry</p><p> 4. Country (country or countries in which the registry is conducted)</p><p> 5. Design (regional/national/multi-country)</p><p> 6. Website (available yes/no)</p><p>\n<bold>Maturity</bold>\n</p><p> 7. Starting year (year of first patient/procedure included)</p><p> 8. First annual report (year of publication)</p><p> 9. Most recent (or last, if registry no longer active) annual report (year of publication)</p><p>\n<bold>Governance</bold>\n</p><p> 10. Mandatory (if mandatory for surgeons/hospitals to submit to the registry; yes/no)</p><p> 11. Patients’ consent (patients’ consent required before entering their data to the registry; required/not-required)</p><p> 12. Funding (public/private/both)</p><p> 13. Who can access the data and see results?</p><p> 14. Privacy regulation for patients’ identifiable information (privacy regulation reported as implemented: yes/no? And if yes: how?)</p><p>\n<bold>Coverage, design & organisation</bold>\n</p><p> 15. Number of participating hospitals and % of hospital-level coverage (defined as number of participating hospitals relative to the total number of eligible hospitals)</p><p> 16. Number of patients/procedures (cumulative total in registry)</p><p> 17. Number of selected patients/procedures in study population (if cumulative total in registry is not reported)</p><p> 18. Annual number of patients/procedures in registry</p><p> 19. Data capture and collection method (eg, electronic/manual/barcodes-industry/surgeon-reported)</p><p> 20. Method of access to registry for users/members (eg, dashboard/real-time/secure server)</p><p> 21. Level of information provided (data is reported at hospital/medical device/surgeon level)</p><p> 22. Data linkage with other sources (eg, registry data is linked to hospital statistics/manufacturer vigilance data/national competent authority on medical devices)</p><p>\n<bold>Data quality & completeness</bold>\n</p><p> 23. Quality assurance system defined/quality check of data (eg, data verification)</p><p> 24. Missing data for patients’ characteristics reported (%) (eg, BMI, ASA classification, gender)</p><p> 25. Methods for handling missing data described</p><p> 26. Data completeness reported at patient/procedure-level (%)</p><p>\n<bold>Safety & performance</bold>\n</p><p> 27. Frequency of feedback provided to surgeons/hospitals (eg, annually/quarterly)</p><p> 28. Level of feedback information provided (eg, hospital/medical device/surgeon level)</p><p> 29. Feedback time period (the duration of observation before assessment of performance is possible)</p><p> 30. Outlier reports procedures (the type of outlier reports or procedures a registry has established and published methods to define outlier performance)</p><p> 31. Accessibility of outlier results (eg, publicly available or only accessible for individual hospitals/surgeons/members)</p><p> 32. Definition of an outlier (eg, using funnel plots)</p><p> 33. Number of outliers identified (has this registry identified and published details of any specific hospitals/medical devices/surgeons with outlier performance?)</p><p>-----------------</p><p> Abbreviations: BMI, body mass Index; ASA, American Society of Anesthesiologists.</p></sec></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"Suppl1\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 1. Literature Search Strategy.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl2\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 2. Tables S1A-S8A.\n</p></caption></supplementary-material>", "<supplementary-material id=\"Suppl3\" position=\"float\" content-type=\"local-data\"><caption><p>\nSupplementary file 3. Tables S1B-S8B.\n</p></caption></supplementary-material>" ]	[ "<table-wrap-foot><fn><p> Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; BCIS, British Cardiovascular Intervention Society.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7648-g001\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7648-g002\" position=\"float\"/>", "<graphic xlink:href=\"ijhpm-12-7648-g003\" position=\"float\"/>" ]	[ "<media xlink:href=\"ijhpm-12-7648-s001.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7648-s002.pdf\"><caption><p>Click here for additional data file.</p></caption></media>", "<media xlink:href=\"ijhpm-12-7648-s003.pdf\"><caption><p>Click here for additional data file.</p></caption></media>" ]	[{"label": ["1"], "mixed-citation": [" International Medical Device Regulators Forum (IMDRF). Principles of International System of Registries Linked to Other Data Sources and Tools. September 30, 2016. "], "uri": ["https://www.imdrf.org/sites/default/files/docs/imdrf/final/technical/imdrf-tech-160930-principles-system-registries.pdf"]}, {"label": ["2"], "mixed-citation": [" AHRQ Methods for Effective Health Care. In: Gliklich RE, Leavy MB, Dreyer NA, eds. Registries for Evaluating Patient Outcomes: A User\u2019s Guide. Rockville, MD: Agency for Healthcare Research and Quality; 2020. "]}, {"label": ["3"], "mixed-citation": [" International Medical Device Regulators Forum (IMDRF). Tools for Assessing the Usability of Registries in Support of Regulatory Decision-Making. March 27, 2018. "], "uri": ["https://www.imdrf.org/sites/default/files/docs/imdrf/final/technical/imdrf-tech-180327-usability-tools-n46.pdf"]}, {"label": ["5"], "mixed-citation": [" Medical Device Coordination Group, European Commission. Regulation (EU) 2017/745: Clinical Evidence Needed for Medical Devices Previously CE Marked Under Directives 93/42/EEC or 90/385/EEC. A Guide for Manufacturers and Notified Bodies. 2020. "], "uri": ["https://ec.europa.eu/health/system/files/2020-09/md_mdcg_2020_6_guidance_sufficient_clinical_evidence_en_0.pdf"]}, {"label": ["9"], "person-group": ["\n"], "surname": ["Campbell", "Wilkinson", "Marlow", "Sheldon"], "given-names": ["B", "J", "M", "M"], "article-title": ["Generating evidence for new high-risk medical devices"], "source": ["BMJ Surg Interv Health Technol"], "year": ["2019"], "volume": ["1"], "issue": ["1"], "fpage": ["e000022"], "pub-id": ["10.1136/bmjsit-2019-000022"]}, {"label": ["13"], "mixed-citation": [" Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). Annual Report 2007. "], "uri": ["https://aoanjrr.sahmri.com/documents/10180/42612/Annual+Report+2007"]}, {"label": ["14"], "mixed-citation": [" DePuy Synthes. DePuy Synthes ASR"], "sup": ["TM"], "uri": ["https://www.jnjmedicaldevices.com/en-US/depuy-synthes/support-resources/asr-recall"]}, {"label": ["21"], "mixed-citation": [" British Cardiovascular Intervention Society. "], "uri": ["https://www.bcis.org.uk/"]}, {"label": ["22"], "mixed-citation": [" East Denmark Heart Registry. "]}, {"label": ["23"], "mixed-citation": [" German Society for Thoracic and Cardiovascular Surgery. "], "uri": ["https://www.dgthg.de/"]}, {"label": ["24"], "mixed-citation": [" Polish National Database of Cardiac Surgery Procedures. "], "uri": ["https://krok.csioz.gov.pl/krok/"]}, {"label": ["25"], "mixed-citation": [" Portuguese National Registry of Intervention Cardiology. "], "uri": ["https://www.apic.pt/"]}, {"label": ["26"], "mixed-citation": [" Spanish Cardiac Catheterization and Coronary Intervention Registry. "]}, {"label": ["27"], "mixed-citation": [" Western Denmark Heart Registry. "]}, {"label": ["28"], "mixed-citation": [" Polish National Percutaneous Coronary Intervention Registry. "], "uri": ["https://www.orpki.cm-uj.krakow.pl/"]}, {"label": ["29"], "mixed-citation": [" Swedish Coronary Angiography and Angioplasty Registry. "], "uri": ["https://www.ucr.uu.se/swedeheart/start-scaar/"]}, {"label": ["30"], "mixed-citation": [" Quality Assurance Registry on Aortic Valve Replacement. "]}, {"label": ["31"], "mixed-citation": [" Austrian-TAVI Registry. "], "uri": ["https://www.tavi.at/"]}, {"label": ["32"], "mixed-citation": [" Belgian TAVI Registry. "]}, {"label": ["33"], "mixed-citation": [" Czech TAVI Registry. "]}, {"label": ["34"], "mixed-citation": [" FinnValve Registry. "]}, {"label": ["35"], "mixed-citation": [" FRANCE-TAVI Registry. "]}, {"label": ["36"], "mixed-citation": [" German Aortic Valve Registry. "], "uri": ["https://www.aortenklappenregister.de/"]}, {"label": ["37"], "mixed-citation": [" Polish Registry of Transcatheter Aortic Valve Implantation. "]}, {"label": ["38"], "mixed-citation": [" Spanish Registry of Heart Valves Repair. "]}, {"label": ["39"], "mixed-citation": [" Swedish Transcatheter Cardiac Intervention Registry. "], "uri": ["https://www.ucr.uu.se/swedeheart/start-swentry/"]}, {"label": ["40"], "mixed-citation": [" Swiss TAVI Registry. "], "uri": ["https://www.swisstavi.ch/"]}, {"label": ["41"], "mixed-citation": [" Croatian Register of endoprothesis. "]}, {"label": ["42"], "mixed-citation": [" German Arthroplasty Register. "], "uri": ["https://www.eprd.de/de/"]}, {"label": ["43"], "mixed-citation": [" Finnish Arthroplasty Register. "], "uri": ["https://www.thl.fi/far/"]}, {"label": ["44"], "mixed-citation": [" Irish National Orthopaedic Register. "], "uri": ["https://www.noca.ie/audits/irish-national-orthopaedic-register/"]}, {"label": ["45"], "mixed-citation": [" Lithuanian Arthroplasty Register. "], "uri": ["https://lsed.lt/"]}, {"label": ["46"], "mixed-citation": [" Dutch Arthroplasty Register. "], "uri": ["https://www.lroi.nl/"]}, {"label": ["47"], "mixed-citation": [" Hungarian Arthroplasty Register. "], "uri": ["https://www.ortopedtarsasag.hu/"]}, {"label": ["48"], "mixed-citation": [" Norwegian Arthroplasty Register. "], "uri": ["https://nrlweb.ihelse.net/"]}, {"label": ["49"], "mixed-citation": [" Nordic Arthroplasty Register Association. "]}, {"label": ["50"], "mixed-citation": [" National Joint Registry for England W, Northern Ireland, the Isle of Man, and the States of Guernsey. "], "uri": ["https://www.njrcentre.org.uk/"]}, {"label": ["51"], "mixed-citation": [" Belgian National Arthroplasty Register. "], "uri": ["https://www.ehealth.fgov.be/nl/egezondheid/beroepsbeoefenaars-in-de-gezondheidszorg/qermidorthopride/"]}, {"label": ["52"], "mixed-citation": [" Catalan Arthroplasty Register. "]}, {"label": ["53"], "mixed-citation": [" National Arthroplasty Registry of Slovenia. "], "uri": ["https://www.ob-valdoltra.si/"]}, {"label": ["54"], "mixed-citation": [" Italian Arthroplasty Registry. "], "uri": ["https://riap.iss.it/riap/it/"]}, {"label": ["55"], "mixed-citation": [" Emilia-Romagna Region Arthroplasty Register. "], "uri": ["https://www.ior.it/en/curarsi-al-rizzoli/register-orthopaedic-prosthetic-implants/"]}, {"label": ["56"], "mixed-citation": [" Romanian National Arthroplasty Register. "], "uri": ["https://www.rne.ro/"]}, {"label": ["57"], "mixed-citation": [" Portuguese National Arthroplasty Register. "], "uri": ["https://www.rpa.spot.pt/"]}, {"label": ["58"], "mixed-citation": [" Scottish Arthroplasty Project Joint Registry. "], "uri": ["https://www.arthro.scot.nhs.uk/"]}, {"label": ["59"], "mixed-citation": [" Slovakian National Arthroplasty Register. "], "uri": ["https://sar.mfn.sk/"]}, {"label": ["60"], "mixed-citation": [" Swiss Arthroplasty Register. "], "uri": ["https://www.siris-implant.ch/"]}, {"label": ["61"], "mixed-citation": [" Czech Republic Arthroplasty Register. "], "uri": ["https://www.ksrzis.cz/"]}, {"label": ["62"], "mixed-citation": [" Danish Hip Arthroplasty Register. "], "uri": ["https://www.dhr.dk/"]}, {"label": ["63"], "mixed-citation": [" Swedish Hip Arthroplasty Register. "], "uri": ["https://shpr.registercentrum.se/"]}, {"label": ["64"], "mixed-citation": [" Danish Knee Arthroplasty Register. "], "uri": ["https://www.danishhealthdata.com/find-health-data/Dansk-Knaealloplastik-Register/"]}, {"label": ["65"], "mixed-citation": [" Swedish Knee Arthroplasty Register. "], "uri": ["https://www.myknee.se/"]}, {"label": ["66"], "mixed-citation": [" French Arthroplasty Register. "], "uri": ["https://www.sofcot.fr/"]}, {"label": ["67"], "mixed-citation": [" Medical Device Coordination Group, European Commission. Post-Market Clinical Follow-Up (PMCF) Plan Template. A Guide for Manufacturers and Notified Bodies. 2020. "], "uri": ["https://ec.europa.eu/health/system/files/2020-09/md_mdcg_2020_7_guidance_pmcf_plan_template_en_0.pdf"]}, {"label": ["68"], "mixed-citation": [" Medical Device Coordination Group, European Commission. MDR \u2013 Article 83 \u2013 Post-Market Surveillance System of the Manufacturer. "], "uri": ["https://www.medical-device-regulation.eu/tag/mdr-article-83-post-market-surveillance-system-of-the-manufacturer/"]}, {"label": ["69"], "mixed-citation": [" Medical Device Coordination Group, European Commission. MDR \u2013 Article 108 \u2013 Device Registers and Databanks. "], "uri": ["https://www.medical-device-regulation.eu/tag/mdr-article-108/"]}, {"label": ["70"], "mixed-citation": [" Orthopedic Data Evaluation Panel (ODEP). Introducing ODEP. "], "uri": ["https://www.odep.org.uk/ODEPExplained/IntroductiontoODEP.aspx"]}, {"label": ["71"], "mixed-citation": [" Orthopedic Data Evaluation Panel (ODEP). Data Sources and Reliability. "], "uri": ["https://www.odep.org.uk/methodology/data-sources-and-reliability/"]}, {"label": ["72"], "person-group": ["\n"], "surname": ["Wyatt", "Frampton", "Whitehouse", "Deere", "Sayers", "Kieser"], "given-names": ["M", "C", "M", "K", "A", "D"], "article-title": ["Benchmarking total hip replacement constructs using noninferiority analysis: the New Zealand joint registry study"], "source": ["BMC MusculoskeletDisord"], "year": ["2021"], "volume": ["22"], "issue": ["1"], "fpage": ["719"], "pub-id": ["10.1186/s12891-021-04602-0"]}, {"label": ["73"], "person-group": ["\n"], "surname": ["Deere", "Whitehouse", "Porter", "Blom", "Sayers"], "given-names": ["KC", "MR", "M", "AW", "A"], "article-title": ["Assessing the non-inferiority of prosthesis constructs used in hip replacement using data from the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man: a benchmarking study"], "source": ["BMJ Open"], "year": ["2019"], "volume": ["9"], "issue": ["4"], "fpage": ["e026685"], "pub-id": ["10.1136/bmjopen-2018-026685"]}, {"label": ["75"], "person-group": ["\n"], "surname": ["Deere", "Whitehouse", "Porter", "Blom", "Sayers"], "given-names": ["KC", "MR", "M", "AW", "A"], "article-title": ["Assessing the non-inferiority of prosthesis constructs used in total and unicondylar knee replacements using data from the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man: a benchmarking study"], "source": ["BMJ Open"], "year": ["2019"], "volume": ["9"], "issue": ["4"], "fpage": ["e026736"], "pub-id": ["10.1136/bmjopen-2018-026736"]}, {"label": ["77"], "person-group": ["\n"], "surname": ["Liebs", "Splietker", "Hassenpflug"], "given-names": ["TR", "F", "J"], "article-title": ["Is a revision a revision? An analysis of national arthroplasty registries\u2019 definitions of revision"], "source": ["Clin OrthopRelat Res"], "year": ["2015"], "volume": ["473"], "issue": ["11"], "fpage": ["3421"], "lpage": ["3430"], "pub-id": ["10.1007/s11999-015-4255-4"]}, {"label": ["85"], "mixed-citation": [" International Society of Arthroplasty Registries (ISAR). International Prosthesis Benchmarking Working Group Guidance Document: Hip and Knee Arthroplasty Devices. 2018. "], "uri": ["https://www.isarhome.org/publications"]}]	{ "acronym": [], "definition": [] }	87	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Jul 18; 12:7648	oa_package/e0/84/PMC10702370.tar.gz
PMC10702371	37579361	[]	[]	[]	[]	[]	[ "<p>Lassa and colleagues’ study is a strong commentary on the biomedical hegemony and professional monopoly of medical doctors in the policy landscape of the Global Fund in Nigeria. Situating this critical dimension of professional power within wider scholarship of power and governance of global health initiatives (such as the Global Fund), in this comment, I put forth two core arguments. I call for a relational perspective of power in a dynamic policy space that the Fund characterises. I argue that a systems-view analysis of power requires a thorough examination of subsystems, how they interact, and the diverse forms of power—individual agentic, ideational, and structural—and the mechanisms through which power is wielded. The lens of governmentality allows linking individual (expertise and practices) with institutional regimes and social practices these enable; and in examining the interface of local/ sub-national, national, and global within which policy formulation and implementation occurs.</p>", "<p>\n<bold>Citation:</bold> Kapilashrami A. Situating biomedical and professional monopoly at the intersections of structural, ideational and agentic power: Comment on \"Power dynamics among health professionals in Nigeria: a case study of the global fund policy process.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8019. doi:10.34172/ijhpm.2023.8019</p>" ]	[ "<p> The starting premise of Lassa et al<sup>##REF##35461207##1##</sup> is that policy failures result, in part, from the absence of ‘systems thinking’ and a multi-disciplinary approach that are necessary for problem solving. A core deterrent to the use of systems thinking the authors argue is the concentration of power in “the hands of a few actors, such as medical doctors,” and the hegemony of the biomedical paradigm that leads to policy failure. So, in order to uncover the “more disruptive effects” of power visible in policy failure, authors establish an urgency around generating a better understanding of various forms of power (and in effect its distribution and exercise). Such analysis of power is a well-acknowledged gap in studies examining global health institutions, especially those with significant influence in global agenda setting, albeit research on Global Fund to fight AIDS, tuberculosis and malaria (or Global Fund), GAVI and Gates Foundation from nearly a decade ago, including from the author, had at its heart the analysis of power and its distribution in the country-level and global governance of these initiatives.<sup>##REF##23144229##2##, ####REF##24499023##3##, ##REF##25203250##4##, ##REF##25156323##5##, ##REF##24502449##6####24502449##6##</sup></p>", "<p> Examining accounts of 34 in-country staff of organisations involved with Global Fund activities, Lassa et al reveal multiple sources of biomedical dominance in the policy process that establish the monopoly of medical profession in policy formulation and implementation within the Global Fund’s in-country governance. These include the dominance of medical or public health doctors in positions that drive the proposal writing and implementation process and their prominence in the Nigerian health system as well as in the international organisations (FHI-360) that constitute the civil society space in HIV/AIDS. Authors argue that medical doctors exercise this power and influence over Global Fund’s processes by virtue of their biomedical/public health training that places them in an authoritative position in relation to other stakeholders when considering evidence or developing policy solutions. This is enabled by the biomedical bias inherent in both the national health systems as well as critical governance mechanisms of the Fund such as the technical review panels. For instance, authors highlight preference for biomedical interventions, such as clinical testing and antiretroviral treatments, and epidemiological evidence that dominated in meetings discussing content of proposals and distanced stakeholders who did not have biomedical training. Authors also highlight the prescriptive nature of the Global Fund processes that made alignment to country roadmaps challenging, and the crucial role of consultants with medical expertise in proposal writing and achieving such alignment. Describing the grant application development processes within the Fund governance,<sup>##REF##23144229##2##,##REF##22239445##7##</sup> I have previously highlighted how individuals regarded as having the ability to work in the context of extensive and complex application procedures became instrumental to successful bids and applications, and were hired as consultants to take on much of the grant preparation process. These studies examine practices of consultants and their embeddedness in elite networks but insufficiently interrogate disciplinary training as source of their professional power, which is a specific contribution of Lassa and colleagues’ study.</p>", "<p> In discussing the findings, the authors emphasise discursive power, and draw on the sociology of professions to examine these power dynamics among professionals. Drawing on sociological works of Freidson and Shiffman, they argue that professional monopoly of medical professionals is achieved through occupational hierarchy established through a colonial ‘professional bureaucrat model’ dominant in the public health sector in Nigeria. Such model places medical professionals at the helm of public (and private) sector institutions, and in the driving seat for agenda setting and policy development. The <italic toggle=\"yes\">productive</italic> power exercised in deliberative processes is combined with the <italic toggle=\"yes\">structural</italic> power through which Global Fund mechanisms invoke conformance and alignment with Global Fund priorities to maintain such professional monopoly and hierarchy.</p>", "<p> Although the paper does not investigate the various institutional and interpersonal consequences of such dominance, authors suggest that such assertive dominance in proposal writing potentially silences alternate views and expertise (for eg, social sciences and other disciplines or embodied knowledge of patients) and disregards or conceals the operational challenges. Notably, authors evidence low community uptake of medical supplies and resulting high wastage of resources (equal to 35 tons of expired HIV commodities at the central and state medical stores) documented in the audit reports. Elsewhere, I have illustrated how such dominance not only silences alternative views but co-opts and depoliticises them. Taking example of embodied movements such as networks of people living with HIV, I discussed how receiving funds from such global-local assemblages (characterising the Fund regime in India) undermines grassroots rights-focused advocacy, and reproduces mainstream discourses on technocratic ‘magic bullet’ solutions for complex socially determined health problems.</p>", "<p> Lassa et al study generates useful insights into professional (biomedical) hegemony within policy processes. However, there are few areas that warrant further attention and investigation.</p>", "<p> First relates to the relational aspect of power in a dynamic policy space such as the Fund governance and the national health <italic toggle=\"yes\">systems</italic>. Previous assessments of these policy spaces reveal these as contested sites characterised by multiple and often conflicting interests, shifting allegiance, strategic brokering of alliances and resources, as well as of practices that effectively conceal power and sanitise narratives to align the reporting structures of the ‘protocol.’<sup>##REF##23144229##2##,##REF##25203250##4##,##REF##29537338##8##</sup> Such dynamic policy spaces establish the importance of seeing “sources of power as relational and context-dependent, rather than as fixed possessions or properties of actors”<sup>##REF##18664526##9##</sup> (p. 364) derived from technical and professional expertise alone. This context also calls for interrogating these sites for the resistance and friction created by the dominance of global and national elites and how civil societies, other professions and embodied health movements (for eg, people living with HIV networks) negotiate spaces, influence agendas, and are transformed in the process. Part of this contestation process is an ongoing negotiation of ideas around how problems and solutions are framed and presentation of these frames or narratives to both internal and external audiences to instigate desired action.<sup>##REF##17933652##10##</sup></p>", "<p> In examining health systems and policy spaces in Nigeria, Badejo et al<sup>##UREF##0##11##</sup> report constant negotiations of professional roles and boundaries among health professionals despite the overall context of medical dominance. Not only did they find system disturbances or disequilibria resulting from such boundary struggles but also evidence of both conflictual and consensual shifts in professional power. They identify several facilitative conditions for the consensual shifts, including the possibility of simultaneous upward expansion of roles for all professions, introduction of new medical diagnostic technology that opened up occupational vacancies, among others. Resistance to medical dominance in Nigerian health systems is also noted by other scholars<sup>##REF##27793984##12##</sup> and evidenced in disputes between medical doctors and other health professionals resulting in strikes and formation of health sector unions that confront medical professions’ hegemony. How these resistances translate into the policy processes involving the Fund and the Nigerian health system remains unexplored in the paper. Furthermore, the notion and forms of expertise desired are constantly changing amid a changing environment defined by ongoing permeation of technologies and artificial intelligence and increasing managerialism in healthcare. Thus, management skills, knowledge of new diagnostics, data sciences and artificial intelligence have growing salience in health policy and may therefore be important sources of exercising professional power. These changing forms of expertise and how they shape professional power merit further examination.</p>", "<p> Second, a more nuanced understanding of discursive power and professional hegemony needs to be situated in the “complex and dialectical interaction between global actors and the nation state and between state and non-state actors” which is being “constantly negotiated, resisted and redefined at multiple levels”<sup>##UREF##1##13##</sup> (p. 2). As previously argued, examining interactions between the global, the national and the ‘local’ allows an appraisal of “the multiple sites of power within which these relations are embedded, and the overt and covert ways in which global and national elites wield such power”<sup>##UREF##1##13##</sup> (p. 2-3). The edited volume of research on global health governance in India enumerates several examples of overt and covert ways in which global health technical agencies and experts influence nutrition policies<sup>##UREF##2##14##</sup> and maternal health programmes.<sup>##UREF##3##15##</sup> In essence, the Nigerian health system and Global Fund governance that serve as the site for medical professionals’ dominance in policy-making examined in the study are themselves multi-tiered; wherein national and local actors from diverse sectors including public, businesses, and civil society are deploying Fund protocols to implement and monitor globally pre-determined priorities and approaches. They are therefore site of elite interactions that are constituted by diverse sources of power including but not restricted to professional power. Sriram et al<sup>##REF##29471544##16##</sup> identify several sources of power and their distribution in health policy and systems. Conceptualised primarily in relation to actors, these sources include power derived from: <italic toggle=\"yes\">technical</italic> knowledge and their authoritative claim to that expertise, <italic toggle=\"yes\">political </italic>authority and legitimacy, knowledge and access to <italic toggle=\"yes\">bureaucracies</italic> and administrative machinery, access to <italic toggle=\"yes\">financial</italic> capital, <italic toggle=\"yes\">personal</italic> attributes including education and professional training, as well as <italic toggle=\"yes\">social capital</italic> or access to networks and epistemic communities and the collective knowledge that comes with it. Examining the shifting inter-professional power relations shaped by the differential access to these sources helps understand actors’ agency as well as their <italic toggle=\"yes\">agentic</italic> power, ie, their ability to act independently of the constraints of social structure.<sup>##UREF##4##17##</sup></p>", "<p> Anthony Giddens proposed that power is clustered around the relations of action and structure.<sup>##UREF##5##18##</sup> Here, the Foucauldian concept of governmentality can be useful for a fuller interrogation of power dynamics in health policy and systems. Governmentality goes beyond actors and formal institutions that govern to include “the organised practices, their rationalities, techniques, and protocols through which subjects are governed.”<sup>##UREF##6##19##</sup> The concept helps bridge the structure-actor dichotomy in social theory that was challenged by Giddens and formed the basis of the structuration theory. As previously argued in the context of Global fund and the HIV/AIDS ecosystem in India, the concept allows investigation of the structures and institutions created within the Global Fund regime, their constitution and functioning, and the local-level practices these enable. In the context of the Fund, the Country Coordinating Mechanism, Technical Review Panel, and the Local Fund Agencies that act as ‘independent auditors’ of country performance tend to become key instruments of governmentality and exercise of <italic toggle=\"yes\">institutional </italic>and <italic toggle=\"yes\">structural</italic> power. Equally, a complex chain of Principal-Agent relationships of diverse actors becomes central to the Global Fund governmentality, as are “Fund brokers” in actively navigating these spaces and exercising <italic toggle=\"yes\">agentic</italic> power. Aligned with Giddens’ structuration theory, this perspective views actors as ‘knowledgeable agents’ who are aware, to a great extent, about the conditions and consequences of their actions, and able to rationalise their actions/practices when needed. These agents act as ‘interpretive communities’ that help align the proposal content with external agendas and international principles and standards (as also observed by Lassa et al) alongside adapting its content to suit the interests of a diverse epistemic community of local and transnational actors. Through such acts of translation and adaptations they continually recruit support of diverse stakeholders, manage conflicting agendas, and demonstrate coherence and success by reproducing ideas (for eg, of participation, voice of people with HIV, as well as effectiveness of clinical and technical solutions) (<italic toggle=\"yes\">ideational</italic> power<italic toggle=\"yes\">)</italic>. Such act of translation demands a wider repertoire of expertise than that derived solely from biomedical expertise, and is critical to the reproduction of institutionalised practices.</p>", "<p> To summarise, as depicted in Figure, the Fund governmentality in country health systems is a complex and contentious policy space where power mediates the dynamic interactions between interacting global and local sub-systems. Here, practices are institutionally constituted and socially constructed by actors through an active process of translation and sensitisation of diverse expertise and interests. These actors or Fund brokers enable the practices of policy-making and its implementation to generate material outcomes and knowledge. The latter serves as a powerful tool in creating ‘order’ amid conflict and uncertainty, reproducing the dominant discourse on effectiveness of biomedical and other interventions and simultaneously legitimising the role of brokers and their practice. In this context, power operates at multiple levels and can be understood in terms of the networks, resources and expertise (eg, biomedical training) which actors leverage in their interactions to influence outcomes and agendas; the authority of institutional protocols and guidelines that shape perceptions and (dis)incentivise certain practices; and via social practices that embody power differentials and reproduce structures of domination (eg, exclusion from decision making and agenda setting mechanisms). Examining power thus demands going beyond professional and agentic power to unpack the role of hegemonic <italic toggle=\"yes\">structures</italic> (systems and protocols) and <italic toggle=\"yes\">discourse</italic> (ideas and meanings) in constituting and constructing practices that legitimise, give meaning and stabilise the fund and health system governance in Nigeria.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that she has no competing interests.</p>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nSources and Interfaces of Power in Global Fund Governmentality. Abbreviations: TRP, Technical Review Panel; CCM, Country Coordinating Mechanism; M&E, monitoring and evaluation.</p></statement></fig>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"ijhpm-12-8019-g001\" position=\"float\"/>" ]	[]	[{"label": ["11"], "person-group": ["\n"], "surname": ["Badejo", "Sagay", "Abimbola", "Van Belle"], "given-names": ["O", "H", "S", "S"], "article-title": ["Confronting power in low places: historical analysis of medical dominance and role-boundary negotiation between health professions in Nigeria"], "source": ["BMJ Glob Health"], "year": ["2020"], "volume": ["5"], "issue": ["9"], "fpage": ["e003349"], "pub-id": ["10.1136/bmjgh-2020-003349"]}, {"label": ["13"], "mixed-citation": [" Kapilashrami A, Baru RV. Introduction: global health governance and commercialisation of public health in India: actors, institutions and the dialectics of global and local. In: Global Health Governance and Commercialisation of Public Health in India. Routledge. 2018:1-12. "]}, {"label": ["14"], "mixed-citation": [" Prasad V, Arthur M, Sundararaman T, Murugan G. Technical agencies and nutrition governance in India: power and influence in the context of contested approaches. In: Global Health Governance and Commercialisation of Public Health in India. Routledge. 2018:29-54. "]}, {"label": ["15"], "mixed-citation": [" Hunter B. Global actors and local \u2018partnerships\u2019: a case study of USAID\u2019s Sambhav scheme in Uttar Pradesh, India. In: Global Health Governance and Commercialisation of Public Health in India. Routledge. 2018:55-73. "]}, {"label": ["17"], "person-group": ["\n"], "surname": ["Campbell"], "given-names": ["C"], "article-title": ["Distinguishing the power of agency from agentic power: a note on Weber and the \u201cblack box\u201d of personal agency"], "source": ["Sociol Theory"], "year": ["2009"], "volume": ["27"], "issue": ["4"], "fpage": ["407"], "lpage": ["418"], "pub-id": ["10.1111/j.1467-9558.2009.01355.x"]}, {"label": ["18"], "mixed-citation": [" Giddens A. Structuration theory, empirical research and social critique. In: The Constitution of Society: Outline of the Theory of Structuration. Oxford: Polity Press; 1984. "]}, {"label": ["19"], "mixed-citation": [" Kapilashrami A. Understanding Public Private Partnerships: The Discourse, the Practice, and the System Wide Effects of the Global Fund to Fight AIDS, Tuberculosis, and Malaria [dissertation]. Queen Margaret University; 2010. "]}]	{ "acronym": [], "definition": [] }	19	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Jul 3; 12:8019	oa_package/05/89/PMC10702371.tar.gz
PMC10702372	37579354	[ "<title>Introduction</title>", "<p> Two years ago, Martens et al published in this journal the results of a study on integrated care (IC) policies management in Belgium.<sup>##REF##34273935##1##</sup> It illustrated the complex process of political and stakeholders gaming in a country where the governance of the state is becoming increasingly complicated as a result of repeated reforms.</p>", "<p> In such a context, IC policies design and implementation run the risk of being the result of political bargaining rather than a clear shared vision of how care should be organized. This is the case in Belgium, for example, when policies have to be designed to improve integration between primary care and mental health or with hospitals.</p>", "<p> At the same time, the jargon around IC can become instrumental for some stakeholders: “<italic toggle=\"yes\">integrated</italic>” becomes, then, the buzzword to impose decisions that increase the power of certain professions or allow the hospital to develop outside its walls.</p>", "<p> Using the lenses of complex adaptive system to improve care integration within health (and social) care system has been advocated.<sup>##UREF##0##2##,##REF##32436330##3##</sup> This may be particularly relevant to overcome challenges such as those identified by Martens et al.<sup>##REF##34273935##1##</sup> In this approach, the policy-making and implementation process needs to adjust to the adaptive nature that results from the interactions between parts of the health (and social) care system. “muddling through,” “tinkering,” and “adaptation” become then key characteristics of policy-making and implementation process.</p>", "<p> Adaptation, to be accountable, needs transparency and informed debate. This is particularly challenging for IC policies management. Indeed, IC is a fuzzy concept and improvement of the integration of care, needs an action at the different levels of a health system (not only at operational, or inter-organizational level, but also at policy level).</p>", "<p> We argue that three type of connections are particularly challenging in improving IC in a context such as Belgium: a conceptual connection between policies, a contextual connection through strengthened place-based governance, and a multi-level connection between governance structures. This is coherent with recent commentaries and publications about IC in Belgium.<sup>##REF##37579493##4##, ####UREF##1##5##, ##UREF##2##6####2##6##</sup></p>" ]	[]	[]	[]	[]	[ "<p>The study on the management of integrated care (IC) policies in Belgium from Martens et al illustrates the complex process of the political and stakeholder game in a country whose governance is changing as a result of successive state reforms. We argue that the way forward for putting health back at the centre of IC policy design and management is to improve three types of connections. First, the conceptual connections should help to articulate the different IC policies into a coherent overall picture. Second, contextual connections should allow for the adaptation of policies to different country contexts. This requires a new form of governance, ie, a place-based and adaptive form of governance. This can be developed, provided that a third connection, between the different levels of governance, is fully revised.</p>", "<p>\n<bold>Citation:</bold> Macq J. Integrated care policies and politics in Belgium: conceptual, contextual and governance linkages for more effective integrated care policy management: Comment on \"Integration or fragmentation of health care? Examining policies and politics in a Belgian case study.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7009. doi:10.34172/ijhpm.2023.7009</p>" ]	[ "<title>Conceptual Connections: From Integrated Care as a Fuzzy Concept to Connected Policies Within a Whole Picture</title>", "<p> In discourses and policies, IC is too often presented as a clear concept. However, when looking at content of policies, it appears fuzzy and subject to multiple interpretations.<sup>##REF##32085770##7##</sup> Its meaning differs, most often, in term of breath of ambitions and strategies to reach these ambitions. This is well illustrated in the article of Maerten et al.<sup>##REF##34273935##1##</sup> On the one hand, type 2 diabetus care trajectory have much narrower ambition with concrete financing mechanisms to achieve it. The primary care reform and more, the joint plan and pilot projects on IC have much broader ambition (quintuple aim). Both use the development of territorial governance as the frame to develop bottom-up strategies and to contribute to quintuple aim.</p>", "<p> The clarification of objectives and strategies in relation to specific policies is probably an initial step. This should allow for a coherent articulation of these policies. The IC policies analyzed by Martens et al makes it possible to illustrate different forms of connections.</p>", "<p> For some policies, desirable connections are more straightforward than others are. For example, type 2 diabetus care trajectory, because of the narrow breath of ambition can only be part of a “bigger picture.” Primary care reform and further, the joint plan could serve as “frame” to develop such policies, complementary to other (in mental health, etc). For that type of connection, there is a clear complementarity between pathways and territorial approaches to improve care integration.</p>", "<p> For other policies, the connection between primary care reform in Flanders and the joint plan on IC is less obvious. Indeed, both seek improved integration of care through territorial approach without clear agreement on the scale and mode of imbrication between territories defined in both policies. This form of incoherence has been recently identified as a key challenge in building IC.<sup>##UREF##3##8##</sup></p>", "<title>Connection With the Context: Implementing “Place Based” Adaptive Form of Governance to Progressively Translate Policies Into Practice</title>", "<p> Even when conceptual connection between policies is achieved, traducing this from policy to action in a given context needs strong capacities at operational level. The most appropriate operational level to meet these capacities is probably the level of inter-organisational networks for a whole population living in a territory also called “integrated” place-base system of care.<sup>##UREF##4##9##</sup> A key component to enable the best use of these skills is the development of new forms of governance at that level. Indeed, given the growing complexity of health systems, traditional approaches of governance do not suite realities anymore. The issue of responsiveness to various stakeholders (including population) becomes particularly important, when network or local system building is at stake. The challenge of responsiveness is particularly important to overcome barriers for integration such as “<italic toggle=\"yes\">lack of trust among key constituencies; insufficient understanding about changing environment and issues affecting healthcare organizations; emphasis on institutions, autonomy, independence; lack of system perspective; ambiguity about roles, responsibilities, relationships, accountabilities; readiness for change.</italic>”<sup>##UREF##5##10##</sup> The most appropriate form of governance to manage all those challenges is probably place-based governance.<sup>##UREF##4##9##</sup> This form of governance groups stakeholders from different organisations for comprehensive solutions. It focusses on learning – by-doing to optimize policy translation to the local context.<sup>##UREF##6##11##</sup> It is therefore adaptive by nature and build on principles that are proposed by Blanchet et al.<sup>##REF##28812842##12##</sup> First, an evaluation of the situation is coupled with the management of different forms of knowledge and information, ie, “hard” data (indicators of healthcare utilization and population needs) and “more practical and locally situated knowledge.”<sup>##UREF##4##9##</sup> This enable the understanding of care provision by all stakeholders and the adaptation of strategies in context of uncertainties. Second, a strong leadership facilitates the negotiation between stakeholders through the management of their interdependency.<sup>##REF##28812842##12##</sup></p>", "<p> This mode of governance is probably a pre-requisite for the proper implementation of the three policies examined in Martens et al paper. Primary care zone (as part of primary care reform in Flanders) or IC pilot project zones (as part of joint plan) are the level to develop such a form of governance.</p>", "<title>Multi-level Connection Between Governance Structure: From Political Bargaining to the Support for the Translation of Policies Into Practice at Operational Level</title>", "<p> The development of place-based governance to manage “integrated” place-base system of care is far to be obvious. It depends of a coherent combination of decision, (governance) structures, skills and goodwill of many stakeholders.<sup>##REF##34273935##1##</sup> The recent covid crisis has shown that this was not the case in Belgium, a country were division of power has been the result of political bargaining rather than health-related reasoning. In such a situation, there is a clearly emerging agenda to connect better the different levels of state governance (namely the federal and federated levels). Indeed, distribution (with sometimes overlapping) of responsibilities in governance functions at multiple level such as local governments, regions, states and intergovernmental systems (such as European Union) give way to more diffused forms of governing. Reflecting and adapting the different level of governance to the others is the way forward for a federal country like Belgium. This should be conceived in such a way that it strengthens place-based governance to manage “integrated” place-base system and avoid the problems with the classical mismatch between policies and local realities whereby stakeholders including local authorities resist to it or translate it into practice.<sup>##REF##19081136##13##</sup></p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that he has no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "mixed-citation": [" Carroll A. Integrated care through the lens of a complex adaptive system. In: Amelung V, Stein V, Suter E, Goodwin N, Nolte E, Balicer R, eds. Handbook Integrated Care. Cham: Springer; 2021:595-609. "], "pub-id": ["10.1007/978-3-030-69262-9_35"]}, {"label": ["5"], "person-group": ["\n"], "surname": ["De Winter"], "given-names": ["M"], "article-title": ["Reshaping health care governance using pilot projects as public policy implementation instruments"], "source": ["Int Rev Public Policy"], "year": ["2020"], "volume": ["2"], "issue": ["3"], "fpage": ["317"], "lpage": ["341"], "pub-id": ["10.4000/irpp.1422"]}, {"label": ["6"], "mixed-citation": [" Lambert AS, Op de Beek S, Herbaux D, et al. Vers des soins (plus) int\u00e9gr\u00e9sen Belgique. Health Services Research (HSR). Report no. 359B. Bruxelles: Centre F\u00e9d\u00e9ral d\u2019Expertise des Soins de Sant\u00e9 (KCE); 2022. "]}, {"label": ["8"], "person-group": ["\n"], "surname": ["Minkman"], "given-names": ["MMN"], "article-title": ["Suitable scales; rethinking scale for innovative integrated care governance"], "source": ["Int J Integr Care"], "year": ["2020"], "volume": ["20"], "issue": ["1"], "fpage": ["1"], "pub-id": ["10.5334/ijic.5468"]}, {"label": ["9"], "mixed-citation": [" Ham C, Alderwick H. Place-Based Systems of Care: A Way Forward for The NHS in England. United Kingdom: The King\u2019s Fund; 2015. "]}, {"label": ["10"], "mixed-citation": [" Human Interface and the Management of Information. Information and Knowledge in Context. Cham: Springer International Publishing; 2015. "]}, {"label": ["11"], "person-group": ["\n"], "surname": ["Marsh", "Crowley", "Grube", "Eccleston"], "given-names": ["I", "K", "D", "R"], "article-title": ["Delivering public services: locality, learning and reciprocity in place based practice"], "source": ["Aust J Public Adm"], "year": ["2017"], "volume": ["76"], "issue": ["4"], "fpage": ["443"], "lpage": ["456"], "pub-id": ["10.1111/1467-8500.12230"]}]	{ "acronym": [], "definition": [] }	13	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Jul 30; 12:7009	oa_package/6d/55/PMC10702372.tar.gz
PMC10702384	37579358	[]	[]	[]	[]	[]	[ "<p>The article seeks to shed light on the role of regional organizations in strengthening health research systems in Africa, how they operate and how they work, as well as debts and future challenges. As can be observed also in South America, the continued strengthening of health research requires strategic thinking about the roles, comparative advantages, and capacity of regional organizations to facilitate the flourishing of health research systems. Health research is a strategic field for the transformation of socio-health inequalities on the one hand and the reduction of regional asymmetries on the other. Thus, regional organizations represent key actors in strengthening health research systems and the regional research agenda reinforces its sovereign condition in the autonomous definition of relevant topics and financing. In this process, integration mechanisms face a great challenge, as shown by the recent pandemic, not only in Africa but also in South America.</p>", "<p>\n<bold>Citation:</bold> Herrero MB, de Oliveira BNL. Health science research at a regional level: insights from South America: Comment on \"The roles of regional organisations in strengthening health research systems in Africa: activities, gaps, and future perspectives.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:8076. doi:10.34172/ijhpm.2023.8076</p>" ]	[ "<p> The article “The roles of regional organizations in strengthening health research systems in Africa: activities, gaps, and future perspectives”<sup>##REF##35279037##1##</sup> discusses the role of international organizations in strengthening health research systems on the African continent, which emerges as an urgent topic in these times.</p>", "<p> The authors note that while regional cooperation in health in Africa is not new, the institutional landscape of regional cooperation for health and health research has undergone important changes, especially since the pandemic. This is interesting, since health emergencies can be an opportunity to strengthen regional organizations in support aspects of national health preparedness and response.</p>", "<p> In order to understand what regional organizations are doing to strengthen health research systems in Africa, the authors conducted a mapping of regional organizations involved in health sciences research and 18 interviews with key informants.</p>", "<p> Regarding the findings, the authors point out two factors that are fundamental and at the same time a challenge also for other regions and, in particular, for South America. One of them is that most organizations reported activities in governance and use of research, and that participation in governance was mainly focused on agenda setting and policy harmonization. The other fundamental aspect is that — according to the authors — the continuous strengthening of health research requires strategic thinking about the roles, comparative conditions and the efficacy of regional organizations to facilitate the capacity and growth of research systems in health.</p>", "<p> The reality presented has its specific contexts, which are quite well explained in the article and help to understand the role of public policies and international cooperation mechanisms in the field of health research. Although the scenario of the African continent is particular, some aspects relate to the reality of health research in South America, as well as the context of health cooperation. As happened in Africa, in Latin America, for decades regionalism has been influenced mainly by international trade and economic interests and, during health emergencies, by disease threats to public health. Some decades ago, health gained more interest within organizations in regional governance in both regions and due to health crises, have increased attention to the role of regional bodies in health sector planning and response, but with less attention in other aspects, such as developing research institutions, networks, or infrastructure. However, while Africa faced the COVID-19 crisis on a regional scale, Latin America, and especially South America, appeared particularly disjointed, something that also was reflected in fragmented regional cooperation.<sup>##UREF##0##2##</sup></p>", "<p> It should be noted that, from the perspective of the Global South, health research systems must be strengthened by the construction of public policies that support national governments in preparing for and responding to emergencies and health crises, in research and in knowledge generation. This requires a political decision that allows prioritizing health research on national and regional political agendas. Although the realities of South America and Africa are different, it is essential to emphasize that, in both cases, the political decision is key.</p>", "<p> The authors point out that regional cooperation is a useful approach to reduce inequities in the research capacity of national health research systems. They suggest, for example, the development of a regional laboratory to develop the efficiency of countries with little or no national research infrastructure. This implies that health research cannot be solely in the hands of the private sector, since they are not committed to the public interest.</p>", "<p> Although the private industry invests a lot in the development of new health technologies, the COVID-19 pandemic has nevertheless shown us that without public investment in research and development, we would not have had as many safe vaccine options in such little time. The vaccines from Oxford-AstraZeneca, Sinovac and the Gamaleya Institute, as well as the case of Cuba, which developed and carried out clinical tests of 3 vaccines in national territory, are proof of the important role of public investment in strengthening national systems of health research.</p>", "<p> The strategic alliance between the public sector and the private sector in the field of health research is important. In any case, it must be aligned not only with private interests, but — and above all — with the needs of the population. Here, the public sector plays a key role in control, monitoring and regulation, and the regional level can strengthen the decision-making level of the public sector.</p>", "<p> Since the authors found that the highest performing countries, as well as those with the greatest human resources and institutional capacity, have generally benefited from substantial long-term international partnerships and collaborations, they therefore highlight that relying on international funding and alliances to develop research at the national level runs the risk of generating inequalities between countries. This point is fundamental given that these asymmetries, as well as the strong dependence on international financing, are also observed in South America. That is why it is of vital importance that countries can strengthen integration mechanisms and generate autonomous cooperation instances that tend to foster and strengthen national and regional capabilities, towards sovereign health research. Multi-stakeholder alliances are also fundamental, for the combination of resources and capacities, between state actors and non-state actors. Here, south-south cooperation and triangular south-south cooperation can be a tool in the development of projects and initiatives to strengthen regional and national health research.</p>", "<p> In the particular case of the South American region, the Union of South American Nations (UNASUR) and the South American Institute of Government in Health (ISAGS) had been created, in 2008 and 2011, respectively. The institute functioned as a think tank, which promoted the exchange of information and health research in different areas, such as access to medicines, disaster management, strengthening of health systems, among others.<sup>##UREF##1##3##</sup> ISAGS, created with strong support from the Oswaldo Cruz Foundation — a large Brazilian science and technology research and production institution — worked actively in Rio de Janeiro between 2011 and 2019, bringing together the 12 countries of South America. With the gradual departure of eight of the 12 countries, UNASUR ended up dissolving, and so the ISAGS. It can be said that this has been a lost opportunity given that the countries gave up an important instance of production and exchange of knowledge, as well as a space for regional advocacy and international insertion in the field of global health.<sup>##UREF##2##4##</sup></p>", "<p> Another of the authors’ interesting results — based on the interviews — is that drug and treatment policies in the African continent constitute one of the key aspects of regulatory policy, on which regional organizations focus their harmonization efforts to improve the inspection, approval and use of quality and affordable medicines. This brings us significantly closer given that one of the greatest advances on the regional agenda in South America in recent years has been in the area of medicines, through the price bank and joint purchases of high-cost medicines, which have been a great opportunity for strengthening national and regional capacities.<sup>##REF##34730691##5##,##REF##33405998##6##</sup> Regarding the Medicines Price Bank of UNASUR, the Group on Universal Access to Medicines of UNASUR, developed a database with the prices of drugs in all the countries of the region as a negotiating strategy. This information was a very useful tool during negotiations with the pharmaceutical companies. About, the joint negotiation of prices for high-cost medicines, this initiative contributed to save millions of dollars in joint purchases of medicines for hepatitis C.<sup>##REF##34730691##5##,##REF##33405998##6##</sup> Studies have shown that the articulation of countries through regional integration mechanisms such as UNASUR and the Southern Common Market, and with the participation of other regional instances, such as Pan-American Health Organization, led to economic savings in terms of drug purchases, with strategies of complementarity between the mechanisms, contrary to the overlapping of initiatives, such as the Joint Purchases of Medicines. Unfortunately, some of these processes were cut short due to the dissolution of UNASUR.</p>", "<p> Another interesting finding is that study informants perceived the greatest gap in health research when it comes to continental or interregional coordination. On this point, the importance of regional coordination mechanisms could also be of great importance in reducing this gap. During the pandemic, the absence of such mechanisms in South America can be considered as an important explanation to why there was not a concerted response.<sup>##UREF##2##4##</sup></p>", "<p> In agreement with the authors, health is increasingly attracting the attention of regional organizations, along with more traditional aspects of regional cooperation such as trade or security, and regional organizations in the global south are considered important political forums within multilevel governance of health. However, as this study also mentions, the way in which health policy is framed and understood as an issue for regional cooperation varies between organizations and has been shown to be influenced by context-specific social, economic and political views on health policy.<sup>##REF##26635497##7##</sup></p>", "<p> The regional failure that the dissolution of UNASUR implied for South America makes us think about the importance of sustaining and strengthening the mandates of regional organizations, at least to guarantee the achievements in multilateral regional spaces, especially when having to face periods of crisis.<sup>##UREF##2##4##</sup> The lack of political will of a country or group of countries has great relevance in the performance of multilateral organizations: in the end, international organizations are what the States want to make of them. With stronger mandates from member States, organizations can improve their international insertion, expand advocacy, improve governance and optimize their performance. In fact, the articulation and coordination of regional actions at the three levels — national, regional, and global — are essential.<sup>##REF##28372479##8##</sup> At the national level, it is necessary with a view to local capacities and, especially, strengthening health systems to meet the demand and cover the need for medical supplies and equipment, a point that has been critical in many countries in the region in times of pandemic.<sup>##UREF##2##4##</sup> At the regional level, joint action is needed to articulate and foster cross-border cooperation; to guarantee the coordination of flights that transport equipment and, now, vaccines; to exchange data and promote joint mechanisms for the production and acquisition of inputs. Finally, on a global scale, coordination facilitates greater access to multilateral organizations in order to join forces to act together and negotiate as a block, understanding and defending health as a right. Joint action also has a backdrop: the possibility of reducing asymmetries, which have been evident in this pandemic crisis and which the consequences of inequitable access to vaccines will reflect more harshly.<sup>##UREF##2##4##</sup> Here, health science research displays a key role. It can sum the capacities, and resources and generate knowledge to address the health needs of member states. The pandemic has demonstrated the need to develop research around new inputs, medicines, and vaccine products, as well as social research. At this point, it should be noted that regional organizations have become central actors in foreign policy, with growing relevance in the international health agenda, positioning issues on the agenda according to the needs identified by the Member States, and based on their capacities. These successive processes can come together in the elaboration of the aforementioned regional research agenda, as input for the design of public health policies, capable of resolving and responding to the needs and expectations that are typical and genuine of the region.</p>", "<p> Understanding then, in agreement with the authors of the article, that health research is a strategic field for the reduction of socio-health inequalities, a starting point is the identification and definition of core issues at the national level/regional, based on a diagnosis of deficiencies, asymmetries and the urgent needs of each population. Some of the elements that should be considered for this are the focus on health as a right, the participation of the main local actors (at different levels); the identification of regional needs and capacities; a health research agenda, at the regional level; regional consensus mechanisms in research; financing of the public research system; and instances of monitoring and evaluation of research in health sciences.</p>", "<p> A central point in this article is that while regional organizations mostly do not fund improvements to health research infrastructure, regional centers of excellence — as noted in the article — have been cited as opportunities for development of the health research infrastructure at the regional level. As some interviews point out, this is a particularly important role for regional health organizations to convene research networks that foster equity in research collaborations.</p>", "<p> A valuable resource in this regard is the promotion and creation of regional research networks, that is, cooperation networks between leaders in this area, in order to add resources to achieve shared goals and objectives. These networks must be constituted based on horizontal structures of co-participation and collaboration, in accordance with research strategies and action plans agreed upon by all participants, promoting the integration of all government areas and national and regional research systems involved with each problem in particular.</p>", "<p> In South America and within the scope of UNASUR, six structuring networks have been formed: Network of National Health Institutes, Network of Technical Health Schools, Network of Public Health Schools, Network of National Institutes of Cancer, Network of Offices of International Relations of Health, and Network of Management of risks and mitigation of disasters. With the dissolution of UNASUR, the first 4 networks — which were the most active — found other institutional paths and, after the necessary adjustments, they continued to exist and develop important work of institutional articulation in the areas of action of each one. In this way, regional organizations, especially in the current global system, can also become knowledge-generating centers to obtain, evaluate, and disseminate information on the countries’ health policies. Likewise, they can generate the necessary alliances to establish project evaluation and monitoring procedures that serve as an input for the states when evaluating the impact of their policies.</p>", "<p> Thus, regional organizations can become a central actor in the field of sovereign health research and in the autonomous definition of relevant topics and in the financing of an agenda (which is often subject to the “priorities” established by external funders). In this process, the integration mechanisms have a great challenge, and these studies shed light on the lessons learned, the limitations and the way forward.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["2"], "mixed-citation": [" Herrero MB, Bouza SL. Lo que la Unasur puede aprender de la pandemia. Buenos Aires: Nueva Sociedad; 2023. "]}, {"label": ["3"], "person-group": ["\n"], "surname": ["Bueno", "Faria", "Bermudez"], "given-names": ["FT", "M", "L"], "article-title": ["A Coopera\u00e7\u00e3o Sul-Sul e as Redes Estruturantes do Conselho de Sa\u00fade da Unasul como instrumentos de desenvolvimento regional"], "source": ["Cad Desenvolv"], "year": ["2018"], "volume": ["8"], "issue": ["12"], "fpage": ["83"], "lpage": ["100"]}, {"label": ["4"], "person-group": ["\n"], "surname": ["Herrero", "de Oliveira"], "given-names": ["MB", "BN"], "article-title": ["COVID-19 in Latin America and the Caribbean: the visible face of a regional health cooperation in crisis"], "source": ["Rev Bras Pol\u00edt Int"], "year": ["2022"], "volume": ["65"], "issue": ["1"], "fpage": ["e003"], "pub-id": ["10.1590/0034-7329202200103"]}]	{ "acronym": [], "definition": [] }	8	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Jul 16; 12:8076	oa_package/fe/5a/PMC10702384.tar.gz
PMC10702385	37579360	[ "<title>Introduction</title>", "<p> Just as other sectors, the healthcare sector has recently experienced an increased digitalisation. This tendency caused the widespread use of software, for example to streamline administrative processes within hospitals and care centres (information technology equipment), but also to support clinical decision making by healthcare professionals (HCPs). Van Laere et al<sup>##REF##34814678##1##</sup> explain the different regulatory frameworks that apply to clinical decision support (CDS) software in the United States (Food and Drug Administration, FDA, 21st Century Cures Act)<sup>##UREF##0##2##</sup> and in Europe (European Union Medical Device Regulation [MDR]).<sup>##UREF##1##3##</sup></p>", "<p> We will mainly comment and ask critical questions on the practical implementation of the regulatory framework for medical device software (especially CDS software), with a reference to the available international guidance documents and their limitations. As mentioned by Van Laere et al,<sup>##REF##34814678##1##</sup> manufacturers of medical device software need to consider those regulatory frameworks carefully as they might impact their time and costs to market significantly.</p>", "<title> Importance of Keeping Guidelines Up to Date With the “State of the Art” Software </title>", "<p> There is a general trend of digitalization in healthcare with a broad spectrum of different medical and non-medical device software functions used. This is confirmed by policy-makers through providing illustrative examples in guidance documents for the qualification of software used in the healthcare environment.<sup>##UREF##2##4##, ####UREF##3##5##, ##UREF##4##6##, ##UREF##5##7##, ##UREF##6##8##, ##UREF##7##9##, ##UREF##8##10####8##10##</sup> It is understood that the examples in the guidelines have been drafted in the light of today’s state of the art. However, we hope that those guidance documents will be treated by policy-makers as living documents that will be updated with innovative examples (eg, software algorithms that operate via machine learning or other artificial intelligence [AI] techniques) following the pace of evolving technologies. It is correctly noted in the viewpoint article that there is an assumption that EU MDR will hamper software development as the FDA Guidances<sup>##UREF##2##4##, ####UREF##3##5##, ##UREF##4##6##, ##UREF##5##7##, ##UREF##6##8##, ##UREF##7##9####7##9##</sup> present more innovative software examples than the EU Medical Device Coordination Group (MDCG) Guidance Documents.<sup>##UREF##8##10##</sup></p>", "<title> Qualifying Software as a Medical Device – Is the Definition Clear?</title>", "<p> To be qualified as a medical device, a product must first fulfil the definition of a medical device according to the applicable legislation. The international harmonization body (former Global Harmonization Task Force or International Medical Device Regulators Forum [IMDRF]) has created non-binding guidance documents (eg, definition of the term “Medical Device”) to encourage regulatory systems’ convergence at the global level by eliminating differences between jurisdictions. Harmonized guidance would ideally result in decreasing the cost of gaining regulatory compliance and in allowing patients earlier access to innovative technologies and treatments.<sup>##UREF##9##11##</sup> The EU MDR definition and its specification of the medical purpose of a device is more leaning towards the Global Harmonization Task Force definition compared to the device definition in section 201 (h) of the Food, Drug & Cosmetic Act.<sup>##UREF##0##2##</sup> In addition, the term “monitoring” in the EU MDR<sup>##UREF##1##3##</sup> is focused on products intended to monitor physiological processes, while “monitoring” is not present in the FDA device definition.<sup>##UREF##0##2##</sup> Unfortunately, there is no clear definition of the term “to monitor” which complicates the qualification of a software product. We would suggest defining monitoring as <italic toggle=\"yes\">“following the evolution of a disease, injury/disability or physiological or pathological process or state at different stages or at different moments in time.”</italic> Many software products are intended to follow up chronic patients at home by visualising parameters measured with different hardware medical devices and notifying deviations to enable HCPsto take treatment decisions. For such software products, we would welcome a clear definition of medical device <italic toggle=\"yes\">monitoring</italic> in updated guidance documents to facilitate their qualification.</p>", "<p> As confirmed by the FDASIA report,<sup>##UREF##10##12##</sup> the development of software products used to take decisions with diagnosis or therapeutic purposes has increased in the last decades (called “decision support software in EU”<sup>##UREF##8##10##</sup> or “CDS software in US”<sup>##UREF##3##5##</sup>). Unfortunately, no harmonized definition is available for CDS software. The authors of the viewpoint article came up with their own definition on CDS software: ‘<italic toggle=\"yes\">any software system that integrates personal patient data with external sources of medical knowledge to assist the HCPs in their decision-making process.’</italic><sup>##REF##34814678##1##</sup> Following MDCG guidance,<sup>##UREF##8##10##</sup> decision support software is <italic toggle=\"yes\">intended to provide HCPs and/or users with recommendations for diagnosis, prognosis, monitoring and treatment of individual patients. </italic>Following FDA guidance,<sup>##UREF##3##5##</sup> CDS software would provide ‘<italic toggle=\"yes\">HCPs and patients with knowledge and person-specific information, intelligently filtered, or presented at appropriate times, to enhance health and healthcare</italic>.’ Generally, the meaning of those definitions seems identical, however limitations exist in the practical qualification of CDS software as a medical device (SaMD). Van Laere et al<sup>##REF##34814678##1##</sup> are correctly requesting further guidance on how FDA will assess the availability of plain language description of the logic or rationale used by an algorithm and the availability of the elements forming the basis of the recommendations to the intended user. The understanding of the basis of a certain CDS might trigger that CDS software being exempted from the 21st Century Cures Act.<sup>##UREF##0##2##</sup> This approach of a software recommendation being or not being understandable has not been considered in the EU MDCG guidance document as a criterion to qualify CDS SaMD. Additional clarification in guidance documents (US and EU) on the basis of the software recommendation and/or the action of the software on the data (eg, data analysis) would improve the qualification assessment of software products.</p>", "<title> Is the Classification of Clinical Decision Support Software Different Between Jurisdictions? </title>", "<p> The EU and FDA medical device legislations have leveraged the IMDRF risk-based framework for categorizing SaMD, based on the risk to patients if the software malfunctions.<sup>##UREF##11##13##</sup> IMDRF’s categorization criteria and framework (##TAB##0##Table 1##)<sup>##UREF##11##13##</sup> are not a regulatory classification, nor imply a convergence of classifications rules. Each jurisdiction has aligned her SaMD or medical device software (EU term) classification rules with this IMDRF framework in a unique way. As indicated by Van Laere et al, the EU MDR classification is much more stringent, especially due to the new classification Rule 11. Software intended to provide <italic toggle=\"yes\">information in the clinical management</italic> is always classified as a Class IIa medical device in Europe, requiring the regulatory approval by a notified body (##TAB##1##Table 2##).<sup>##UREF##1##3##,##UREF##8##10##</sup></p>", "<p> The FDA approach is more pragmatic. FDA has drafted guidance on CDS software functions with a specific focus on CDS software used for informing clinical management.<sup>##UREF##3##5##</sup> The categorization method for regulatory oversight is based on the user (a HCP, patient, or caregiver) on the one hand and on the fact that the user can review the basis of the information on the other hand (##TAB##2##Table 3##). With this approach, FDA strikes the right balance between ensuring patient safety and promoting innovation by clarifying which products would be the focus of FDA’s oversight and which would not. As noted by Van Laere et al,<sup>##REF##34814678##1##</sup> two medical devices with the same intended use may obtain different classifications in those two jurisdictions. Unfortunately, EU MDR does not consider the lower significance of <italic toggle=\"yes\">informing clinical management</italic> of the IMDRF framework nor the stage of healthcare condition of the patient, to allow a lower classification and thus regulatory burden for such CDS software (leading to a class IIa classification for low impact SaMD in non-serious situation or patient condition in ##TAB##1##Table 2##).</p>", "<title> Are There Other Limitations in the Practical Implementation of Medical Device Legislations?</title>", "<p> Advanced technologies such as AI are becoming more frequently used in healthcare for diagnostic or therapeutic purposes. The US FDA clearly has taken the path forward for embracing this technology by drafting an AI/machine learning SaMD action plan.<sup>##UREF##12##14##</sup> In Europe, guidance on interpretation of significant changes to AI are not yet available. Due to the promotion of those innovative products to the market, there is a growing need for software experts in Europe, especially within the conformity assessment bodies for reviewing the CE certification applications. As suggested by the FDA,<sup>##UREF##12##14##</sup> there is a great need for more harmonization in the AI domain, more specifically in the development of good machine learning practice through the creation of consensus standards and other guidelines.</p>" ]	[]	[]	[]	[ "<title>Conclusion</title>", "<p> The topic of CDS software is relevant as it became more widespread in different healthcare fields. With the evolution of software technologies such as AI, CDS software is expected to consolidate its position in healthcare. To keep up with the technological evolutions, it is desirable that the different regulators consult with industry and users and publish and continuously update more practical guidance documents. US FDA already takes a proactive approach in providing multiple guidance documents<sup>##UREF##2##4##, ####UREF##3##5##, ##UREF##4##6##, ##UREF##5##7##, ##UREF##6##8##, ##UREF##7##9####7##9##</sup> on software, but also on CDS software and an action plan for AI/machine learning based SaMD.<sup>##UREF##12##14##</sup> Although the European Commission had good intentions when considering the IMDRF risk categorization framework, it did not classify CDS software which informs HCPs for non-serious patient conditions in a low medical device class. This results to the fact that manufacturers will most likely need a notified body to place this type of products on the market in Europe. This will certainly increase the costs and timelines to go to the market, probably making Europe a less attractive market to deploy digital health innovations in a first stage. Currently, some manufacturers are reducing their product portfolio in Europe to limit regulatory cost related to EU MDR. As expected by Van Laere et al,<sup>##REF##34814678##1##</sup> the real clinical impact on patient’s health will only be measurable in the next few years.</p>" ]	[ "<p>The increasing use in clinical practice of software such as mobile apps and clinical decision support (CDS) software has only recently been taken up by regulators around the world. Specifically, the European Commission and the US Food and Drug Administration (FDA) have updated their regulatory framework in the last years. Van Laere et al have given an extensive overview of the European and US approaches to regulate CDS software. This commentary further discusses regulatory differences between the two geographies and their impact on manufacturers of medical device software. We discuss the practical implementation of the regulatory framework for medical device software (especially CDS software) with a reference to the available international guidance documents and their limitations. Given the direction of stricter regulatory oversight in Europe, additional European guidelines/examples are desirable to enable a pragmatic regulatory approach ensuring continued access to innovative medical device software for European patients.</p>", "<p>\n<bold>Citation:</bold> Beckers R, Van Hoydonck P. Impact of the regulatory framework on medical device software manufacturers: are the guidance documents supporting the practical implementation? Comment on \"Clinical decision support and new regulatory frameworks for medical devices: are we ready for it? – A viewpoint paper.\" <italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7470. doi:10.34172/ijhpm.2023.7470</p>" ]	[ "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>IMDRF SaMD Working Group - “Software as a Medical Device”: Possible Framework for Risk Categorization and Corresponding Considerations\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>State of Healthcare Situation or Condition</bold>\n</td><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Significance of Information Provided by SaMD to Healthcare Decision</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Treat or Diagnose</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Drive Clinical Management</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Inform Clinical Management</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Critical</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">IV</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">III</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">II</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Serious</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">III</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">II</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">I</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Non-serious</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">II</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">I</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">I</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>MDCG 2019-11 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR: Classification Guidance on Rule 11\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<bold>State of Healthcare Situation or Patient Condition</bold>\n</td><td colspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Significance of Information Provided by SaMD to Healthcare Decision Related to Diagnosis/Therapy</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>High</bold>\n<break/>\n<bold>Treat or Diagnose</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Medium</bold>\n<break/>\n<bold>Drive Clinical Management</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Low</bold>\n<break/>\n<bold>Inform Clinical Management</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Critical situation or patient condition</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class III</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class IIb</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class IIa</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Serious situation or patient condition</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class IIb</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class IIa</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.75pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class IIa</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Non-Serious situation or patient condition</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class IIa</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class IIa</td><td style=\"text-align:center;vertical-align:middle;border-width:0.75pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">Class IIa</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Draft Guidance on Clinical Decision Support Software: Summary of Regulatory Policy for CDS Software Functions\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" colspan=\"1\">\n<bold>IMDRF Risk Categorization</bold>\n</td><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" colspan=\"1\">\n<bold>Can the User Independently Review the Basis?</bold><sup>a</sup>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Intended User</bold>\n<break/>\n<bold>HCP</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Intended User</bold>\n<break/>\n<bold>Patient or Caregiver</bold>\n</td></tr><tr><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>FDA Regulation</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>FDA Regulation</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" colspan=\"1\">Inform and critical</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Not a device</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Oversight focus</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Oversight focus</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Oversight focus</td></tr><tr><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Inform and serious</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Not a device</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Oversight focus</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Oversight focus</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Oversight focus</td></tr><tr style=\"background-color:#eeeeee\"><td rowspan=\"2\" style=\"text-align:left;vertical-align:middle;\" colspan=\"1\">Inform and non-serious</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Not a device</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Enforcement discretion<sup>b</sup></td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">No</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Enforcement discretion<sup>b</sup></td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Oversight focus</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p> Abbreviations: IMDRF, International Medical Device Regulators Forum; SaMD, Software as a Medical Device.</p><p> Source: IMDRF SaMD Working Group.<sup>##UREF##11##13##</sup></p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: MDCG, Medical Device Coordination Group; MDR, Medical Device Regulation; SaMD, Software as a Medical Device; IVDR, In Vitro Diagnostic Regulation.</p><p> Source: Medical Device Coordination Group Document MDCG 2019-11.<sup>##UREF##8##10##</sup></p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: FDA, Food and Drug Administration; IMDRF, International Medical Device Regulators Forum; HCP, healthcare professional; CDS, clinical decision support.</p><p>\n<sup>a</sup> “Can the User Independently Review the Basis?” asks whether the function is intended for the purpose of enabling the user to independently review the basis for the recommendations so that it is not the intent that user relies primarily on any such recommendation.</p><p>\n<sup>b</sup> “Enforcement Discretion” indicates that, based on our current understanding of the risks of these devices, does not intend at this time to enforce compliance with applicable device requirements.</p><p> Source: US FDA.<sup>##UREF##3##5##</sup></p></fn></table-wrap-foot>" ]	[]	[]	[{"label": ["2"], "mixed-citation": [" U.S. Government Publishing Office. Public Law 114-255 - 114th Congress (In Short: 21st Century Cures Act). "], "uri": ["https://www.govinfo.gov/app/details/PLAW-114publ255"]}, {"label": ["3"], "mixed-citation": [" European Parliament and Council. Regulation (EU) 2017/745 (In Short: Medical Device Regulation (MDR)). "], "uri": ["https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:02017R0745-201705052017"]}, {"label": ["4"], "mixed-citation": [" US Food and Drug Administration. Policy for Device Software Functions and Mobile Medical Application. "], "uri": ["https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-device-software-functions-and-mobile-medical-applications"]}, {"label": ["5"], "mixed-citation": [" US Food and Drug Administration. Draft Guidance on Clinical Decision Support (CDS) Software. "], "uri": ["https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-decision-support-software"]}, {"label": ["6"], "mixed-citation": [" US Food and Drug Administration. Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act: Guidance for Industry and Food and Drug Administration Staff. "], "uri": ["https://www.fda.gov/regulatory-information/search-fda-guidance-documents/changes-existing-medical-software-policies-resulting-section-3060-21st-century-cures-act"]}, {"label": ["7"], "mixed-citation": [" US Food and Drug Administration. General Wellness: Policy for Low Risk Devices. "], "uri": ["https://www.fda.gov/regulatory-information/search-fda-guidance-documents/general-wellness-policy-low-risk-devices"]}, {"label": ["8"], "mixed-citation": [" US Food and Drug Administration. Off-The Shelf Software Use in Medical Devices.\u2005"], "uri": ["https://www.fda.gov/regulatory-information/search-fda-guidance-documents/shelf-software-use-medical-devices"]}, {"label": ["9"], "mixed-citation": [" US Food and Drug Administration. Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices. "], "uri": ["https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-data-systems-medical-image-storage-devices-and-medical-image-communications-devices"]}, {"label": ["10"], "mixed-citation": [" Medical Device Coordination Group Document MDCG 2019-11. Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 \u2013 MDR and Regulation (EU) 2017/746 \u2013 IVDR. "], "uri": ["https://ec.europa.eu/docsroom/documents/37581"]}, {"label": ["11"], "mixed-citation": [" Global Harmonization Task Force. GHTF/SG1/N071:2012. Definition of the Terms \u2018Medical Device\u2019 and \u2018In Vitro Diagnostic (IVD) Medical Device.\u2019 "], "uri": ["https://www.imdrf.org/documents/ghtf-final-documents/ghtf-study-group-1-pre-market-evaluation"]}, {"label": ["12"], "mixed-citation": [" US Food and Drug Administration. FDASIA Health IT Report. April 2014. "], "uri": ["https://www.fda.gov/about-fda/cdrh-reports/fdasia-health-it-report"]}, {"label": ["13"], "mixed-citation": [" IMDRF SaMD Working Group. \u201cSoftware as a Medical Device\u201d: Possible Framework for Risk Categorization and Corresponding Considerations. "], "uri": ["http://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-140918-samd-framework-risk-categorization-141013.pdf"]}, {"label": ["14"], "mixed-citation": [" US Food and Drug Administration. Artificial Intelligence/Machine Learning (AI/ML) Based Software as a Medical Device (SaMD) Action Plan. "], "uri": ["https://www.fda.gov/medical-devices/software-medical-device-samd/artificial-intelligence-and-machine-learning-software-medical-device"]}]	{ "acronym": [], "definition": [] }	14	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Jul 10; 12:7470	oa_package/67/77/PMC10702385.tar.gz
PMC10702392	0	[]	[]	[]	[]	[]	[ "<p>Labonté’s first commentary<sup>1</sup> concluded with what I wholeheartedly agree, namely that \"we need an activist public health movement to ensure there is sufficient political will to adopt them.\" In their follow-up commentary, Moers and colleagues<sup>2</sup> looked at things from a slightly different angle saying that to achieve equity will need radical changes in economic thinking and policies; they added that advocates needed to be strategic about framing and use hope-based communication and develop attractive and convincing narratives: \"By doing so, hopefully we can bring these messages across to larger groups of people.\" Well, I think that, together with many others, I have been strategic and radical, but only to accumulate a large bag of disappointments and broken hopes in trying to ‘bring the message across.’ But I come back to memories of so many defeats that I, with others, have lived through. Here, I describe my frustrations but explain why I do not give up hope.</p>", "<p>\n<bold>Citation:</bold> Schuftan C. Frustrations of a longtime global issues activist: Comment on \"Ensuring global health equity in a post-pandemic economy.\" <italic toggle=\"yes\">Int J Health Policy Mana</italic>g. 2023;12:8242. doi:10.34172/ijhpm.2023.8242</p>" ]	[ "<title>Can We Work Towards Building a People’s Governance Grounded in Multilateralism and Human Rights?</title>", "<p>\n<italic toggle=\"yes\">It just takes courage to stand up for the things we do at this moment of history</italic>.</p>", "<p> Frustrations can cause us to brood, but they also make us rethink. It is perhaps pertinent here to recall a few of the negotiations I was involved in that justify my frustration: negotiation of Food and Agriculture Organization’s (FAO’s) Voluntary Guidelines on the Right to Food and those on Food Systems, reforming FAO’s Committee on Food Security, the introduction of a coordinated COVID-19 and current food crisis action agenda at the same Committee on Food Security, the COVID-19 waiver at the World Trade Organization allowing the transfer of vaccine technology, the United Nations’ (UN’s) Food Systems Summit that ended up being a showcase of corporate capture and conflicts of interest, the Binding Treaty on Transnational Corporations and Human Rights being painfully negotiated for nine+ years at the Human Rights Council, World Health Organization’s (WHO’s) Framework of Engagement with Non-State Actors and other WHO resolutions, the Scaling Up Nutrition Initiative, UN Nutrition rising from the demise of the UN’s Standing Committee on Nutrition, WHO’s COVID-19 Vaccines Global Access Initiative (COVAX), 26 Conferences of the Parties on Climate Change since the Rio Earth Summit in 1992… And the list could go on… The common denominator here is that the unambiguous position of public interest organizations, literally representing millions, did not fare too well in all of these thus the frustration I here ventilate.</p>", "<p> In this commentary I want to zero-in on the challenges social movements actors have chronically faced in relation to having so unsuccessfully tackled and continue to tackle global governance issues. Am I and these actors fooling ourselves that ‘things are going to eventually be alright?’ or Does everybody involved need to work in a totally different way given that the private sector and countries rendered rich have pushed our backs totally against the wall on these issues and fora? My hope is that smart young people pick up the challenges I depict below.</p>", "<title>Bringing the Relevant Issues to Mind (Needed Elements for a Cool-Headed Analysis)</title>", "<p> Public interest civil society organizations (PICSOs) and social and indigenous movements forever seek meaningful participation in global fora in an effort to influence and strengthen — beyond voice — the decisions that can lead to lasting, legally binding changes. Unfortunately, too many times their pleas are ultimately ignored. But, they keep trying despite all odds: …“<italic toggle=\"yes\">I participate. You participate. He/she participates. We participate; but… They decide</italic>” (chalkboard in La Paz, Bolivia).</p>", "<p> Risking being brief to the point of offering only a caricature, I here distill my experience on the most relevant issues: (I have written in more detail explaining and backing up each of these bullet points. If interested, go to <uri xlink:href=\"https://claudioschuftan.com/133-frustrations-of-a-lifelong-global-issues-activist/\">https://claudioschuftan.com/133-frustrations-of-a-lifelong-global-issues-activist/</uri>)</p>", "<p>The UN system is fatally flawed as the basis for multilateral/sectoral agreements and needs wholesale reform; but this reform can and will only ‘come from below.’ </p>", "<p>As said, PICSOs have insufficient power to influence UN-related negotiations yet are often better informed/resourced than lower- and middle-income country delegations who vote for relevant resolutions. </p>", "<p>Opportunities are given to PICSOs simply to give the illusion of genuine consultation/inclusivity. </p>", "<p>Final decisions that PICSOs try to influence too often clash with the call for consensus-arrived resolutions by UN bodies and member states. It remains to be proven though that such a consensus is reached by genuine choice or by pressure reflecting an international system captured by the powerful influence of countries rendered rich. </p>", "<p>Michael Fakhri, the UN Special Rapporteur for the Right to Food reminded us that “PICSOs coming to the table to discuss better, global solutions’ is not as simple as it sounds, especially if the table is already set, the seating plan non-negotiable and the menu highly limited. …And what if the real conversation is actually happening at a different table?”<sup>##UREF##0##3##</sup></p>", "<p>Consensus using softened language is usually hammered out at the wee-wee hours of the night before the deadline a resolution must be passed — only to make PICSOs bitterly complain. </p>", "<p>Business interest non-governmental organizations are significantly more powerful in UN-related negotiations both directly and indirectly as members of multistakeholder platforms and public-private partnerships that lobby at country level and at international UN agencies (To little avail, civil society actors incessantly and forcefully denounce and dispute this). </p>", "<p>The global political economy continues to concentrate resources in the hands of private actors so that the international rules-based system of global governance currently enables, rather than resists their influence. </p>", "<p>The drivers of global governance have access to enormous and growing resources so that those rendered rich will find more and more ways to resist regulations that hamper their interests. </p>", "<p>A global conscience raising effort is needed to frame and push for effective reform of the UN system and global governance more generally — PICSOs may be well or better placed to do this since through political engagement, activists can indeed make some scenarios more likely — and other undesirable ones less likely and ultimately make more resolutions binding to member states. </p>", "<p>The risk of inaction in this realm is for new UN resolutions to only tinker with pat solutionsso that, by the end of the Sustainable Development Goals (2030), we will be again discussing these same issues. </p>", "<p> Moreover, all the signing of letters of complaint and the writing of declarations and petitions, as well as the three-minutes-reading-of-statements at UN meetings PICSOs are allowed to make may make us feel better, but how much do they help? Do we follow-up on them?</p>", "<p> Finally here, I want to emphasize that nothing is going to come from the ‘member states or this or that UN agency or the international community <italic toggle=\"yes\">should</italic>’ parlance in recommendations. World Bank Reports are full of these ‘shoulds’(!) and look where that has taken us. Assessing claim holders’ capacity and space to de-facto demand is thus part of the broader challenge. In short, any call must be coupled with human rights learning at the bases so as to help claim holders empower themselves to start demanding the needed changes. Otherwise, our calls will become yet more wish letters to Santa Claus that only bring us toys …‘batteries not included.’ Worldwide coordination among all social movements that support the human rights-based framework is thus the crucial challenge: forget relying on the ill-defined ‘international community!’</p>", "<title>What I Think Needs, Among Other, to Be Done</title>", "<p> [Actions suggested here to address the deplorable current situation in global governance are, again, brief and not exhaustive; they are presented in no particular order of priority and I am not as pretentious as to think I have the package-of-actions-to-follow to propose to you — they are rather terribly prescriptive and normative; they complement Labonté and colleagues’ and Meurs and colleagues’ views].</p>", "<p> The main challenges I suggest be addressed can be gathered under two rubrics:</p>", "<title>Need for Collective Action</title>", "<p> A strong advocacy work at UN agencies is needed in several fronts: First, I would say is to keep demanding resolutions do not require being passed by consensus, ie, allowing for member states voting for them thus eventually allowing minority reports. Second, is to be careful not to compromise when, so often — in a mockery of opening up to democratic decision-making — PICSOs are asked to comment on and/or endorse ‘zero’ or advanced drafts of official UN documents. This goes together with not accepting more promises in these documents if they do not go with concrete measures that can be legally enforced and monitored. This, I strongly feel is why so many resolutions end up with what only appears-to-be well hammered-out recommendations; in the end, the latter are only aspirations; without a commensurate call for matching policies based on legally enforceable measures, these resolutions are of no relevance to the fulfilment of “We The People of the United Nations” rights. Add to this the deceiving, poorly defined language used in these resolutions: no more stakeholders, no more loosely defined partnerships among unequal allies, no more non-state actors, no more evidence-based, no more international community, no more mutual accountability…</p>", "<p> To make progress on the above, the PICSOs communications capacity has to significantly increase and become more punching; since the traditional media are controlled by the forces of the status-quo, social media are the best option they have (I note that Twitter storms have achieved some victories, if limited).</p>", "<p> As a take-home message here for actions needed, consider: As much as more political analyses are needed, so are more political actions. I would therefore posit that to make sense of current world problems, we too often fall back on a ‘shish-kebab mentality.’ This much easier and convenient approach looks at the various problems affecting the world as if they were all separate events skewed together by tragedy or destiny. So, we set out to tackle each individual morsel …when the problem is in the skewer, ie, in the structural determinants or, if you wish, the common systemic drivers of the problems behind each morsel. These are linked to the prevailing neoliberal system that is at the very core-of and affecting each of the morsels. The point thus is: The focus has to be on changing the skewer as a means to more radically change the morsels. So, the morsels have to come together as a collective rather than letting themselves be pinched up individually on the skewer.</p>", "<title>Closer Zeroing in on Structural Determinants<sup>[<xref rid=\"fn1\" ref-type=\"fn\">1</xref>]</sup></title>", "<p> PICSOs alone will hardly achieve the needed structural changes; this means they have to actively work with sympathetic UN member states willing to speak up in international fora partnering with PICSOs — since civil society representatives are not given the floor to openly demand the changes their respective constituencies call for. As important, is for them to connect and exchange analyses and tactics with like-minded social movements constituencies and other civil society platforms in an effort to broaden the mobilization around the structural determinants depicted in the shish-kebab above, from local to global levels. The rationale is that the broader the base of organized claim holders that can be reached to exercise counter-power, the more sustainable the outcome will be, noting that, for this to happen, claim holders must progressively get inside spaces where they have been traditionally uninvited and/or excluded. Some political parties and ‘sympathetic champions’ inside UN agencies and other international agencies ought not to be off-limits in this effort either since such persons do exist and are key assets and need to be nurtured and encouraged to speak out [A caveat here is to watch out for Business interest non-governmental organizations that pretend to be on the public interest’s side, but are hiding who their financial sponsors are. The tactic has been called ‘astroturfing’<sup>##UREF##1##4##</sup>].</p>", "<p> As a take-home message here for zeroing in on what is urgent, consider: Many small struggles are to coalesce; among other, this means additionally engaging with academics, trade unions and with youth and women’s and indigenous peoples grassroots organizations — emulating the climate movement and their effective denunciation, eg, the Fridays For Future movement and Greta’s Blah! Blah! Blah! Denunciation. This broadening of alliances is to include engagement with the different UN mandate holders (including UN special rapporteurs), as well as with the progressive organizations advocating for the struggle of PICSOs’ struggle in Geneva (the South Center, the Third World Network, the Europe-Third World Centre, Centre Europe-Tier Monde…), in the Netherlands Transnational Institute, Transnational Institute and in so many other places that I feel guilty not to mention.</p>", "<p> Last but not least, if PICSOs are to achieve much of the above, their internal organization must be strengthened so they can redouble their efforts to get involved, as well as to mentor more able spokespersons, especially young activists, to speak out.</p>", "<title>Bottom Line</title>", "<p> I started asking: Can we work towards building a people’s governance grounded in multilateralism and human rights? The answer may be to adopt new, more drastic and far-reaching ways of engagement. If this fails, PICSOs and people’s movements may as well ponder the alternative to leave working with UN bodies coopted by powerful interests and moving their demands to encourage action at grassroots organizations with a greater potential to influence governance decisions that break away from the neoliberal chokehold. I recognize we are not there yet. The example of the People’s Health Movement’s ‘WHO Watch’ active in the World Health Assembly and its Executive Board meetings every year adds an important action point suggestion here.<sup>##UREF##2##5##</sup></p>", "<p> PICSOs and social movements are not giving priority to this grassroots mobilization yet. They are giving priority to continue staying in UN spaces to be watchdogs and to continue demanding conditions and procedures they want to see in place. In that sense, it is about resisting, but hardly about being radically forward-looking.</p>", "<title>An Afterthought</title>", "<p> In grieving for the alleged failures of our progressive struggles of the past, do weigh what may have happened if as PICSOs and social movements, we would not have engaged in those struggles!</p>", "<title>On a More Facetious Note</title>", "<p> En un café de Madrid escuché esta conversación, que mostraba un gran pesimismo, pero ningún dramatismo:</p>", "<p> Uno de los contertulios le decía a otro:</p>", "<p> -A mi, lo que más me gusta es perder a las barajas.</p>", "<p> -¿Pero es que no te gusta ganar?</p>", "<p> -¡Coño! ¿se puede? (you can <uri xlink:href=\"https://deepl.com\">https://deepl.com</uri> translate this).</p>", "<title>Acknowledgements</title>", "<p> Some concepts were inspired from the Civil Society Mechanism and Indigenous Peoples’ document ‘Towards a Strategy on Global Food Governance’ (<uri xlink:href=\"https://www.csm4cfs.org/policy-working-groups/global-food-governance/\">https://www.csm4cfs.org/policy-working-groups/global-food-governance/</uri>). Otherwise, I acknowledge the generous inputs of Nora Mckeon, Sofia Monsalve, Raffaele Morgantini, Patti Rundall, Ted Greiner, David Legge, and Stefano Prato.</p>", "<title>Ethical issues</title>", "<p> Not applicable.</p>", "<title>Competing interests</title>", "<p> Author declares that he has no competing interests.</p>", "<title>Disclaimers</title>", "<p> The views expressed in this commentary are those of the author and do not constitute a position of the People’s Health Movement. The commentary is primarily, but not only, for reflection by colleagues and fellow travelers who, with me and for many years, have been quixotically fighting the windmills of global development governance.</p>", "<title>Endnotes</title>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<fn-group><fn id=\"fn1\"><p> [1] here I focus on challenges PICSOs ought to be picking up on.</p></fn></fn-group>" ]	[]	[]	[{"label": ["3"], "mixed-citation": [" Fakhri M, Elver H. and De Schutter O. The UN Food Systems Summit: How not to Respond to the Urgency of Reform. Inter Press Service. August 11, 2023. "], "uri": ["https://www.ipsnews.net/2021/03/un-food-systems-summit-not-respond-urgency-reform/"]}, {"label": ["4"], "mixed-citation": [" Astroturfing. Wikipedia website. "], "uri": ["https://en.wikipedia.org/wiki/Astroturfing"]}, {"label": ["5"], "mixed-citation": [" People\u2019s Health Movement. WHO Watch website. "], "uri": ["https://phmovement.org/who-watch/"]}]	{ "acronym": [], "definition": [] }	5	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Oct 23; 12:8242	oa_package/f9/9f/PMC10702392.tar.gz
PMC10702393	37579357	[ "<title>Background</title>", "<p> Pneumonia is one of the leading causes of hospital admission in the United States,<sup>##UREF##0##1##</sup> with a global health burden of about 6.8 million hospitalizations and 1.1 million deaths in patients over 65 years old in 2015.<sup>##REF##30849172##2##</sup> Pneumonia is a lung infection caused by either fungi, bacteria, or viruses, leading to moderate to severe disease characterized by cough, fever, and trouble breathing.<sup>##UREF##1##3##</sup> In the United States, it mainly affects adults, with about 1.5 million people presenting to the Emergency Department with pneumonia in 2018,<sup>##UREF##1##3##,##UREF##2##4##</sup> causing about 40 000 pneumonia-related deaths.<sup>##UREF##1##3##</sup> Pneumonia is preventable through the pneumococcal vaccine<sup>##UREF##2##4##</sup> and is treatable with antibiotics or antivirals.<sup>##UREF##1##3##</sup> However, in 2020, only about 25% of people in the United States over 18 years old had received the pneumococcal vaccine.<sup>##UREF##2##4##</sup></p>", "<p> There are three main ways to classify pneumonia based on how it is acquired, in the community, in the hospital, or through healthcare.<sup>##REF##35090707##5##</sup> Community-acquired pneumonia is the leading cause of infectious disease death and is correlated with increased risk for in-hospital mortality.<sup>##REF##35090707##5##,##REF##29859184##6##</sup> Factors associated with in-hospital mortality include comorbidities like chronic heart and respiratory disease and age (also associated with increased severity and comorbidities), which hospitals cannot control.<sup>##REF##35090707##5##,##REF##29859184##6##</sup> Other community-acquired pneumonia risk factors include diabetes, alcohol intake, HIV, chronic renal failure, and leukemia or lymphoma.<sup>##REF##31072732##7##</sup> Similarly, ventilated hospital-acquired bacterial pneumonia and non-ventilated hospital-acquired pneumonia increasingly affect older patients with more comorbidities.<sup>##REF##34534129##8##</sup> However, non-ventilated and ventilated hospital-acquired pneumonia had higher hospital charges, length of stay, and mortality rates than patients with community-acquired pneumonia.<sup>##REF##29050905##9##</sup> One study contends that because non-ventilator-associated hospital-acquired pneumonia is associated with high mortality rates but generally unclear risk factors, all patients should be monitored, and strong prevention efforts should be promoted.<sup>##REF##35231564##10##</sup></p>", "<p> Understanding patient and hospital factors that increase pneumonia mortality rates outside of common clinical characteristics is necessary. For example, patient demographics like low socioeconomic status and race are associated with worse disease outcomes.<sup>##REF##32195315##11##,##REF##31948262##12##</sup> There is also some discussion on how the geographic location of hospitals may affect patient outcomes based on surrounding community demographics.<sup>##REF##32195315##11##, ####REF##31948262##12##, ##UREF##3##13##, ##REF##31995171##14##, ##REF##24712374##15##, ##REF##31895306##16####31895306##16##</sup> It is now vital to connect patient and hospital factors to better characterize differences in patient needs in various locations and address possible health disparities in pneumonia outcomes.</p>", "<p> Socioeconomic status and race have important implications on pneumonia outcomes. One study discussed how systemic race and socioeconomic factors play more significant roles in patient outcomes than hospital factors.<sup>##REF##30646146##17##</sup> Generally, patients with low socioeconomic status tend to have an increased risk of in-hospital mortality, decreased palliative care usage, worse health outcomes, decreased life expectancy, and earlier disease onset.<sup>##REF##34857485##18##,##REF##29730971##19##</sup> Further, differences in insurance have also impacted health outcomes, with Medicaid and Medicare patients having worse results than private insurance and Medicaid patients faring the worst.<sup>##REF##34857485##18##,##REF##29730971##19##</sup> Lower reimbursement rates than private insurance may be to blame.<sup>##REF##34857485##18##,##REF##29730971##19##</sup></p>", "<p> Differences also tend to appear in the outpatient setting. Those with lower socioeconomic factors have higher one-year mortality rates, an increased risk for respiratory infections and community-acquired pneumonia, and greater disease severity.<sup>##REF##32228396##20##</sup> Hospitalized pneumonia patients, in general, have high 1-year mortality rates, possibly due to chronic inflammation exacerbating comorbidities.<sup>##REF##32228396##20##</sup> Minorities are at increased risk for comorbidities with higher disease rates and lower socioeconomic status and health outcomes.<sup>##REF##32195315##11##,##REF##31948262##12##,##REF##26673674##21##</sup> Minority hospitals penalized for performance outcomes face more significant economic challenges as their patients may already have decreased healthcare access due to low socioeconomic status.<sup>##REF##31948262##12##</sup></p>", "<p> Another study outlined the demographics of children with pneumonia. They found higher incidence rates in the South; more than half of the patients had Medicare, and care was more expensive in the West.<sup>##UREF##4##22##</sup> Further, there are similar mortality rates between large and small hospitals, and greater severity/morality could be related to socioeconomic status.<sup>##UREF##4##22##</sup> For different disease states, results are mixed on if hospital teaching status affects disease outcomes,<sup>##REF##34761093##23##,##REF##28535236##24##</sup> and such a connection has yet to be shown for pneumonia. Previous research on health outcomes from teaching vs. non-teaching hospitals has found that public safety-net hospitals, treating patients regardless of insurance, tend to have worse results, treat more severe patients, and can still be costly, possibly because of patient sociodemographic factors.<sup>##REF##28535236##24##, ####REF##32014296##25##, ##UREF##5##26####5##26##</sup></p>", "<p> Other hospital factors that may be related to pneumonia outcomes include geographic location. Few studies have connected the geographic location of hospitals to pneumonia mortality. However, community demographics and geographic location can affect hospital quality. Unfortunately, hospitals in underserved regions may not have sufficient resources, leading to poor quality scores, influencing coverage decisions, and creating financial obstacles exacerbating the situation.<sup>##REF##31895306##16##</sup> Previous research describes how minority-serving hospitals have been unable to decrease vital disease outcomes like mortality and length of stay compared to non-minority-serving hospitals.<sup>##REF##31948262##12##</sup> One study looked at flu and pneumonia rates for hospitalized long-term care facility patients by geographic location between 2015-2016. Bosco et al found that the Midwest and the Southern US had the highest incidence rates and risk-standardized incidence rates.<sup>##REF##31995171##14##</sup> Differences in hospitalizations may have varied by location based on staffing, vaccination rates, and hospital relations to the care facilities.<sup>##REF##31995171##14##</sup></p>", "<p> There is a lack of research focusing on how patient factors, like race and socioeconomic demographics, and hospital factors, like location, size, and teaching status, are related to pneumonia death. Though there have been discussions on these characteristics separately or towards readmission rates, there is a need to identify their impact on pneumonia mortality rates. With pneumonia being a common preventable and treatable disease, it is vital to determine the factors driving mortality rates outside of treatment and vaccination rates. This study will explore patient and hospital characteristics related to pneumonia mortality in the United States and analyze how health disparities are influenced by geographic location and socioeconomics. Such descriptions may pinpoint necessary changes to public health programs and promote hospitals re-evaluating their compliance with standards of care for pneumonia and any obstacles to doing so.</p>" ]	[ "<title>Materials and Methods</title>", "<title> Data Collection</title>", "<p> The latest 2016-2019 National Inpatient Sample (NIS) database was used to obtain a population-based estimate for nationwide patients with pneumonia. Among all 2016-2019 NIS samples (N = 28 484 087), shown in Figure, we first identified a primary diagnosis of pneumonia (J189, n = 394 455) using the International Classification of Diseases 10th Revision (ICD-10-CM/PCS) codes for pneumonia. Then, after patients with missing variables were excluded, we obtained patients with pneumonia for final analysis (n = 374 766, weighted n = 1 873 828). We collected our samples from the NIS. Although we used NIS data for the analysis, our collected samples from the NIS are independent of the NIS.</p>", "<title> Variables</title>", "<p> The primary outcome of this study was to investigate the factors associated with in-hospital death among pneumonia patients. Therefore, the dataset included the “Died during hospitalization” variable. In addition, we adjusted for various patient and hospital confounders. Patient characteristics included age, race, annual median household income, primary payer (Medicare, Medicaid, Self-Pay/No Charge, Other, and Private insurance), and the severity of illness. Hospital characteristics include bed size, ownership, location, teaching status, and region.</p>", "<title> Statistical Analysis</title>", "<p> Sampling weights were applied to all statistical analyses to represent nationwide pneumonia patients. First, we examined the characteristics of the final dataset, which included patient/hospital characteristics by in-hospital death status. Patient/hospital characteristics were presented as weighted frequency (percentage) or means (standard deviation). Rao-Scott chi-square tests were used for categorical variables to investigate groups. Then we explored how patient and hospital characteristics were associated with in-hospital death using multivariate survey logistic regression analysis. Finally, we conducted an investigation where we ran the model with different regional variables. The additional analysis was performed by adjusting all other variables. All studies used SAS statistical software (version 9.4; SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided, and statistical significance was determined at <italic toggle=\"yes\">P</italic> < .05.</p>" ]	[ "<title>Results</title>", "<title> Patient/Hospital Characteristics and Descriptive Statistics</title>", "<p> A total of 374 766 pneumonia patients were identified in the 2016-2019 NIS data (weighted n=1 873 828, ##TAB##0##Table 1##). Among them, 8479 (weighted n = 42 395, 2.26%) died during hospitalization. The general characteristics of patients and hospitals are presented in ##TAB##0##Table 1##.</p>", "<p>\n##TAB##1##Table 2## shows temporal trends of in-hospital death of nationwide pneumonia patients during 2016-2019. Again, we found a decreasing in-hospital death rate among national pneumonia patients over the years (2.45% in 2016, 2.32% in 2017, 2.25% in 2018, and 2.19% in 2019).</p>", "<title> Factors Associated With In-Hospital Death </title>", "<p> The factors associated with in-hospital death from the survey logistic regression model are shown in ##TAB##2##Table 3##. After controlling for all other variables, patient characteristics include older age, male, 0-25th percentile household income, payer other than Medicare, and severe comorbidity or complications were associated with higher odds of in-hospital death. Furthermore, hospital characteristics such as government or rural status and location in the Northeast, South, or West were associated with higher in-hospital death odds than their reference groups.</p>", "<p>\n##TAB##3##Table 4## shows the primary model results with more specific region variables. We used nine categories for census division, and the reference group is East North-Central. Except for the Mountain region, every division has higher in-hospital death odds than East North-Central.</p>" ]	[ "<title>Discussion</title>", "<p> The current study has demonstrated that in-hospital pneumonia mortality rates may be affected by geographic region, insurance status, hospital ownership, and urban vs. rural location. These hospital and sociodemographic factors have vital implications for health disparities. Like previous research, we found increased mortality rates amongst elderly patients and patients with severe comorbidity or complications.<sup>##REF##35090707##5##,##REF##29859184##6##,##REF##34534129##8##,##REF##29050905##9##</sup> Unlike studies on other disease states,<sup>##REF##34857485##18##,##REF##29730971##19##</sup> which found that Medicare was associated with higher mortality, we had a higher odds ratio for those with private insurance. Looking at hospital-related factors, we found higher mortality rates for rural hospitals than urban and more significant mortality rates across the Northeast, South, and West.</p>", "<p> Socioeconomic differences had a small but significant effect on mortality rates. The lack of a substantial impact could be because hospital treatments are largely standardized regardless of socioeconomic status.<sup>##REF##30646146##17##,##REF##32228396##20##</sup> The current study found that patients in the 0-25th percentile for median household income had slightly higher in-hospital mortality rates. Previous research characterized how hospitals treating patients in low socioeconomic areas may have poorer outcomes because patients present with more severe disease<sup>##REF##31948262##12##</sup> partly due to differences in the built environment.<sup>##REF##29474451##27##</sup></p>", "<p> With wealth disparities across the United States, it becomes necessary to identify the geographic location of hospitals with increased pneumonia mortality to discuss the expanding needs of low socioeconomic populations. In 2019, 34 million people lived in poverty<sup>##UREF##6##28##</sup>; thus, patients’ socioeconomic status remains a vital health determinant. Our study found higher in-hospital mortality rates in the South, Northeast, and West. Looking into more specific regions, we found the highest mortality rates in areas like the Pacific, East South Central, and Middle Atlantic.</p>", "<p> The Pacific had 9.5%-11.9% of their population living in poverty in 2019.<sup>##UREF##7##29##</sup> East South Central, with the second-highest in-hospital mortality, had 12%-15% and higher of their people in poverty.<sup>##UREF##7##29##</sup> The Middle Atlantic had about 9.2%-13% of their population living in poverty in 2019.<sup>##UREF##7##29##</sup> Wealth may affect health and has been related to worse health outcomes for other disease states.<sup>##REF##34857485##18##,##REF##29730971##19##</sup> According to Healthy People 2030, economic factors are part of the social determinants of health as they can affect access to care, healthy food, and housing.<sup>##UREF##8##30##</sup></p>", "<p> Private insurance and self-pay had higher in-hospital pneumonia mortality rates than Medicare and Medicaid patients. Our finding differs from previous research, which found that Medicare and Medicaid patients typically have worse health outcomes.<sup>##REF##34857485##18##,##REF##29730971##19##</sup> Because treatments are standardized,<sup>##REF##30646146##17##,##REF##32228396##20##</sup> insurance reimbursement rates may not have had less impact. Lack of insurance for self-pay patients may also have affected access to healthcare.</p>", "<p> Another contributing factor may be hospital status. Areas like the East South Central, South Atlantic, New England, and West North Central had some of the highest mortality rates, possibly due to rural areas.<sup>##UREF##9##31##</sup> Rural hospitals may have an increased risk for poor health outcomes.<sup>##REF##30225336##32##</sup> Mortality rates for rural hospitals have not improved significantly as urban hospitals and rural residents have a decreased life expectancy.<sup>##REF##30225336##32##</sup> Rural patients may have worse water quality, less education, increased preventable death, and more significant socioeconomic barriers to health.<sup>##REF##30225336##32##</sup> For example, previous research found that in-hospital mortality rates for myocardial infarctions were raised in rural hospitals compared to urban teaching or non-teaching.<sup>##REF##31221462##33##</sup> Similarly, the current study saw rural hospitals had higher in-hospital pneumonia mortality rates than urban teaching or non-teaching.</p>", "<p> The ownership of the hospital was separated into government-owned, private not-for-profit, and private investor-owned. Our study found lower hospitality mortality rates for private not-for-profit and investor-owned than government-owned. Studies on other disease states also found that government hospitals have worse health outcomes than private investor-owned hospitals.<sup>##REF##34126452##34##</sup> Our findings suggest that hospitals may need to re-evaluate their compliance with existing pneumonia care standards and identify barriers to achieving compliance. In addition, small, rural, and government hospitals may need further discussion on improving outpatient comorbidity management and education to mitigate disease complexity and examine their existing care for pneumonia patients.</p>", "<p> This study has described the geographic and patient factors that may influence in-hospital pneumonia outcomes, highlighting minority health disparities across the United States; however, there are limitations to this research. First, the data set was from 2016 to 2019, which may reflect something other than the current situation. With the COVID-19 pandemic, pneumonia rates have increased globally. Secondly, the National Inpatient Dataset uses International Classification of Diseases-10th Version-Clinical Modification/Procedure Coding System (ICD-10-CM/PCS) codes for pneumonia which could have restricted patient selection. Approximately 5% of data were excluded due to missing race or insurance status information to achieve a more uniform dataset. This method is consistent with previous research using NIS data.<sup>##REF##29066439##35##, ####UREF##10##36##, ##REF##15802395##37####15802395##37##</sup> Still, excluding records may have impacted the study’s findings. Another area for improvement is the lack of clinical information and severity in the dataset, which may impact the real-life implications of our results. The NIS dataset does not include information on patient transfers between hospitals and intensive care unit vs. non-intensive care unit mortality rates, which could affect overall mortality rates between hospital types.</p>", "<p> Additionally, because of limitations with the dataset, we cannot gauge compliance to guideline therapy based on hospital resources, such as access to a pulmonologist in small hospitals or standard treatment for community-acquired pneumonia. Despite these limitations, the current study described multiple patient and hospital factors across the United States, making it generalizable. The results described here investigate health disparities and identify areas where public health programs may significantly impact patient outcomes by promoting vaccinations, chronic disease management, and education on respiratory infections.</p>" ]	[ "<title>Conclusion</title>", "<p> Pneumonia is a severe multifaceted disease affected by patient and hospital factors. Despite available treatment, patients continue to die from this disease in the United States and beyond. Understanding risk factors involved with in-hospital mortality can improve patient care and provider understanding of the community they serve. Our analysis found that in-hospital pneumonia rates are related to older age, increased disease severity and comorbidities, income, insurance type, hospital location (rural or urban), ownership, and census region. The connections to older age, disease severity, and comorbidities are well studied in the literature. However, our exploration of socioeconomics and rural location has strong connotations. Poverty and rural areas played heavy roles in pneumonia mortality and could translate to other disease states. Healthy People 2030 has outlined the need to overcome economic barriers to health; more outstanding research is required to understand how assistive programs impact patient care and best address health disparities in rural and low-income areas. Implications from our study include promoting outpatient chronic disease management and prevention to reduce mortality risk and disease complications. Greater vaccination education and rates could also help prevent disease rates and severity. Public health programs should discuss the different types of respiratory infections and when individuals should seek medical treatment. Regions like the East South Central had one of the highest mortality and significant poverty rates, and many rural areas could benefit from such public health programs.</p>" ]	[ "<p>\n<bold>Background:</bold> Pneumonia is one of the leading causes of hospital admission in the United States with a global health burden of about 6.8 million hospitalizations and 1.1 million deaths in patients over 65 years old in 2015. This study aimed to identify possible patient and hospital-related risk factors for in-hospital pneumonia death across US hospitals.</p>", "<p>\n<bold>Methods:</bold> The National Inpatient Sample (NIS) was used to identify nationwide pneumonia patients (n=374 766, weighted n=1 873 828) from 2016 to 2019. We examined the characteristics of the study sample and their association with in-hospital death. Multivariate survey logistic regression models were used to identify risk factors. </p>", "<p>\n<bold>Results:</bold> During the study periods, in-hospital death rates continuously decreased (2.45% in 2016 to 2.19% in 2019). Descriptive statistics showed that patient and hospital factors had varied in-hospital death rates. Survey logistic regression results suggested that male, very low income, non-Medicare, government hospitals, rural hospitals, and specific hospital regions were associated with higher in-hospital death rates than their reference groups.</p>", "<p>\n<bold>Conclusion:</bold> Socioeconomic factors, including income and insurance, are associated with pneumonia mortality. Census region, hospital ownership, and rural location are also related to in-hospital mortality. Such findings in underserved, impoverished, and rural areas to identify possible health disparities.</p>", "<p>\n<bold>Citation:</bold> Kim SJ, Medina M, Zhong L, Chang J. Factors associated with in-hospital death among pneumonia patients in US hospitals from 2016~2019.<italic toggle=\"yes\">Int J Health Policy Manag</italic>. 2023;12:7390. doi:10.34172/ijhpm.2023.7390</p>" ]	[ "<title>Ethical issues</title>", "<p> The data we use was secondary data and all patient data were encrypted and unable to identify. This study was approved for waiver from the Institutional Review Board of Soonchunhyang University (202203-SB-027).</p>", "<title>Competing interests</title>", "<p> Authors declare that they have no competing interests.</p>" ]	[]	[ "<fig position=\"float\" id=\"F1\"><label>Figure</label><statement><p>\nFlow Chart of Sample Selection.</p></statement></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1</label><caption><title>General Characteristics of Sample\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th rowspan=\"3\" style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n</th><th colspan=\"4\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>In-Hospital Death</bold>\n</th><th rowspan=\"3\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" colspan=\"1\">\n<italic toggle=\"yes\">\n<bold>P </bold>\n</italic>\n<bold>Value</bold>\n</th></tr><tr><th colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>Yes</bold>\n</th><th colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>No</bold>\n</th></tr><tr><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>No.</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>%</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>No.</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">%</th></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">N</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">8479</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">2.26</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">366 287</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\"> 97.74</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Weighted N [National Estimates]</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">42 395</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.26</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 1 831 433</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.74</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Age<sup>a</sup></td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">64.24</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">23.08</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">77.03</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12.95</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> <.0001</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Gender</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.0002</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Male</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">20 715</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.36</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">857 704</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.64</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Female</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">21 680</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.18</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">973 729</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.82</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Race</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.0001</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> White</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">32 900</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.43</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 320 863</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.57</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Black</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4170</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.73</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">236 510</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">98.27</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Hispanic</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3115</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.77</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">172 935</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">98.23</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Asian or Pacific Islander</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">970</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.33</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">40 660</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.67</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Native American</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">185</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.41</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12 950</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">98.59</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Other</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1055</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.17</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">47 515</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.83</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Median household income </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.0764</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 0-25th percentile</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14 035</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.23</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">614 284</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.77</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 26th to 50th percentile </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11 675</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.27</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">503 609</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.73</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 51st to 75th percentile</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9135</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.20</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">405 820</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.80</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 76th to 100th percentile</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">7550</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.39</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">307 720</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.61</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Primary payer</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.0001</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Medicare</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">32 670</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.73</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 165 949</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.27</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Medicaid</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2180</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.84</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">257 875</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">99.16</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Private insurance</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5300</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.66</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">314 655</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">98.34</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Self-pay</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">585</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.06</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">54 695</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">98.94</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> No charge</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">50</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.18</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4170</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">98.82</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Other</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1610</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.51</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">34 090</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">95.49</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Severity of Illness </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> No/Minor comorbidity or complications</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">595</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.29</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">204 180</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">99.71</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.0001</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Moderate comorbidity or complications</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3645</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.54</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">671 344</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">99.46</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Major comorbidity or complications</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">14 860</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.94</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">752 814</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">98.06</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Extreme comorbidity or complications</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">23 295</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10.29</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">203 095</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">89.71</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Bed size of the hospital</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.0001</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Small</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10 815</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.11</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">502 129</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.89</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Medium</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">12 720</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.24</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">555 224</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.76</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Large</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">18 860</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.38</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">774 080</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.62</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Ownership of hospital</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.0006</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Government nonfederal</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5725</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.34</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">238 593</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.66</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Private not-profit</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">30 670</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.29</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 305 745</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.71</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Private invest-own</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">6000</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.05</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">287 095</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.95</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Location/teaching status of the hospital</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">.0185</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Rural</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8130</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.40</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">330 399</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.60</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Urban nonteaching</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">11 275</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.27</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">486 454</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.73</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Urban teaching</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">22 990</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.22</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1 014 580</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.78</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Region of hospital</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"><.0001</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Northeast</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8220</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.42</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">332 020</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.58</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Midwest</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8940</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.09</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">419 499</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.91</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> South</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">17 610</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.20</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">784 504</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">97.80</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\"> West</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">7625</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2.52</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">295 409</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">97.48</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T2\"><label>Table 2</label><caption><title>Temporal Trend of In-Hospital Death of Pneumonia Patients\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>2016</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>2017</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>2018</bold>\n</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>2019</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">N</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">113 417</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">87 780</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">96 646</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">76 923</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Weighted N [National Estimates]</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">567 084</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">438 900</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">483 229</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">384 615</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">In-hospital death</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> No</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">553 504</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">428 965</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">472 595</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">376 370</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Yes</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">13 580</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">9 935</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">10 635</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">8245</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\"> % Of yes</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2.45%</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2.32%</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2.25%</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">2.19%</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T3\"><label>Table 3</label><caption><title>Results of Survey Logistic Regression Models: Factors Associated With In-Hospital Death\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><th style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Variables</bold>\n</th><th style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>OR</bold>\n</th><th colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>95% CLs</bold>\n</th></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Age</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1.046</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1.043</td><td style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">1.048</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Gender</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Male</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.103</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.055</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.154</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Female</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Race</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> White</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Black</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.033</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.956</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.116</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Hispanic</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.017</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.931</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.112</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Asian or Pacific Islander</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.038</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.891</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.208</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Native American</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.904</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.650</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.258</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Other</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.178</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.019</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.361</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Median household income </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 0-25th percentile</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.102</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.025</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.184</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 26th to 50th percentile </td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.027</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.958</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.102</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 51st to 75th percentile</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.964</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.897</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.036</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> 76th to 100th percentile</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Primary payer</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Medicare</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Medicaid</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.294</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.160</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.444</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Private insurance</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.660</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.540</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.790</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Self-pay</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.578</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.302</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.914</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> No charge</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.668</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.886</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.139</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Other</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.063</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">2.690</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.489</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Severity of illness </td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> No/Minor comorbidity or complications</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Moderate comorbidity or complications</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.311</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.079</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.592</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Major comorbidity or complications</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">4.539</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">3.776</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">5.457</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Extreme comorbidity or complications</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">28.267</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">23.529</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">33.960</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Bed size of the hospital</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Small</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.014</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.958</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.073</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Medium</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.973</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.922</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.026</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Large</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Ownership of hospital</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Government, nonfederal</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Private, not-profit</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.828</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.773</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.887</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Private, invest-own</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.748</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.686</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.815</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Location/teaching status of the hospital</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Rural</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.307</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.225</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.394</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Urban nonteaching</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.012</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.959</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.068</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Urban teaching</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">Region of hospital</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Northeast</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.285</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.196</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.380</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Midwest</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> South</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.137</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.068</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.210</td></tr><tr><td style=\"vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> West</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.202</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.115</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.295</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">Year</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.845</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.827</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">0.863</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"T4\"><label>Table 4</label><caption><title>Results of Survey Logistic Regression Models Using Census Division of Hospital\n</title></caption><table frame=\"hsides\" rules=\"none\"><tbody><tr><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>Variables </bold>\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\" colspan=\"1\">\n<bold>OR</bold>\n</td><td colspan=\"2\" style=\"text-align:center;vertical-align:middle;border-width:0.5pt 0pt 0.5pt 0pt;border-style: solid none solid none;\" rowspan=\"1\">\n<bold>95% CLs</bold>\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">Census division of hospital </td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;border-width:0.5pt 0pt 0pt 0pt;border-style: solid none none none;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> New England</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.288</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.148</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.446</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Middle Atlantic</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.373</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.262</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.493</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> East North Central</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.000</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">\n</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> West North Central</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.189</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.070</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.321</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> South Atlantic</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.123</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.038</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.215</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> East South Central</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.335</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.215</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.467</td></tr><tr><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> West South Central</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.214</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.107</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.330</td></tr><tr style=\"background-color:#eeeeee\"><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\"> Mountain</td><td style=\"text-align:left;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.019</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">0.907</td><td style=\"text-align:center;vertical-align:middle;\" rowspan=\"1\" colspan=\"1\">1.146</td></tr><tr><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\"> Pacific</td><td style=\"text-align:left;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1.399</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1.279</td><td style=\"text-align:center;vertical-align:middle;border-width:0pt 0pt 0.5pt 0pt;border-style: none none solid none;\" rowspan=\"1\" colspan=\"1\">1.530</td></tr></tbody></table></table-wrap>" ]	[]	[ "<boxed-text id=\"BT1\" position=\"float\"><sec id=\"bx1\"><title>Key Messages</title><p>\n<bold>Implications for policy makers</bold>\n</p><list list-type=\"bullet\"><list-item><p>Pneumonia is one of the leading causes of hospital admission in the United States. </p></list-item><list-item><p>It is necessary to understand patient and hospital factors that increase pneumonia mortality rates outside of common clinical characteristics. </p></list-item><list-item><p>Socioeconomic status and race have important implications on pneumonia outcomes. </p></list-item><list-item><p>This study focuses on patient and hospital characteristics related to pneumonia mortality in the United States and analyzes how health disparities are influenced by geographical location and socioeconomics. </p></list-item></list><p>\n<bold>Implications for the public</bold>\n</p><p> Pneumonia is a severe multifaceted disease affected by patient and hospital factors. Despite available treatment, patients continue to die from this disease in the United States and beyond. Understanding risk factors involved with in-hospital mortality can improve patient care and provider understanding of the community they serve. Implications from our study include promoting preventative strategies and assistance programs for disadvantaged patients. Hospitals serving low-income or rural patients may see worse health outcomes and require greater resource allocation. Regions like the East South Central, which had one of the highest mortality rates, significant poverty rates, and many rural areas could benefit from such assistance programs</p></sec></boxed-text>" ]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>\n<sup>a</sup>Mean/standard deviation.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: OR, odds ratio; CLs, confidence limits.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p> Abbreviations: OR, odds ratio; CLs, confidence limits.</p><p> * All other variable were adjusted.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"ijhpm-12-7390-g001\" position=\"float\"/>" ]	[]	[{"label": ["1"], "mixed-citation": [" American Thoracic Society. Top 20 Pneumonia Facts-2019. ATS. "], "uri": ["https://www.thoracic.org/patients/patient-resources/resources/top-pneumonia-facts.pdf"]}, {"label": ["3"], "mixed-citation": [" Centers for Disease Control and Prevention. Pneumonia. U.S. Department of Health and Human Services. "], "uri": ["https://www.cdc.gov/dotw/pneumonia/index.html"]}, {"label": ["4"], "mixed-citation": [" National Center for Health Statistics. Pneumonia. Centers for Disease Control and Prevention. "], "uri": ["https://www.cdc.gov/nchs/fastats/pneumonia.htm"]}, {"label": ["13"], "person-group": ["\n"], "surname": ["Jindal", "Gauri", "Singh", "Nicholson"], "given-names": ["RP", "DK", "G", "S"], "article-title": ["Factors influencing hospital readmission penalties: are they really under hospitals\u2019 control?"], "source": ["Decis Support Syst"], "year": ["2018"], "volume": ["110"], "fpage": ["58"], "lpage": ["70"], "pub-id": ["10.1016/j.dss.2018.03.006"]}, {"label": ["22"], "person-group": ["\n"], "surname": ["Sulley", "Ndanga"], "given-names": ["S", "M"], "article-title": ["Pediatric pneumonia: an analysis of cost & outcome influencers in the United States"], "source": ["Int J PediatrAdolesc Med"], "year": ["2019"], "volume": ["6"], "issue": ["3"], "fpage": ["79"], "lpage": ["86"], "pub-id": ["10.1016/j.ijpam.2019.04.002"]}, {"label": ["26"], "mixed-citation": [" Zheng M, Arora N, Chambers T, O\u2019Dell K, Johns MM. Comparison of treatment for recurrent respiratory papillomatosis at a public county versus private academic hospital. J Voice. 2022. "], "pub-id": ["10.1016/j.jvoice.2022.01.019"]}, {"label": ["28"], "mixed-citation": [" Semega J, Kollar M, Shrider EA, Creamer J. Income and Poverty in the United States: 2019. United States Census Bureau. "], "uri": ["https://www.census.gov/library/publications/2020/demo/p60-270.html"]}, {"label": ["29"], "mixed-citation": [" United States Census Bureau. 2019 Poverty Rate in the United States. "], "uri": ["https://www.census.gov/library/visualizations/interactive/2019-poverty-rate.html"]}, {"label": ["30"], "mixed-citation": [" Healthy People 2030. Economic Stability. U.S. Department of Health and Human Services. "], "uri": ["https://health.gov/healthypeople/objectives-and-data/browse-objectives/economic-stability"]}, {"label": ["31"], "mixed-citation": [" United States Census Bureau. Rural America. census.gov. "], "uri": ["https://mtgis-portal.geo.census.gov/arcgis/apps/MapSeries/index.html?appid=49cd4bc9c8eb444ab51218c1d5001ef6"]}, {"label": ["36"], "person-group": ["\n"], "surname": ["Khorgami", "Aminian", "Shoar"], "given-names": ["Z", "A", "S"], "article-title": ["Cost of bariatric surgery and factors associated with increased cost: an analysis of national inpatient sample"], "source": ["Surg ObesRelat Dis"], "year": ["2017"], "volume": ["13"], "issue": ["8"], "fpage": ["1284"], "lpage": ["1289"], "pub-id": ["10.1016/j.soard.2017.04.010"]}]	{ "acronym": [], "definition": [] }	37	CC BY	no	2024-01-13 00:02:18	Int J Health Policy Manag. 2023 Jul 24; 12:7390	oa_package/fe/96/PMC10702393.tar.gz
PMC10716168	38087047	[ "<title>Introduction</title>", "<p id=\"Par3\">From childhood to adolescence, the neural circuitry of the human brain undergoes dramatic changes, which supports rapid behavior and cognitive development<sup>##REF##25441756##1##–##REF##27865786##4##</sup>. As the anatomical substrate of the neural circuitry, white matter (WM) shapes functional synchronization and undergoes extensive biophysical development, such as myelination, synaptic pruning, and increased axonal density<sup>##REF##29229299##5##,##REF##19595493##6##</sup>, which facilitates rapid neural signal communication between regions. Importantly, brain development exhibits heterogeneous patterns across different regions, and the primary sensorimotor cortex matures earlier than the higher-order association cortex<sup>##REF##15737818##7##</sup>. Genes play an important role in regulating brain structural and functional development across age and regions<sup>##REF##22031440##8##–##REF##34244483##11##</sup>. Although previous studies have characterized the age-related trajectory of typical WM development<sup>##REF##29229299##5##</sup>, the genetic and cellular mechanisms of WM development from a longitudinal perspective remain largely unknown.</p>", "<p id=\"Par4\">As the brain is a complex system, network modeling and graph theory-based analyses have provided an important approach in investigating brain integration and segregation from a system level<sup>##REF##19190637##12##–##REF##26505566##15##</sup>. With diffusion MRI (dMRI) and tractography techniques, the whole-brain WM structural connectome can be delineated in vivo. This delineation captures the tangible fiber connections interconnecting distinct cerebral regions and unveils several nontrivial topological properties, such as small-worldness, modular structure, and rich-club organization<sup>##REF##19190637##12##,##REF##19819337##13##,##REF##22049421##16##</sup>. With normal development, increased global and local efficiency, stable or decreased clustering, and the modularity of the WM structural connectome can be observed, typically indicating a WM network reconfiguration from being local to more distributed and integrated<sup>##REF##22982357##17##–##REF##28552358##21##</sup>. Our previous studies also revealed increased trade-off between the integration and segregation of the WM connectome with development, which may be the outcome of both the heterogeneous strengthening and the pruning of specific fibers<sup>##REF##24335033##22##–##REF##29913282##24##</sup>.</p>", "<p id=\"Par5\">Longitudinal cohorts can be evaluated to characterize brain development trajectory more accurately than cross-sectional cohorts by disentangling within-person developmental change from between-person variation<sup>##REF##29229299##5##</sup>. With a longitudinal cohort, a spatial refinement of WM connectivity between hub regions appears in late adolescence<sup>##REF##26085632##25##</sup>. Another longitudinal study reported spatial distribution and topological differences with development across different edge types of the WM connectome<sup>##REF##28960629##26##</sup>. However, there were hardly longitudinal studies with large samples on multiscale WM connectome development from global to regional/connectional levels, limiting insight into patterns and trends in multiscale WM connectome development.</p>", "<p id=\"Par6\">Genes play important roles in regulating WM development. Typical twin studies have observed moderate to high heritability of specific WM tracts<sup>##REF##17021179##27##</sup>, and genetic factors can mediate the relationship between WM microstructure and intelligence<sup>##REF##19228974##28##</sup>. Furthermore, large-scale genome-wide association studies have found that the WM microstructure is regulated by hundreds of genes that are associated with brain neurodevelopment, cognitive functions and multiple brain disorders<sup>##REF##31666681##10##,##REF##34140357##29##,##REF##29365026##30##</sup>, but these previous studies lack information of spatial variations on gene expression. The Allen Human Brain Atlas (AHBA, <ext-link ext-link-type=\"uri\" xlink:href=\"http://human.brain-map.org/\">http://human.brain-map.org/</ext-link>) offered RNA expression levels of more than 20,000 genes taken from 3,702 spatially distinct brain tissue samples<sup>##REF##22996553##31##</sup>, making it possible to bridge the gap between neuroimaging and transcriptomics<sup>##REF##30455082##32##</sup>. With imaging transcriptomic analysis, genes whose expression pattern co-varying with brain imaging phenotypes can be identified and further enrichment analyses can be carried out to explore potentially functional pathways and cellular processes<sup>##REF##34244483##11##,##REF##33787489##33##–##REF##27457931##35##</sup>. A recent functional network study investigated the association between modular variability with development and gene expression profiles, which identified the genes enriched for ion transport and nucleobase-containing compound transport<sup>##REF##34378030##36##</sup>. Another study revealed that the transition of functional gradient during development is associated with the expression levels of calcium ion regulated exocytosis and synaptic transmission-related genes<sup>##UREF##0##37##</sup>. WM structural connectivity between brain regions has been shown to correlate with cortical gene expression using AHBA<sup>##REF##27720199##38##</sup>. However, the transcriptomic architecture of WM connectome development remains largely unknown.</p>", "<p id=\"Par7\">Developmental studies have demonstrated heterogeneous age-related increases in cortical myelination which may underlie the enhanced cognitive ability<sup>##REF##27457931##35##,##REF##25695268##39##,##REF##35705486##40##</sup>. The age-related increases in cortical myelination accompanied by cortical shrinkage are maximized approximately at the internal layer of projection neurons<sup>##REF##27457931##35##</sup>. Recently, a quantitative laminar atlas<sup>##REF##32243449##41##</sup> derived from a 3D histological atlas of the human brain at 20-micrometer isotropic resolution (BigBrain)<sup>##REF##23788795##42##</sup>, provided high level of cytoarchitectonic detail to capture six cortical laminas formed by cellular division and differentiation. Thus, we attempted to establish a link between the developmental patterns of the macroscale WM connectome and microscale myelin content<sup>##REF##21832190##43##</sup> or cortical laminar thickness.</p>", "<p id=\"Par8\">In the present study, we aimed to characterize the age-related longitudinal trajectory of the WM structure connectome from global, regional, and connectional levels, based on a large-sample cohort with 604 typically developing children from 6 to 13 years of age. To explore the potential genes regulating spatial patterns of WM connectivity development, we referred to the AHBA, and recognized the enrichment pathways and their cellular organizations based on connectome and transcriptome association analyses. Moreover, we examined whether the heterogeneous spatial development of the WM connectome can reflect the cytoarchitectural properties of cortical organization. Finally, different modeling methods and an independent development cohort were used to assess the reproducibility of our findings.</p>" ]	[ "<title>Methods</title>", "<title>Participants</title>", "<p id=\"Par31\">We used a cohort from the CBD<sup>##UREF##1##44##</sup>, an ongoing longitudinal dMRI study, in the present study. From the cohort, typically developing children were recruited from Beijing primary schools. The exclusion criteria included the presence of intellectual or developmental abnormalities, a history of neurological or psychiatric disorders, the use of psychoactive drugs, and the presence of a significant head injury. All the participants underwent at least one MRI acquisition at three-time points 1 year apart. A total of 604 typically-developing children (age range of 6 to 13 years, 339 males and 266 females), including 1033 scans were selected for analysis in the present study (Supplementary Table ##SUPPL##0##1##) after age matching and quality control during MRI preprocessing. This study was conducted according to the guidelines of the Declaration of Helsinki and was approved by Beijing Normal University Institutional Review Board. Informed consent was obtained from parents/guardians of all participants.</p>", "<title>Imaging acquisition and preprocessing</title>", "<p id=\"Par32\">The MRI data were acquired using the same Siemens Trio 3 T scanner with a 16-channel phased array head coil at the Beijing University center and the Beijing Huilongguan Hospital center. MRI scanning included the collection of 3D T1-weighted structural MRI with a 1 mm<sup>3</sup> isotropic voxel size (TR = 2530 ms, TE = 2.98 ms, TI = 1100 ms, flip angle = 7°, FOV = 256 × 224 mm<sup>2</sup>, and 192 sagittal slices) and diffusion-weighted MRI (DWI) with a 2 mm<sup>3</sup> isotropic voxel size (64 diffusion directions with b = 1000 s/mm<sup>2</sup> and 10 images with <italic>b</italic> = 0 s/mm<sup>2</sup>, TR = 7500 ms, TE = 64 ms, flip angle = 90°, FOV = 224×224 mm<sup>2</sup>, and 70 axial slices). The preprocessing procedures for dMRI data comprised the correction of the eddy current and motion artefacts, the estimation of the diffusion tensor elements, and the calculation of the fractional anisotropy (FA). The eddy current distortions and motion artefacts in the dMRI data were corrected by applying an affine alignment of each DWI image to the b0 image. Then the diffusion tensor elements were estimated by solving the Stejskal and Tanner equations, and the FA value of each voxel was calculated. All procedures were executed using the FMRIB’s Diffusion Toolbox of the FMRIB Software Library (<ext-link ext-link-type=\"uri\" xlink:href=\"https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FDT\">https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FDT</ext-link>).</p>", "<title>Image quality control</title>", "<p id=\"Par33\">Rigorous quality control was conducted for T1 and dMRI images. An experienced radiologist examined each T1 image to ensure the absence of arachnoid cysts, neuroepithelial cysts, or any other intracranial occupying lesions. Subsequently, five trained raters visual inspected the T1 images for brain damage, missing layers, or evident noise. Out of the original 1072 T1 images, 32 were excluded due to poor image quality, leaving 1040 images entering the subsequent analysis. For dMRI image, images reported as failures by DTIprep<sup>##UREF##6##108##</sup> were excluded. Additionally, visual inspections by five trained raters were conducted, and images with abnormal volume proportions exceeding 10% were excluded. Out of the 1053 dMRI images initially acquired, 1033 images passed the quality control. Finally, 1033 scans with both T1 and dMRI images were included in the subsequent analysis.</p>", "<title>WM network construction</title>", "<p id=\"Par34\">The BNA246<sup>##REF##27230218##51##</sup> template was used to define network nodes. Briefly, a b0 image was first aligned to a native T1 image, and then the native T1 image was normalized to an asymmetric T1 template for 6-12 years from Chinese Paediatric Atlases<sup>##REF##30625395##109##</sup> using the FMRIB Software Library (<ext-link ext-link-type=\"uri\" xlink:href=\"https://fsl.fmrib.ox.ac.uk/fsl\">https://fsl.fmrib.ox.ac.uk/fsl</ext-link>). Inverse transformation matrices derived from the aforementioned steps were applied to transform the brain atlas of standard space into native space. Following our previous methodological evaluation study<sup>##REF##35475571##107##</sup>, the dMRI data with single b value is suitable for a deterministic tractography with a single tensor model to reconstruct whole-brain fiber tracts based on the Diffusion Toolkit (<ext-link ext-link-type=\"uri\" xlink:href=\"http://www.trackvis.org/dtk/\">http://www.trackvis.org/dtk/</ext-link>). Based on the tractography results, the FAFN-weighted network of each participant was constructed, where the FAFN weight was defined as the average FA value of the voxels traversed along the connected fibers between two regions times the number of fiber streamlines (FN) connecting two brain regions. Two regions are deemed structurally connected if there is at least one streamline fiber present, with both of its end-points located within these two regions<sup>##REF##29913282##24##</sup>.</p>", "<title>Global network properties</title>", "<p id=\"Par35\">Leveraging graph theory model, network properties can be derived to reflect the brain’s various characteristics. Eight whole-brain properties were calculated according to the constructed network, including global efficiency, local efficiency, shortest path, network strength, clustering coefficient, and small-world parameters (, and )<sup>##REF##19819337##13##</sup>.</p>", "<p id=\"Par36\">The global efficiency measures the efficiency of parallel information transfer in the whole network <sup>##REF##11690461##110##</sup>, which can be computed as:where is the shortest path length between node and node in . is the number of nodes in .</p>", "<p id=\"Par37\">The local efficiency of reveals how much the network is fault tolerant, showing how efficient the communication is among the first neighbors of the node when it is removed. The local efficiency of a graph is measured as:where denotes the subgraph composed of the nearest neighbors of node .</p>", "<p id=\"Par38\">The shortest path of a network quantifies the ability for information to propagate in parallel. The shortest path length of a network was computed as follows:where the shortest path length between any pair of nodes (e.g., node and node ) is defined as the sum of the edge lengths along this shortest path. For weighted networks, the length of each edge was assigned by computing the reciprocal of the edge weight ().</p>", "<p id=\"Par39\">The network strength quantifies the overall connectivity within the brain network. For a network , the strength of was calculated as:where is the sum of the edge weights linking to node . And the strength of a network is the average of the strengths across all of the nodes in this network.</p>", "<p id=\"Par40\">The clustering coefficient indicates the extent of the local interconnectivity or cliquishness in a network<sup>##REF##9623998##111##</sup>, and calculated as:where is the likelihood of whether the neighborhoods of node were connected with each other or not, and is computed as follows:<sup>##UREF##7##112##</sup>where is the degree of node and is the weight of edge, which is scaled by the largest weight of the network. Of note, the clustering coefficient is zero if the nodes are isolated or have just one connection.</p>", "<p id=\"Par41\">The small-world network exhibits a high level of clustering close to regular networks, while still maintaining a short average path length close to random networks. The clustering coefficient and the shortest path length of the brain networks were compared with those of random networks. In this study, we generated 5,000 matched random networks, which had the same number of nodes, edges, and degree distribution as the real networks<sup>##REF##11988575##113##</sup>. Furthermore, we computed the normalized and as follows:where and are the mean and the mean of 5,000 matched random networks, respectively. A real network would be considered small-world if and <sup>##REF##9623998##111##</sup>. Thus, the small-worldness can be defined as follows:where is typically greater than 1 for small-world networks<sup>##REF##18446219##114##</sup>.</p>", "<title>Local network properties</title>", "<p id=\"Par42\">For each brain region, four common nodal properties were calculated: nodal efficiency, nodal local efficiency, nodal degree centrality, and nodal betweenness centrality<sup>##REF##19819337##13##</sup>.</p>", "<p id=\"Par43\">The nodal efficiency<sup>##REF##17274684##115##</sup> quantifies the nodal contribution to the overall efficiency of communication across the entire network, which can be calculated using the following equation:where n is the number of nodes and is the shortest path length between nodes and .</p>", "<p id=\"Par44\">The nodal local efficiency<sup>##REF##17274684##115##</sup> quantifies the nodal contribution to the local communication efficiency, which can be calculated as:</p>", "<p id=\"Par45\">The nodal degree centrality quantifies the total number/strength of the connections of one node in the network:</p>", "<p id=\"Par46\">The nodal betweenness centrality<sup>##UREF##8##116##</sup> quantify the role of a node in facilitating communication between other node pairs in the network. The nodal betweenness centrality of node was defined as:where is the number of shortest paths between node and node , and is the number of shortest paths between node and node passing through node .</p>", "<title>Functional subnetwork properties</title>", "<p id=\"Par47\">From the perspective of the functional subnetwork, brain regions were assigned to seven different functional networks<sup>##REF##21653723##54##</sup> according to an official corresponding table provided by the official website (<ext-link ext-link-type=\"uri\" xlink:href=\"http://www.brainnetome.org/\">http://www.brainnetome.org/</ext-link>), and subcortical regions within BNA246<sup>##REF##27230218##51##</sup> were defined as the subcortical function network. Furthermore, the properties of different functional networks were the average properties of assigned regions.</p>", "<title>Connection properties</title>", "<p id=\"Par48\">Various measures of centrality enable the identification of central brain hubs characterized by high-degree connectivity. To reduce false-positive edges, one edge was zero if its nonzero number was less than 75% at the group level<sup>##REF##18567609##117##</sup>. Then, one node of the group-averaged network was defined as the hub if its nodal degree centrality or nodal betweenness centrality was greater than the <italic>mean</italic> <italic>std</italic> of all nodes; otherwise, it was defined as a nonhub. According to the different categories of two nodes, the existing edges between them were classified into three types: local (nonhub to nonhub), feeder (hub to nonhub) and rich-club (hub to hub)<sup>##REF##22049421##16##</sup>.</p>", "<p id=\"Par49\">The brain networks have a pronounced tendency to form functional modules, reflected by an abundance of connectivity within each module and the relatively sparse connectivity between modules. Based on the functional modular architecture consisting of the 8 subnetworks, the edges of all participations were assigned as two types: within-modular edge and between-modular edge.</p>", "<p id=\"Par50\">The physical distance of streamline fibers was defined as the average length of all streamline fibers between two regions, removing the effects of brain size. Edge length in the group-averaged network was the average of the lengths of corresponding edges across individual participants. The threshold was calculated as the average of all edge lengths to define two edge types: short edge and long edge.</p>", "<title>Age-related trajectory of WM network organization</title>", "<p id=\"Par51\">To characterize developmental trajectories of various properties of WM network organization, a mixed effect model<sup>##REF##7168798##52##</sup> was applied to mine the intrinsic longitudinal relationship between properties and age in our study. For each measure, both linear and quadratic models were constructed after controlling for total brain volume, center, and sex.</p>", "<p id=\"Par52\">The linear model was as follows:where is the network measures of participation at the time point, is the fixed effect, is the random effect of participation , is the acquisition age of participation at the time point. Total brain volume (), center () and sex () are considered as covariates. is the residual of participation at the time point.</p>", "<p id=\"Par53\">The quadratic model was as follows:where is the fixed effect and is the random effect of participation .</p>", "<p id=\"Par54\">For sex difference, a linear model which included age-by-sex interaction term was utilized as follows:</p>", "<p id=\"Par55\">Notably, the network strength was included as a covariate in edge analysis to delineate intrinsic edge topology alteration<sup>##REF##28552358##21##,##REF##31874926##47##</sup>. The Akaike information criterion<sup>##UREF##3##53##</sup> was used to determine the optimal model, with a lower value reflecting a trade-off between the likelihood and simplicity of a model. The Markov Chain Monte Carlo method estimated the standard error and 95% confidence interval (CI) of age effect. In local and functional subnetwork level models, nodal and functional subnetwork measures were z-score standardized to obtain a standard slope for facilitating comparisons of different measures. The <italic>p</italic> values of models were corrected for multiple comparisons by the Bonferroni method.</p>", "<title>Main gradients of the developmental slope</title>", "<p id=\"Par56\">To explore how developmental slope varied along various gradients, we extracted the mean slope of each nodal property across all regional voxels for posterior-to-anterior, medial-to-lateral or inferior-to-superior slice including more than 500 voxels. Then we tested whether a change was significantly different along gradients by comparing slopes between two group slices separated by a midline of the brain. Of note, medial-to-lateral slices were separated into the lateral group and medial group in every hemisphere. The <italic>t</italic>-test was used to verify its significance with <italic>p</italic> < 0.05.</p>", "<title>Association between WM development and gene expression</title>", "<p id=\"Par57\">For the AHBA dataset, the preprocessing of anatomic and genomic information was performed by referencing a recommended pipeline<sup>##REF##30648605##55##</sup>. Specifically, we generated preprocessed structural data by FreeSurfer (<ext-link ext-link-type=\"uri\" xlink:href=\"https://surfer.nmr.mgh.harvard.edu/fswiki/\">https://surfer.nmr.mgh.harvard.edu/fswiki/</ext-link>) for each donors. According to official scripts (<ext-link ext-link-type=\"uri\" xlink:href=\"http://www.brainnetome.org/resource/\">http://www.brainnetome.org/resource/</ext-link>), the BNA246 template was projected on native fsaverage space. Finally, an averaged gene expression profile of 10,027 genes covering 199 cortical regions (excluding 47 cortical regions that had an insufficient number of assigned samples) was produced.</p>", "<p id=\"Par58\">PLS correlation<sup>##REF##20656037##56##</sup> was performed to mine the weighted linear combinations (components) of gene expression profiles associated with the spatial development slopes of the WM connectome. Specifically, we utilized development slopes from 199 brain regions that spatially matched with the gene expression profile. For each PLS component, We calculated Pearson’s correlation coefficient to assess the association between the PLS score and development slopes . To correct for spatial autocorrelation, we compared the empirically observed value with spatially constrained null models generated by 10,000 permutations of surrogate maps of development slopes <sup>##REF##32139786##57##</sup>. Furthermore, we transformed the gene weight into a z-score value by dividing the standard deviation of the corresponding weights estimated from bootstrapping and ranked all genes. The significant genes with a Bonferroni of 1% were identified for the positive or negative gene list. Then, we performed gene functional enrichment for the GO biological process pathway search with Metascape<sup>##REF##30944313##58##</sup>, focusing on selected high positive or negative genes. The resulting enrichment pathways were retained for significance at FDR < 0.05. Briefly, enriched terms were filtered by calculating accumulative hypergeometric <italic>p</italic> values and enrichment factors, and then hierarchically clustered into a tree according to Kappa similarity among their gene memberships. A threshold value kappa score of 0.3 was applied to cast the tree into term clusters.</p>", "<title>Cell type-specific analysis</title>", "<p id=\"Par59\">The selected genes were initially assigned to 58 cell types derived from five studies focusing on single-cell research using the human postnatal cortex<sup>##REF##30545854##9##,##REF##26687838##59##–##REF##26060301##62##</sup>, and these cell types were subsequently integrated into seven canonical classes<sup>##REF##32620757##63##</sup>. Specifically, the cell classes comprised of astrocytes, endothelial cells, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, and oligodendrocyte precursors. The method avoided possible bias including acquisition methodology, analysis, or threshold method<sup>##REF##32620757##63##,##REF##34931033##118##</sup>. For statistics of cell types, we calculated overlapping numbers of the selected positive/negative genes in each cell class. A null model was generated by 10,000 random resamples in genes within each cell type to test the significance of the results. In addition, the genes involved in each enriched term were subjected to the aforementioned analysis to explore the specificity of the cell type.</p>", "<title>Relationship to the cytoarchitecture of cortical organization</title>", "<p id=\"Par60\">To explore whether the developmental pattern of the WM connectome aligns with the fundamental cytoarchitecture of cortical organization, we focused on myelin content<sup>##REF##21832190##43##</sup> and the thicknesses of L1-L6<sup>##REF##32243449##41##</sup>. For each cortical organization map, the vertex values were assigned and averaged to regional values according to the BNA246 template on fsaverage5 space. Then, we calculated Spearman’s correlation coefficient between the developmental slope of the nodal property and the extracted regional values of each cortical organization map. For each laminar thickness, we also calculated a partial correlation coefficient to explore laminar specificity after controlling remaining laminar thickness. The corresponding <italic>p</italic> value was corrected for spatial autocorrelation by calculating the number of times that the correlation coefficients derived from 10,000 spatially constrained null models were greater than the observed correlation coefficient. In addition, FreeSurfer (<ext-link ext-link-type=\"uri\" xlink:href=\"https://surfer.nmr.mgh.harvard.edu/fswiki/FreeSurferWiki\">https://surfer.nmr.mgh.harvard.edu/fswiki/FreeSurferWiki</ext-link>) was used to directly calculate the cortical thickness of each individual and obtain the average cortical thickness for subsequent validation of the cytoarchitecture results.</p>", "<title>Validation analyses</title>", "<p id=\"Par61\">We assessed the consistency of the results with the head movement as an additional covariate. Briefly, we computed the relative mean displacement as the measure of head movement and integrated it into the mixed effect model to delineate the developmental changes of global and nodal properties. The normalized gene weights were derived though PLS correlation between of nodal efficiency and gene expression. To assess the consistency of the results, we employed Pearson’s correlation coefficient to compare models with and without the inclusion of head motion. The corresponding <italic>p</italic> value was corrected for spatial autocorrelation by calculating the number of times that the correlation coefficients derived from 10,000 spatially constrained null models were greater than the observed correlation coefficient.</p>", "<p id=\"Par62\">We validated the sensitivity of the result based on a distinct template. A native brain parcellation derived from AAL90<sup>##REF##11771995##64##</sup> was obtained by applying inverse transformation matrices. For each participant, an FAFN-weighted WM network was constructed. Statistical analyses were utilized for mainly global and nodal network properties to investigate the effects of age and sex differences on the topological organization of the AAL90 WM network.</p>", "<p id=\"Par63\">We also proceeded to create networks weighted by FN, FA, and 1/MD employing the BNA246 template. These networks were formulated to assess the results of diverse connection-weighted approaches, complementing the principal findings of global and nodal properties. Spearman’s correlation coefficients were computed to quantify the association between the developmental slopes of node properties across distinct weighted networks. The corresponding <italic>p</italic> value was corrected for spatial autocorrelation by determining the frequency with which correlation coefficients from 10,000 spatially constrained null models exceeded the observed correlation coefficient. To evaluate the robustness of the tractography approach, following our previous methodological evaluation study<sup>##REF##35475571##107##</sup>, an FAFN-weighted network derived by the Camino toolbox (<ext-link ext-link-type=\"uri\" xlink:href=\"http://camino.cs.ucl.ac.uk/\">http://camino.cs.ucl.ac.uk/</ext-link>) and a probabilistic tractography weighted network<sup>##REF##30537563##119##</sup> were constructed based on a ball-and-stick model estimated from bedpostx results<sup>##REF##23658616##65##</sup>. The gene association and cell type-specific analysis were performed as for the nodal efficiency .</p>", "<p id=\"Par64\">We employed the ABAnnotate toolbox<sup>##UREF##4##66##,##UREF##5##67##</sup>, which takes into account both gene coexpression and spatial autocorrelation, to validate the enrichment results of spatial correlation between the developmental slope of WM nodal efficiency and gene expression profiles. Specially, we conducted gene category enrichment analysis on GO categories for positively and negatively correlated genes selected by PLS, where the weight of genes served as the gene score. Then, we generated 10,000 spatially autocorrelated maps<sup>##REF##32139786##57##</sup> of the developmental to estimate a category-level null distribution of gene score. Finally, we inferred the statistical <italic>p</italic> value on category enrichment by comparing observed mean gene score to the null distribution. Multiple comparison correction was applied using the FDR method.</p>", "<p id=\"Par65\">To evaluate whether the heterogeneous spatial development and transcriptomic architecture obtained from our study were replicated in another independent cohort, the HCP-D 2.0 data release was utilized for validation. We applied minimal preprocessing pipelines<sup>##REF##23668970##120##</sup> according to imaging acquisition details<sup>##REF##30142446##45##,##REF##30261308##46##</sup>. Following our previous methodological evaluation study<sup>##REF##35475571##107##</sup>, the Camino toolbox (<ext-link ext-link-type=\"uri\" xlink:href=\"http://camino.cs.ucl.ac.uk/\">http://camino.cs.ucl.ac.uk/</ext-link>) was used to reconstruct fibers with a ball-and-stick model estimated from bedpostx results<sup>##REF##23658616##65##</sup> and to generate an FAFN-weighted network with the BNA246 template. After demographic matching and quality control during MRI preprocessing, we selected a cross-sectional cohort composed of 179 typically developing children (age range of 6–13 years, 76 males and 103 females) who were unrelated to others in the HCP-D (Supplementary Table ##SUPPL##0##2##). The network properties were calculated by GRETNA<sup>##REF##26175682##121##</sup> and the general linear model was applied to analyse age-related changes. The subsequent gene association analysis, cell type-specific analysis and cortical organization correlation were adopted for the CBD cohort. Pearson’s correlation coefficient was applied to calculate the consistency of nodal efficiency between two cohorts and to measure the consistency of normalized gene weights between two cohorts. The corresponding <italic>p</italic> value was corrected for spatial autocorrelation by calculating the number of times that the correlation coefficients derived from 10,000 spatially constrained null models were greater than the observed correlation coefficient.</p>", "<title>Statistics and reproducibility</title>", "<p id=\"Par66\">Mixed effect model<sup>##REF##7168798##52##</sup> was performed to obtain the statistical correlation between WM network properties and age (<italic>n</italic> = 1033). For linear associations between the spatial development slopes of WM nodal efficiency and other brain phenotypes (gene expression profiles and cortical organization maps), we generated 10,000 surrogate maps of development slopes<sup>##REF##32139786##57##</sup> to correct for spatial autocorrelation of MRI data. All linear models were fitted for the original data as well as 10,000 corresponding surrogate maps. P-values were obtained by the occupied null models (<5th, or >95th centile). Six analysis strategies were considered to verify the reproducibility, including (i) head movement as an additional covariate (<italic>n</italic> = 1033); (ii) defining brain nodes based on a distinct brain template (<italic>n</italic> = 1033); (iii) using different connection-weighted approaches (<italic>n</italic> = 1033); (iv) using another tractography approach (<italic>n</italic> = 1033); (v) using another gene category enrichment analysis pipeline; and (vi) using another independent dataset (HCP-D, <italic>n</italic> = 179). Spatial development patterns of WM network properties, gene association, and cell type-specific analysis were examined in these cases.</p>", "<title>Reporting summary</title>", "<p id=\"Par67\">Further information on research design is available in the ##SUPPL##1##Nature Portfolio Reporting Summary## linked to this article.</p>" ]	[ "<title>Results</title>", "<p id=\"Par9\">In the present study, we used the 3-year longitudinal development data from the Children School Functions and Brain Development Project (CBD, Beijing Cohort)<sup>##UREF##1##44##</sup>, including 604 typically developing children from 6 to 13 years of age (339 males and 266 females) (Supplementary Table ##SUPPL##0##1##, Fig. ##FIG##0##1##). A total of 1033 scans taken at up to three time-point were used for following modeling and analysis. The overview of analysis workflow is shown in (Fig. ##FIG##1##2##). For validation analysis, we employed a cross-sectional development cohort from the Human Connectome Project in Development (HCP-D)<sup>##REF##30142446##45##,##REF##30261308##46##</sup> (<ext-link ext-link-type=\"uri\" xlink:href=\"https://www.humanconnectome.org/study/hcp-lifespan-development\">https://www.humanconnectome.org/study/hcp-lifespan-development</ext-link>), including 179 typically-developing children from 6 to 13 years of age (76 males and 103 females) who were unrelated to each other (Supplementary Table ##SUPPL##0##2##).</p>", "<title>Longitudinal developmental trajectory of the WM structural connectome</title>", "<p id=\"Par10\">The network efficiency of the WM connectome reflects information integration, stands as a critical aspect of brain maturation, essential for information processing and cognitive functions<sup>##REF##27590832##20##</sup>. The development of WM structural connectivity also promotes functional specialization<sup>##REF##31874926##47##–##UREF##2##50##</sup>. For each participant, individual dMRI and T1 data were utilized to construct the brain WM structural connectome based on the Human Brainnetome Atlas with 246 brain regions (BNA246)<sup>##REF##27230218##51##</sup> template. Our study comprehensively delineates the development of the WM connectome in children aged 6 to 13 years from global, nodal, and connectional perspectives. We measured global integration and local segregation properties, including global efficiency, local efficiency, network strength, shortest path length, and clustering coefficient in relation to age. To understand the contribution of individual nodes (brain regions) to information transmission within the WM network, changes in nodal efficiency, nodal local efficiency, and nodal degree centrality were evaluated with age. Additionally, age-related changes were analyzed at the connection level, encompassing rich-club, feeder, and local edges; within-module and between-module edges; and long-range and short-range edges. For a detailed description of network properties, please refer to the Methods section. For each property, both linear and quadratic models were estimated by a mixed effect model<sup>##REF##7168798##52##</sup> to characterize the intrinsic longitudinal relationship between brain network properties and age. By comparing the Akaike information criterion<sup>##UREF##3##53##</sup> of the linear and quadratic models, we found that most brain network properties followed a linear developmental trajectory over the age range of 6 to 13 years.</p>", "<p id=\"Par11\">At the global level, we observed that the global efficiency ( = 0.35, CI = [0.31,0.40], <italic>t</italic> = 16.05, <italic>p</italic> = 4.05E-51), local efficiency ( = 0.53, CI = [0.46,0.60], <italic>t</italic> = 14.35, <italic>p</italic> = 2.46E-42) and network strength ( = 8.82, CI = [7.86,9.77], <italic>t</italic> = 18.12, <italic>p</italic> = 1.16E-61) of the whole-brain WM network linearly increased with age, and the shortest path length ( = −4.88E-03, CI = [−5.51E-03,−4.25E-03], <italic>t</italic> = −15.25, <italic>p</italic> = 8.20E-47) significantly decreased with age, as shown in Fig. ##FIG##2##3a##. The clustering coefficient ( = −1.23E-05, CI = [−9.08E-05,1.16E-05], <italic>t</italic> = 0.23, <italic>p</italic> = 0.81, Supplementary Fig. ##SUPPL##0##1a##) showed no significant changes with age. For small-world properties, ( = −6.79E-02, CI = [−9.75E-02,−3.84E-02], <italic>t</italic> = −4.55, <italic>p</italic> = 6.05E-06) and ( = −5.55E-02, CI = [−8.11E-02,−2.99E-02], <italic>t</italic> = −4.27, <italic>p</italic> = 2.16E-05) significantly decreased with age, and ( = −1.14E-03, CI = [−3.21E-03,9.31E-04], <italic>t</italic> = −1.08, <italic>p</italic> = 0.28) remained stable with age, as shown in Supplementary Fig. ##SUPPL##0##1b–d##. The effects of sex and age-by-sex interaction were nonsignificant for all global network properties (<italic>p</italic> > 0.05, Bonferroni corrected).</p>", "<p id=\"Par12\">At the regional level, we calculated the nodal efficiency, nodal local efficiency and nodal degree centrality for each brain region. For nodal efficiency, 229 regions exhibited a linear increase with age (<italic>p</italic> < 0.05, Bonferroni corrected), with various development slopes (, Fig. ##FIG##2##3b##), which were distributed across most regions of the brain. For nodal local efficiency, 85 regions showed a linear increase with age (, <italic>p</italic> < 0.05, Bonferroni corrected, Fig. ##FIG##2##3b##). For nodal degree centrality, 115 regions exhibited a significant age-related increase (, <italic>p</italic> < 0.05, Bonferroni corrected, Fig. ##FIG##2##3b##). Of note, regions with a high rate of development were mainly located in the occipital cortex, fusiform gyrus, superior temporal gyrus, cingulate gyrus, hippocampus and precuneus. Furthermore, we also observed different developmental slopes of nodal properties, which followed posterior-to-anterior and inferior-to-superior gradients (Supplementary Fig. ##SUPPL##0##2##). Similar spatial patterns of development were observed when categorizing brain regions into 8 functional subnetworks according to Yeo’s brain parcellation<sup>##REF##21653723##54##</sup> (visual, somatomotor, dorsal attention, ventral attention, limbic, frontoparietal and default networks) and subcortical network within BNA246 template. Among the different networks, the visual network and somatomotor network had relatively higher than the other networks (Fig. ##FIG##2##3c##).</p>", "<p id=\"Par13\">At the connectional level, the rich-club, feeder and local edges were categorized according to hub and nonhub regions (Supplementary Fig. ##SUPPL##0##3a##). The within-module or between-module edges were assigned based on a functional module architecture consisting of the 8 subnetworks (Supplementary Fig. ##SUPPL##0##3b##), and the long-range or short-range edges were classified by comparing the mean strength of the group-averaged network. When fitted with age, we calculated the connectivity strength changes of different types of edges after controlling for the global network strength. In Supplementary Fig. ##SUPPL##0##3c-e##, the connectivity strength of the local edge ( = 0.22, CI = [0.15,0.30], <italic>t</italic> = 5.64, <italic>p</italic> = 2.18E-08), within-module edge ( = 0.19, CI = [0.10,0.29], <italic>t</italic> = 4.12, <italic>p</italic> = 4.03E-05) and short edge ( = 0.22, CI = [0.15,0.29], <italic>t</italic> = 6.42, <italic>p</italic> = 2.17E-10) increased with age, while that of the between-module edge ( = −0.19, CI = [−0.31,−0.07], <italic>t</italic> = −3.09, <italic>p</italic> = 2.10E-03) and long edge ( = −0.38, CI = [−0.61,−0.15], <italic>t</italic> = −3.30, <italic>p</italic> = 1.00E-03) decreased with age. The connectivity strength of the feeder edge ( = −0.08, CI = [−0.20,0.04], <italic>t</italic> = −1.28, <italic>p</italic> = 0.20) and rich-club edge ( = −0.37, CI = [−0.77,0.02], <italic>t</italic> = −1.85, <italic>p</italic> = 0.07) remained stable with age. Additionally, the strength comparisons of different edges are shown in Supplementary Fig. ##SUPPL##0##3f##.</p>", "<title>Transcriptomic and cellular architectures of WM connectome development</title>", "<p id=\"Par14\">To explore the potential transcriptomic association with WM connectome development, we employed AHBA<sup>##REF##22996553##31##</sup> along with a standardized processing pipeline<sup>##REF##30648605##55##</sup> to obtain spatial gene transcriptomic profiles across brain regions. Employing the partial least square (PLS) analysis<sup>##REF##20656037##56##</sup>, we linked the spatial pattern () of WM nodal efficiency development (Fig. ##FIG##3##4a##) and gene transcriptomic profiles (Fig. ##FIG##3##4b##). The gene expression score of the first PLS component accounted for the highest spatial variance explained at 28.2% (Fig. ##FIG##3##4c##). After spatial autocorrelation correction (SAC)<sup>##REF##32139786##57##</sup>, there was a significant positive correlation (<italic>r</italic> = 0.53, <italic>p</italic> = 0.001, permutation test with SAC, Fig. ##FIG##3##4c##) between the first PLS component score of genes and the spatial pattern of WM regional development. Furthermore, we identified potential transcriptomic architectures in the GO biological process pathway<sup>##REF##30944313##58##</sup> using positive/negative genes with high weight on the first PLS component, respectively. The positive weight genes (771 genes) were prominently enriched for ion transport-related and development-related terms (<italic>p</italic> < 0.05, FDR corrected, Fig. ##FIG##3##4d##), such as “metal ion transport”, “regulation of peptide transport”, “regulation of neuron projection development”, and “axon development”. The negative weight (714 genes) gens were mainly enriched for synapse-related and brain development pathways (<italic>p</italic> < 0.05, FDR corrected, Fig. ##FIG##3##4e##), such as “synaptic signaling”, “synapse pruning”, and “brain development”.</p>", "<p id=\"Par15\">To further investigate cell-specific expression of genes related to WM nodal efficiency development, the related genes were agglomerated into seven canonical cell classes<sup>##REF##30545854##9##,##REF##26687838##59##–##REF##32620757##63##</sup>. These classes encompassed astrocytes, endothelial cells, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, and oligodendrocyte precursors. Our findings showed that the selected genes with high positive weights were significantly expressed in excitatory neurons and inhibitory neurons (118/88 genes, <italic>p</italic> < 0.001, permutation test, Fig. ##FIG##4##5a##). The genes with negative weights were expressed in astrocytes, inhibitory neurons and microglia (62/67/57 genes, <italic>p</italic> < 0.001, permutation test, Fig. ##FIG##4##5b##).</p>", "<title>Relationship to the cytoarchitecture of cortical organization</title>", "<p id=\"Par16\">To assess the spatial correspondence between the developmental pattern of WM nodal efficiency and fundamental cytoarchitecture, we considered myelin content<sup>##REF##21832190##43##</sup> and the thicknesses of six cortical laminas (L1-L6) from the BigBrain atlas<sup>##REF##32243449##41##</sup>. The high-resolution laminar thickness provided a more direct marker to map the relationship between WM nodal efficiency development and cytoarchitecture. We found that the spatial development pattern of WM nodal efficiency (Fig. ##FIG##5##6a##) was significantly associated with myelin content (<italic>r</italic> = 0.40, <italic>p</italic> = 0.025, permutation test with SAC, Fig. ##FIG##5##6b##) and L4 thickness (<italic>r</italic> = 0.40, <italic>p</italic> = 0.018, permutation test with SAC, Fig. ##FIG##5##6d##). In contrast, the nodes with higher development slopes tended to have lower thicknesses in the three laminas (L1: <italic>r</italic> = −0.37, <italic>p</italic> = 0.022, permutation test with SAC, Fig. ##FIG##5##6c##; L5: <italic>r</italic> = −0.38, <italic>p</italic> = 0.001, permutation test with SAC, Fig. ##FIG##5##6e##; L6: <italic>r</italic> = −0.43, <italic>p</italic> < 0.001, permutation test with SAC, Fig. ##FIG##5##6f##). After controlling effects of remaining laminas, L5 and L6 thicknesses showed specific positive correlations with the spatial development pattern of nodal efficiency, while L4 thickness exhibited a tendency of specific negative correlation (L4: <italic>r</italic><sub><italic>par</italic></sub> = 0.41, <italic>p</italic> = 0.056, permutation test with SAC, Fig. ##FIG##5##6c##; L5: <italic>r</italic><sub><italic>par</italic></sub> = −0.26, <italic>p</italic> = 0.016, permutation test with SAC, Fig. ##FIG##5##6e##; L6: <italic>r</italic><sub><italic>par</italic></sub> = −0.37, <italic>p</italic> = 0.044, permutation test with SAC, Fig. ##FIG##5##6f##). By directly calculating the cortical thickness on individuals, it was found that the development slope of brain region was negatively correlated with the group-average cortical thickness (<italic>r</italic> = 0.39, <italic>p</italic> = 0.036, permutation test with SAC, Supplementary Fig. ##SUPPL##0##4##).</p>", "<title>Reproducibility analyses</title>", "<p id=\"Par17\">We assessed the consistency of the results by incorporating head movement as an additional covariate. Briefly, we integrated head movements as an additional covariate within the mixed effect model to assess the developmental changes of global and nodal properties. The normalized gene weights were derived from PLS correlation between of nodal efficiency and gene expression. At the global level, global efficiency, local efficiency, and network strength exhibited a significant positive correlation with age, and the shortest path showed a significant negative correlation with age (<italic>p</italic> < 0.05, Bonferroni corrected, Supplementary Fig. ##SUPPL##0##5a##). At the regional level, the developmental slope across nodal efficiency, local efficiency and degree centrality were consistently significant, aligning with the results from the original model (Supplementary Fig. ##SUPPL##0##5b, c##). The normalized gene weights demonstrated consistency between the two models, based on the significance of the correlation (<italic>r</italic> = 0.998, <italic>p</italic> < 0.001, permutation test with SAC, Supplementary Fig. ##SUPPL##0##5d##).</p>", "<p id=\"Par18\">We examined whether changes in the WM connectome were robust to distinct brain parcellation templates. Using the Automated Anatomical Labeling with 90 brain regions (AAL90)<sup>##REF##11771995##64##</sup>, we repeated the network construction and analysis procedures. At the global level, several global network metrics, including global efficiency, local efficiency, and network strength exhibited a significant positive correlation with age, and the shortest path showed a significant negative correlation with age (<italic>p</italic> < 0.05, Bonferroni corrected, Supplementary Fig. ##SUPPL##0##6a##). At the regional level, the spatial distributions of the regions with significant age-related alterations were similar to the results from BNA246 template, which were mainly distributed across the occipital cortex, fusiform gyrus, superior temporal gyrus, cingulate gyrus, hippocampus and precuneus (Supplementary Fig. ##SUPPL##0##6b##). To examine sex differences, similar results were found between the male and female groups and none of properties with significant sex differences were observed (<italic>p</italic> > 0.05, Bonferroni corrected).</p>", "<p id=\"Par19\">We proceeded to create networks weighted by FN, FA, and the inverse of mean diffusivity (1/MD) employing the BNA246 template. These networks were formulated to systematically assess the resilience of diverse connection-weighting approaches in delineating WM connectomes, complementing the principal findings. At the global level, various weighting strategies exhibited similar outcomes (Supplementary Table ##SUPPL##0##3##-##SUPPL##0##5##). At the regional level, spatial distributions were similar to those observed in the FN×FA-weighted network outcomes (Supplementary Fig. ##SUPPL##0##7a–c##), with the FN-weighted network demonstrating greater consistency than that of FA and 1/MD (Supplementary Table ##SUPPL##0##7##).</p>", "<p id=\"Par20\">We constructed an additional FN×FA-weighted network using deterministic tractography based on a ball-and-stick model<sup>##REF##23658616##65##</sup>. The validation of global and nodal properties is detailed in Supplementary Table ##SUPPL##0##6## and illustrated in Supplementary Fig. ##SUPPL##0##7d##. Additionally, a significant correlation was established with the nodal outcomes of a tensor model-based FN×FA-weighted network (Supplementary Table ##SUPPL##0##7##). Through PLS analysis, we identified a significant positive correlation (<italic>r</italic> = 0.46, <italic>p</italic> < 0.001 permutation test with SAC, Supplementary Fig. ##SUPPL##0##8a##) between the first PLS component score of genes and the of nodal efficiency. The gene analysis results remained consistent, contingent on the significance of the correlation (<italic>r</italic> = 0.94, <italic>p</italic> < 0.001, permutation test, Supplementary Fig. ##SUPPL##0##8b##) of the normalized gene weight. Notably, the positively correlated genes were predominantly enriched for transport- and development-related terms, while the negatively correlated genes exhibited significant enrichment for synapse- and development-related terms (Supplementary Fig. ##SUPPL##0##8c,####SUPPL##0##d##). In cell-specific analysis, genes positively correlated expressed in excitatory neurons and inhibitory neurons, whereas negatively correlated genes expressed in astrocytes and microglia (<italic>p</italic> < 0.01, permutation test, Supplementary Fig. ##SUPPL##0##8e##, ##SUPPL##0##f##). We additionally found that the gene association and cell specificity results based on probabilistic tractography exhibited agreement with the original results as shown in Supplementary Fig. ##SUPPL##0##9##.</p>", "<p id=\"Par21\">Utilizing the ABAnnotate toolbox<sup>##UREF##4##66##,##UREF##5##67##</sup>, which considered both gene coexpression and spatial autocorrelation, we validated the enrichment results regarding the spatial correlation between the developmental slope of WM nodal efficiency and gene expression profiles. The results revealed that the majority of the initially identified functional pathways remained significantly enriched, as illustrated in Supplementary Fig. ##SUPPL##0##10##.</p>", "<p id=\"Par22\">Finally, we also evaluated whether our connectomic and transcriptomic findings could be replicated in an independent development cohort (HCP-D). The changes of global properties were consistent with those of the CBD cohort (Supplementary Table ##SUPPL##0##8##). For developmental alterations in nodal efficiency (Supplementary Fig. ##SUPPL##0##11a##), a significant correlation (<italic>r</italic> = 0.43, <italic>p</italic> < 0.001, permutation test with SAC, Supplementary Fig. ##SUPPL##0##11b##) existed across nodal age-related changes between two distinct cohorts, indicating that the heterogeneous spatial development found in this study was robust during childhood and adolescence. The findings of the gene analysis were consistent between two cohorts, depending on the significance of the correlation (<italic>r</italic> = 0.80, <italic>p</italic> < 0.001, permutation test, Supplementary Fig. ##SUPPL##0##11c##) of the normalized gene weight. The selected positive genes were mainly enriched for transport-related terms, while the negative genes were significantly enriched for development-related terms, as shown in Supplementary Fig. ##SUPPL##0##11d##. In cell-specific analysis, the positively correlated genes expressed in excitatory neurons, and the negatively correlated genes expressed in astrocytes (<italic>p</italic> < 0.001, permutation test, Supplementary Fig. ##SUPPL##0##11e##). We also replicated a tendency that the spatial development pattern of global efficiency is associated with L4 thickness (<italic>r</italic> = 0.32, <italic>p</italic> = 0.04, permutation test with SAC) but not with other fundamental properties.</p>" ]	[ "<title>Discussion</title>", "<p id=\"Par23\">This study performed a multiscale evaluation of WM connectome development from childhood to adolescence. Using a large longitudinal cohort aged 6 to 13 years old of up to 3 times of MRI scans, we observed a linear increase in brain network efficiency with increasing age, and more rapid development were found mainly in the occipital cortex, fusiform gyrus, superior temporal gyrus, cingulate gyrus, hippocampus and precuneus. Moreover, we found that the spatially heterogeneous development of the WM connectome was associated with transcriptomic architectures. Specifically, the positive genes were enriched in transport-related and development-related pathways, with significant expression in excitatory neurons and inhibitory neurons. The negative genes were enriched in synapse-related and development-related pathways, relating to astrocytes, microglia, and inhibitory neurons. Additionally, we demonstrated that the heterogeneous development was related to the myelin content and laminar thickness properties of cortical organization, providing microscopic evidence for the underlying mechanisms at the gene and cell levels. Together, our study characterized the age-related trajectory of WM connectome development from childhood to adolescence and investigated whether its heterogeneous development is associated with transcriptomic architecture, cellular organization, or cortical properties.</p>", "<p id=\"Par24\">From childhood to adolescence, the WM connectome exhibits enhanced integration capacity that can be characterized by increases in global efficiency, local efficiency, and network strength with age. These findings not only are consistent with previous findings mainly from cross-sectional studies and small-sample longitudinal studies<sup>##REF##29229299##5##,##REF##22982357##17##–##REF##27590832##20##</sup> but also extend to longitudinal evidence of higher statistical power with the large-sample, and multiple assessments<sup>##REF##24879112##68##</sup>. Our results also revealed a heterogeneous development layout in nodal network properties, with primary regions (e.g., visual cortex, sensorimotor cortex) showing more rapid growth in nodal efficiency than other regions. From the perspective of structure-function coupling, the development of WM structural connectivity promoted the maturation of functional specialization<sup>##REF##31874926##47##–##UREF##2##50##</sup>. Combing with findings from previous studies of early childhood<sup>##REF##29449712##69##</sup> and late adolescence<sup>##REF##29139172##70##</sup>, this study particularly suggested that the rapid development in the WM connectome of the primary cortex between 6 and 13 years may support the subsequent development of higher-order cognitive functions. Furthermore, we observed a broad pattern of heterogeneous development across brain regions along posterior-to-anterior and inferior-to-superior gradients, in line with findings of previous WM microstructure studies of development<sup>##REF##26375208##71##,##REF##20708693##72##</sup>. More changes in medial than lateral regions for local efficiency and degree centrality were also in agreement with an FA study of the WM skeleton<sup>##REF##26375208##71##</sup>. Therefore, the development of the WM connectome may also follow major gradients in the brain. Neurodevelopmental changes in network connections are characterized by simultaneous progressive and regressive changes<sup>##REF##19819337##13##</sup>. Likewise, our results demonstrated a developmental pattern of WM connections characterized by integration and segregation. Additionally, we observed a strengthening of connectivity in local, within-module and short-distance edges, as well as a pruning of connectivity in between-module and long-distance edges. Such findings suggest that over the course of development, the WM connectome is dominated by spatial increases in intramodule connections, along with the refinement of intermodule connections. The connectivity of the feeder edge and rich-club edge remained stable with age, highlighting the stability of the hubs structure that supports the enhancement of complex information integration during this period<sup>##REF##22049421##16##,##REF##26324898##73##,##REF##34896927##74##</sup>. In recent years, the topology of WM functional connectome have been gradually studied<sup>##REF##32404889##75##–##REF##33127899##77##</sup>. Comparative studies examining both functional and structural integration and separation of WM networks, alongside the consideration of mental illness, could provide valuable insights into the neurodevelopmental processes and disease mechanisms associated with the WM network.</p>", "<p id=\"Par25\">The AHBA<sup>##REF##22996553##31##</sup> has been pivotal in bridging the gap between neuroimaging and transcriptomics<sup>##REF##30455082##32##</sup>. The analyses of regional expression has proven valuable in identifying associations between regional gene variations and some regional properties<sup>##REF##30455082##32##,##REF##36725139##78##</sup>. Earlier studies in mouse and rat brains have uncovered correlations between regional gene profiles and nodal degree centrality as well as participation coefficients<sup>##REF##21253556##79##,##REF##26216962##80##</sup>. In human brain studies, spatial correlations between transcriptome patterns and WM network disconnection patterns have been leveraged to identify pathologically associated genes<sup>##REF##27720199##38##,##REF##29174593##81##</sup>. A recent study utilized spatial patterns of nodal degree centrality for correlating transcriptome patterns as a methodological validation<sup>##UREF##5##67##</sup>. These collective findings give rise to a common hypothesis suggesting that genes in the cortex of corresponding locations influence the nodal properties of the WM connectome. Additionally, the WM network efficiency is considered a key aspect of brain maturation, crucial for information processing and cognitive functions<sup>##REF##27590832##20##</sup>. The heritability of global efficiency during adolescence has been demonstrated by twin studies<sup>##REF##26368846##18##,##REF##29139172##70##</sup>. In light of these contexts, we regarded the pattern of developmental changes in nodal efficiency of cortical regions as a brain phenotype, seeking to identify gene associations within the transcriptome of cortical regions.</p>", "<p id=\"Par26\">Our results showed that positively correlated genes were enriched for ion transport-related and development-related pathways, while negatively correlated genes were enriched for synapse-related and development-related pathways. Interestingly, the finding of ion transport we identified coincided with previous studies of cortical structural connectome development<sup>##REF##27457931##35##</sup> and functional connectome development<sup>##REF##34378030##36##</sup>. Ion transport balances intracellular and extracellular concentration difference to stabilize brain neural circuits<sup>##REF##26068849##82##,##REF##24105342##83##</sup>. It is speculated that ion transport-related gene pathways may regulate development in the brain connectome by maintaining and enhancing network stability. Synaptogenesis (especially synaptic pruning) is considered critical for brain connectome specificity during childhood and adolescence<sup>##REF##36792753##84##,##REF##27054487##85##</sup>. Notably, genes related to ion channels and synapses have been found to shape neuronal timescales, which are associated with higher-order cognitive functions, such as memory, decision making, and reasoning<sup>##REF##33226336##86##</sup>. Axon development and neuron projection development<sup>##REF##25213356##87##</sup> were important pathways directly associated with enhanced and refined changes in WM connectome through processes such as axonal fasciculation and defasciculation. Our findings suggested that the transport-related, synapse-related, and development-related pathways may regulate gradual integration and differentiation in WM connectome from childhood to adolescence, thus laying the foundation for their cognitive and learning development.</p>", "<p id=\"Par27\">Additionally, we investigated cell-specific types in spatial gene expression of WM connectome development. We found that the positively correlated genes related to WM connectome development were significantly expressed in excitatory neurons and inhibitory neurons also known as glutamatergic neurons and GABAergic neurons, respectively. These neurons have different neuronal subsets and projection patterns, which jointly constitute a homeostatic regulatory mechanism of the brain connectome to control signal flow, sculpt network dynamics<sup>##REF##27477017##88##,##REF##18984155##89##</sup>, and regulate different behavioral functions<sup>##REF##34792021##90##</sup>. A recent study of developmental neuroplasticity markers found that the decreased cortical excitation-inhibition ratio is driven by the pruning of excitatory neurons and the maturation of GABAergic neurons<sup>##REF##35119918##91##</sup>. In contrast, the negatively correlated genes were expressed in astrocytes, inhibitory neurons, and microglia. Both astrocytes and microglia have been implicated in synaptic pruning, or the elimination of weak and inappropriate synapses, a critical developmental process for the formation of fully functional neuronal circuits<sup>##REF##30986749##92##–##REF##34545240##94##</sup>. Notably, the specific and precise expression of synapses is conducive to the establishment of intercellular connection patterns of GABAergic neurons<sup>##REF##30679375##95##</sup>. From childhood to adolescence, learning and the environment factors can drive changes in the brain while maintaining a balance of brain activity is key to constant fine-tuning of the brain<sup>##REF##26291155##96##,##REF##11127835##97##</sup>. Learning-related adaptations are encoded as changes in synaptic strength or other cellular properties<sup>##REF##11127835##97##</sup> and may be further refined through synaptic pruning<sup>##REF##34545240##94##</sup>, ultimately resulting in the precise wiring of mature neural circuits. This process is particularly important for cortical plasticity in children and adolescents<sup>##REF##22232689##98##</sup>. Therefore, genes associated with the developmental WM connectome exhibit specific expression patterns in cellular organization, may be closely related to the construction and maintenance of connectomic homeostasis within the brain during learning and development. Nevertheless, the associated physiological mechanisms will require further study.</p>", "<p id=\"Par28\">One crucial question concerns whether the heterogeneous development of the WM connectome across regions can reflect fundamental properties of cortical organization. We found that the spatial development of the WM connectome conformed to the myelin content, which is present in most long-distance projection neurons and supports the enhancement of the neural signal-to-noise ratio and the coordination of distributed neural activity<sup>##REF##21832190##43##</sup>. Histologically, cortical regions that are more heavily myelinated generally tend to be thinner<sup>##REF##21832190##43##</sup>. The spatial pattern of accelerated cortical thinning from childhood to adulthood is associated with increased expression of genetic markers related to inhibitory and excitatory neurons, with enriched axon-related terms (e.g., axonal development)<sup>##REF##32276068##99##</sup>, further supporting our findings at the gene and cell levels. We also found that the spatial development of the WM connectome was inversely associated with the cortical thickness of L1, L5, and L6, with L5 and L6 contributing to overall thickness gradients and sending information externally<sup>##REF##28817797##100##</sup>. In contrast, L4 may be involved in the reception, integration, synchronization, and regulation of sensory peripheral signals in the human cortex and extracortex<sup>##REF##36792753##84##,##REF##31746736##101##</sup>. Interestingly, the cortical thickness of L4 had a positive association with the development of the WM connectome, indicating that the transfer function of L4 is enhanced in conjunction with the transmission efficiency of the developing WM connectome. A recent study has proposed that glutamatergic pathways between the cortex and thalamus transmit information to L4 through transthalamic circuits, and from L4 to other laminas via internal intercellular communication<sup>##REF##28333385##102##</sup>. In the rat barrel cortex, L4 has averaged 62% more GABA contacts per unit volume than any other cortical layer<sup>##REF##8144746##103##</sup>, and the axonal projection of spiny L4 neurons highly associates with the structure of a cortical column<sup>##REF##10884314##104##</sup>. These findings highlight that the cortical differentiation microstructure underpins the developmental of the WM connectome and predict that the association may be dominated by genes that tend to regulate neuronal cell proliferation, differentiation, and migration.</p>", "<p id=\"Par29\">Several methodological issues should be addressed. First, the observed developmental trajectories in the WM connectomes could be influenced by the age range of 6 to 13 years in this study. Conducting future longitudinal studies across a wider age spectrum will enhance the precision of WM connectome trajectories. Second, although we contributed by uncovering the transcriptomic architecture of the spatial development pattern of the WM connectome using the AHBA, it is essential to acknowledge that the results might miss the main factor of development due to indirect gene association and variable gene expression during development. Nevertheless, a study found that the relative spatial patterns of genes did not change much after birth<sup>##REF##22031440##8##</sup>. Third, the network topologies usually involve different structures, including cortical regions and extra-cortical WM pathways. This raises the possibility that results associated with gene expression in cortical regions may reflect the overall gene effects on different structures. Moreover, the construction of WM network is constrained by issues like directionality and time variability, which could impact spatial gene association results. Addressing these challenges will necessitate more reasonable assumptions and advanced methods to broaden our understanding of the spatial transcriptome patterns of WM connectome. Fourth, a multivariate paradigm that encompasses gene–brain–behavior–environment has been advocated to understand the complex neurodevelopmental processes of growth and specialization that modify the brain to adapt to the environment<sup>##REF##23672542##105##</sup>. Future research should incorporate this paradigm to further refine our findings in WM connectome development. Fifth, coupling studies of WM and functional connectomes revealed that brain function is structurally constrained by WM structure<sup>##REF##31874926##47##,##REF##35776541##48##,##UREF##2##50##</sup>. Therefore, future longitudinal studies combining multimodal connectomes will provide a more comprehensive view of the developmental process during this period. Finally, validating the sensitivity of the analytical pipeline and ensuring compatibility with independent longitudinal data is crucial. In our study, we took steps to validate our main findings by employing different network construction<sup>##REF##30303550##106##,##REF##35475571##107##</sup> and gene association<sup>##UREF##5##67##</sup> methods. We observed that the choice of pipeline had some impact on the subsequent findings, underscoring the importance of methodological guidance in studies of this nature. Additionally, we obtained a moderate correlation of a main finding using a cross-sectional cohort from the HCP-D, which can arise from a variety of factors including ethnicity, environment, the paradigm of data acquisition, etc., which also emphasizes the importance of research harmonization.</p>", "<p id=\"Par30\">In conclusion, we have demonstrated the multiscale development pattern of the WM connectome from childhood to adolescence. The spatially heterogeneous development of WM connectivity was regulated by transcriptomic architectures. In particular, positively correlated genes contribute to the cellular organization of excitatory and inhibitory neurons, while negatively correlated genes relate to astrocytes, inhibitory neurons, and microglia. Additionally, the heterogeneous development of the WM connectome was associated with myelin content and the thicknesses of specific lamina of the cortex. Therefore, our findings may offer insights into understanding the normal development of the brain connectome and plasticity, which may provide clues for the early diagnosis and treatment of development-related brain disorders.</p>" ]	[]	[ "<p id=\"Par1\">From childhood to adolescence, the spatiotemporal development pattern of the human brain white matter connectome and its underlying transcriptomic and cellular mechanisms remain largely unknown. With a longitudinal diffusion MRI cohort of 604 participants, we map the developmental trajectory of the white matter connectome from global to regional levels and identify that most brain network properties followed a linear developmental trajectory. Importantly, connectome-transcriptomic analysis reveals that the spatial development pattern of white matter connectome is potentially regulated by the transcriptomic architecture, with positively correlated genes involve in ion transport- and development-related pathways expressed in excitatory and inhibitory neurons, and negatively correlated genes enriches in synapse- and development-related pathways expressed in astrocytes, inhibitory neurons and microglia. Additionally, the macroscale developmental pattern is also associated with myelin content and thicknesses of specific laminas. These findings offer insights into the underlying genetics and neural mechanisms of macroscale white matter connectome development from childhood to adolescence.</p>", "<p id=\"Par2\">Joint connectomic and transcriptomic analyses of longitudinal dMRI data reveal the multiscale developmental pattern of the human white matter connectome from childhood to adolescence.</p>", "<title>Subject terms</title>" ]	[ "<title>Supplementary information</title>", "<p>\n\n\n</p>" ]	[ "<title>Supplementary information</title>", "<p>The online version contains supplementary material available at 10.1038/s42003-023-05647-8.</p>", "<title>Acknowledgements</title>", "<p>The authors thank all the volunteers for their participation in the study and anonymous reviewers for their insightful comments and suggestions. This work was supported by the STI2030-Major Projects (2021ZD0200500, 2021ZD0200503, 2022ZD0213300), National Natural Science Foundation of China (32271145, 81871425), Fundamental Research Funds for the Central Universities (2017XTCX04), Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning (CNLZD2101) and the 111 project (BP0719032). Data in this publication were provide (in part) by the Human Connectome Project-Development (HCP-D), which is supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number U01MH109589 and by funds provided by the McDonnell Center for Systems Neuroscience at Washington University in St. Louis. Part of the data used in this study were obtained from the National Protein Science Center (NPSC) in Beijing, China.</p>", "<title>Author contributions</title>", "<p>G.F. performed acquisition and analysis of data, contributed new analytic tools, drafted, and revised the paper. R.C. performed acquisition and analysis of data, drafted, and revised the paper. R.Z. performed analysis of data, drafted and revised the paper. Y.L., L.M., Y.W., W.M., J.G., and S.T. (Shuping Tan) performed acquisition of data. J.C., Y.H., S.Q., and Q.D. contributed to the design of the work and performed acquisition of data. S.T. (Sha Tao) contributed to the design of the work, performed acquisition of data, and revised the paper. N.S. contributed to the design of the work, contributed new reagents/analytic tools, performed analysis of data, and revised the paper.</p>", "<title>Peer review</title>", "<title>Peer review information</title>", "<p id=\"Par68\"><italic>Communications Biology</italic> thanks Didac Vidal-Pineiro and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: George Inglis.</p>", "<title>Data availability</title>", "<p>The CBD data that support the findings of this study are available from the corresponding author upon reasonable request. The HCP-D 2.0 release data that support the findings of this study are publicly available on <ext-link ext-link-type=\"uri\" xlink:href=\"https://www.humanconnectome.org/study/hcp-lifespan-development\">https://www.humanconnectome.org/study/hcp-lifespan-development</ext-link>. The AHBA dataset are available on the Allen Brain Atlas (<ext-link ext-link-type=\"uri\" xlink:href=\"https://human.brain-map.org/static/download\">https://human.brain-map.org/static/download</ext-link>). The processed transcriptomic data in this study are available from the corresponding author upon reasonable request. The source data underlying Figs. ##FIG##0##1##, ##FIG##2##3##, ##FIG##3##4##, ##FIG##4##5##, and ##FIG##5##6## can be accessed at <ext-link ext-link-type=\"uri\" xlink:href=\"https://figshare.com/articles/dataset/WM-connectome-development/24588585\">https://figshare.com/articles/dataset/WM-connectome-development/24588585</ext-link>.</p>", "<title>Code availability</title>", "<p>The code for preprocessing of the AHBA dataset can be found at <ext-link ext-link-type=\"uri\" xlink:href=\"https://github.com/BMHLab/AHBAprocessing\">https://github.com/BMHLab/AHBAprocessing</ext-link>. The gene enrichment analysis is performed at <ext-link ext-link-type=\"uri\" xlink:href=\"https://metascape.org/gp/index.html#/main/step1\">https://metascape.org/gp/index.html#/main/step1</ext-link>. The spatial permutation testing is performed based on BrainSpace (<ext-link ext-link-type=\"uri\" xlink:href=\"https://brainspace.readthedocs.io/en/latest/index.html\">https://brainspace.readthedocs.io/en/latest/index.html</ext-link>). The minimal preprocessing pipelines can be found at <ext-link ext-link-type=\"uri\" xlink:href=\"https://github.com/Washington-University/HCPpipelines\">https://github.com/Washington-University/HCPpipelines</ext-link>. The code relevant to this study can be accessed at <ext-link ext-link-type=\"uri\" xlink:href=\"https://github.com/FelixFengCN/WM-connectome-development\">https://github.com/FelixFengCN/WM-connectome-development</ext-link><sup>##UREF##9##122##</sup>.</p>", "<title>Competing interests</title>", "<p id=\"Par69\">The authors declare no competing interests.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><title>Age distributions of scans (<italic>n</italic> = 1033) in different sexes and different acquisition times.</title><p><bold>a</bold> Each point represents an individual scan, and the connecting lines indicate the interval between scans for each participant. <bold>b</bold> Age distribution of participants who completed different waves of scans. Of note, “1 time, 2 times, 3 times” represents the number of scans for each participant.</p></caption></fig>", "<fig id=\"Fig2\"><label>Fig. 2</label><caption><title>Overview of analysis workflow.</title><p><bold>a</bold> Based on WM network, the age-related longitudinal trajectories of global, regional, and connectional properties were analyzed using mixed effect model. <bold>b</bold> By correlating developmental slope of nodal efficiency and AHBA transcriptomic data, the significant genes were identified and were recognized the enrichment pathways and cell-type-specific expression. Meanwhile, the relationships between the developmental slope of nodal efficiency and the cytoarchitectural properties of cortical organization were identified.</p></caption></fig>", "<fig id=\"Fig3\"><label>Fig. 3</label><caption><title>longitudinal changes in network organization properties during childhood and adolescence.</title><p><bold>a</bold> Age effect on mainly global network properties (<italic>n</italic> = 1033 scans). <bold>b</bold> Spatial patterns with significant development (<italic>p</italic> < 0.05, Bonferroni correction, <italic>n</italic> = 1033 scans) in various nodal properties. The size of the circle was proportional to the statistical <italic>t</italic> value, and its color indicated the developmental slope (standard effect value ), with red for large changes and blue for small changes. <bold>c</bold> Developmental slope of the functional subnetwork (<italic>n</italic> = 1033 scans). In each radar chart, a line with a different color corresponded to an age subgroup and values for each subnetwork were the average of properties over all scans in that subgroup. Of note, *<italic>p</italic> < 0.001; n.s.<italic>p</italic> > 0.05, Bonferroni correction.</p></caption></fig>", "<fig id=\"Fig4\"><label>Fig. 4</label><caption><title>Association between the development slope of nodal efficiency and gene transcriptional profiles.</title><p><bold>a</bold> The map of standardized development slope () in nodal efficiency across 199 brain regions. <bold>b</bold> The normalized gene transcriptional profiles comprised 10,027 genes in 199 brain regions, in which each row denotes the gene expression level for each gene in a brain region. <bold>c</bold> Explained ratios (left vertical axis) and correlation coefficients (right vertical axis) for the first 15 components obtained from PLS regression analysis. Enriched terms of positive genes (<bold>d</bold>) and negative genes (<bold>e</bold>). In <bold>d</bold> and <bold>e</bold>, the length of the bar denotes the enrichment significance and its color denotes the number of input genes falling under that term. Each circle node within network layout represented a term colored by cluster identity and its size denoted the number of genes falling into the term. The edge represents a similarity score between filtered terms.</p></caption></fig>", "<fig id=\"Fig5\"><label>Fig. 5</label><caption><title>Cell type-specific analysis.</title><p>Cell type-specific expression of positive genes (<bold>a</bold>) and negative genes (<bold>b</bold>). In <bold>a</bold> and <bold>b</bold>, the length and color of the bar shows overlapping numbers of the selected genes in each cell class. The color of the heatmap shows the statistically enriched terms in each cell class. Of note, OPCs: oligodendrocyte precursors. *<italic>p</italic> < 0.001, permutation test.</p></caption></fig>", "<fig id=\"Fig6\"><label>Fig. 6</label><caption><title>Developmental alterations of nodal efficiency align with cytoarchitecture of cortical organization.</title><p>Developmental alterations in nodal efficiency (<bold>a</bold>) were significantly associated with myelin content (<bold>b</bold>) and laminar thickness of L1 and L4-L6 (<bold>c</bold>–<bold>f</bold>). The inset brain map in each panel is the pattern of fundamental properties of brain organization.</p></caption></fig>" ]	[]	[ "<inline-formula id=\"IEq1\"><alternatives><tex-math id=\"M1\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M2\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq2\"><alternatives><tex-math id=\"M3\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M4\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq3\"><alternatives><tex-math id=\"M5\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M6\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq4\"><alternatives><tex-math id=\"M7\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M8\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq5\"><alternatives><tex-math id=\"M9\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M10\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq6\"><alternatives><tex-math id=\"M11\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\gamma$$\\end{document}</tex-math><mml:math id=\"M12\"><mml:mi>γ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq7\"><alternatives><tex-math id=\"M13\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M14\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq8\"><alternatives><tex-math id=\"M15\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma$$\\end{document}</tex-math><mml:math id=\"M16\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq9\"><alternatives><tex-math id=\"M17\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M18\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq10\"><alternatives><tex-math id=\"M19\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda$$\\end{document}</tex-math><mml:math id=\"M20\"><mml:mi>λ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq11\"><alternatives><tex-math id=\"M21\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M22\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq12\"><alternatives><tex-math id=\"M23\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M24\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq13\"><alternatives><tex-math id=\"M25\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}\\in [0.07,0.21]$$\\end{document}</tex-math><mml:math id=\"M26\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:mo>∈</mml:mo><mml:mrow><mml:mo>[</mml:mo><mml:mrow><mml:mn>0.07</mml:mn><mml:mo>,</mml:mo><mml:mn>0.21</mml:mn></mml:mrow><mml:mo>]</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq14\"><alternatives><tex-math id=\"M27\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}\\in [0.08,0.15]$$\\end{document}</tex-math><mml:math id=\"M28\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:mo>∈</mml:mo><mml:mrow><mml:mo>[</mml:mo><mml:mrow><mml:mn>0.08</mml:mn><mml:mo>,</mml:mo><mml:mn>0.15</mml:mn></mml:mrow><mml:mo>]</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq15\"><alternatives><tex-math id=\"M29\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}\\in [0.07,0.19]$$\\end{document}</tex-math><mml:math id=\"M30\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:mo>∈</mml:mo><mml:mrow><mml:mo>[</mml:mo><mml:mrow><mml:mn>0.07</mml:mn><mml:mo>,</mml:mo><mml:mn>0.19</mml:mn></mml:mrow><mml:mo>]</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq16\"><alternatives><tex-math id=\"M31\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M32\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq17\"><alternatives><tex-math id=\"M33\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M34\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq18\"><alternatives><tex-math id=\"M35\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M36\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq19\"><alternatives><tex-math id=\"M37\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M38\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq20\"><alternatives><tex-math id=\"M39\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M40\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq21\"><alternatives><tex-math id=\"M41\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M42\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq22\"><alternatives><tex-math id=\"M43\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M44\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq23\"><alternatives><tex-math id=\"M45\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M46\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq24\"><alternatives><tex-math id=\"M47\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M48\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq25\"><alternatives><tex-math id=\"M49\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M50\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq26\"><alternatives><tex-math id=\"M51\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M52\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq27\"><alternatives><tex-math id=\"M53\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M54\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq28\"><alternatives><tex-math id=\"M55\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M56\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq29\"><alternatives><tex-math id=\"M57\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M58\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq30\"><alternatives><tex-math id=\"M59\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\times$$\\end{document}</tex-math><mml:math id=\"M60\"><mml:mo>×</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq31\"><alternatives><tex-math id=\"M61\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\times$$\\end{document}</tex-math><mml:math id=\"M62\"><mml:mo>×</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq32\"><alternatives><tex-math id=\"M63\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\gamma$$\\end{document}</tex-math><mml:math id=\"M64\"><mml:mi>γ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq33\"><alternatives><tex-math id=\"M65\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda$$\\end{document}</tex-math><mml:math id=\"M66\"><mml:mi>λ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq34\"><alternatives><tex-math id=\"M67\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma$$\\end{document}</tex-math><mml:math id=\"M68\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq35\"><alternatives><tex-math id=\"M69\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$G$$\\end{document}</tex-math><mml:math id=\"M70\"><mml:mi>G</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ1\"><label>1</label><alternatives><tex-math id=\"M71\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${E}_{{glob}}\\left(G\\right)=\\frac{1}{N}{\\sum }_{i\\in G}\\frac{{\\sum }_{j\\in G,j\\ne i}{d}_{{ij}}^{-1}}{N-1}$$\\end{document}</tex-math><mml:math id=\"M72\"><mml:msub><mml:mrow><mml:mi>E</mml:mi></mml:mrow><mml:mrow><mml:mi>g</mml:mi><mml:mi>l</mml:mi><mml:mi>o</mml:mi><mml:mi>b</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>G</mml:mi></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi>N</mml:mi></mml:mrow></mml:mfrac><mml:msub><mml:mrow><mml:mo mathsize=\"big\">∑</mml:mo></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mo mathsize=\"big\">∑</mml:mo></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi><mml:mo>,</mml:mo><mml:mi>j</mml:mi><mml:mo>≠</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:msubsup><mml:mrow><mml:mi>d</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow><mml:mrow><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq36\"><alternatives><tex-math id=\"M73\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${d}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M74\"><mml:msub><mml:mrow><mml:mi>d</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq37\"><alternatives><tex-math id=\"M75\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M76\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq38\"><alternatives><tex-math id=\"M77\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M78\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq39\"><alternatives><tex-math id=\"M79\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$G$$\\end{document}</tex-math><mml:math id=\"M80\"><mml:mi>G</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq40\"><alternatives><tex-math id=\"M81\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$N$$\\end{document}</tex-math><mml:math id=\"M82\"><mml:mi>N</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq41\"><alternatives><tex-math id=\"M83\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$G$$\\end{document}</tex-math><mml:math id=\"M84\"><mml:mi>G</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq42\"><alternatives><tex-math id=\"M85\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$G$$\\end{document}</tex-math><mml:math id=\"M86\"><mml:mi>G</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq43\"><alternatives><tex-math id=\"M87\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M88\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ2\"><label>2</label><alternatives><tex-math id=\"M89\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${E}_{{loc}}(G)=\\frac{{\\sum }_{i\\in G}{E}_{{glob}}({G}_{i})}{N}$$\\end{document}</tex-math><mml:math id=\"M90\"><mml:msub><mml:mrow><mml:mi>E</mml:mi></mml:mrow><mml:mrow><mml:mi>l</mml:mi><mml:mi>o</mml:mi><mml:mi>c</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>G</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mo mathsize=\"big\">∑</mml:mo></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>E</mml:mi></mml:mrow><mml:mrow><mml:mi>g</mml:mi><mml:mi>l</mml:mi><mml:mi>o</mml:mi><mml:mi>b</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mi>G</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow><mml:mrow><mml:mi>N</mml:mi></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq44\"><alternatives><tex-math id=\"M91\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${G}_{i}$$\\end{document}</tex-math><mml:math id=\"M92\"><mml:msub><mml:mrow><mml:mi>G</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq45\"><alternatives><tex-math id=\"M93\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M94\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ3\"><label>3</label><alternatives><tex-math id=\"M95\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${L}_{p}\\left(G\\right)=\\frac{{\\sum }_{j\\in G,j\\ne i}{d}_{{ij}}}{N\\left(N-1\\right)}$$\\end{document}</tex-math><mml:math id=\"M96\"><mml:msub><mml:mrow><mml:mi>L</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>G</mml:mi></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mo mathsize=\"big\">∑</mml:mo></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi><mml:mo>,</mml:mo><mml:mi>j</mml:mi><mml:mo>≠</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>d</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>N</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfenced></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq46\"><alternatives><tex-math id=\"M97\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${d}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M98\"><mml:msub><mml:mrow><mml:mi>d</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq47\"><alternatives><tex-math id=\"M99\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M100\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq48\"><alternatives><tex-math id=\"M101\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M102\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq49\"><alternatives><tex-math id=\"M103\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$1/{w}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M104\"><mml:mn>1</mml:mn><mml:mo>/</mml:mo><mml:msub><mml:mrow><mml:mi>w</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq50\"><alternatives><tex-math id=\"M105\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$G$$\\end{document}</tex-math><mml:math id=\"M106\"><mml:mi>G</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq51\"><alternatives><tex-math id=\"M107\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$G$$\\end{document}</tex-math><mml:math id=\"M108\"><mml:mi>G</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ4\"><label>4</label><alternatives><tex-math id=\"M109\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${S}_{p}\\left(G\\right)=\\frac{{\\sum }_{i\\in G}S\\left(i\\right)}{N}$$\\end{document}</tex-math><mml:math id=\"M110\"><mml:msub><mml:mrow><mml:mi>S</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>G</mml:mi></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mo mathsize=\"big\">∑</mml:mo></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi></mml:mrow></mml:msub><mml:mi>S</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:mfenced></mml:mrow><mml:mrow><mml:mi>N</mml:mi></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq52\"><alternatives><tex-math id=\"M111\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$S(i)$$\\end{document}</tex-math><mml:math id=\"M112\"><mml:mi>S</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>i</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq53\"><alternatives><tex-math id=\"M113\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${w}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M114\"><mml:msub><mml:mrow><mml:mi>w</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq54\"><alternatives><tex-math id=\"M115\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M116\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ5\"><label>5</label><alternatives><tex-math id=\"M117\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${C}_{p}\\left(G\\right)=\\frac{{\\sum }_{i\\in G}{C}_{p}\\left(i\\right)}{N}$$\\end{document}</tex-math><mml:math id=\"M118\"><mml:msub><mml:mrow><mml:mi>C</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>G</mml:mi></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mo mathsize=\"big\">∑</mml:mo></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>C</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:mfenced></mml:mrow><mml:mrow><mml:mi>N</mml:mi></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq55\"><alternatives><tex-math id=\"M119\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$C(i)$$\\end{document}</tex-math><mml:math id=\"M120\"><mml:mi>C</mml:mi><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>i</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq56\"><alternatives><tex-math id=\"M121\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M122\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ6\"><label>6</label><alternatives><tex-math id=\"M123\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${C}_{p}\\left(i\\right)=\\frac{2\\times {\\sum }_{j,l\\in G}{\\left({\\bar{w}}_{{ij}}{\\bar{w}}_{{jl}}{\\bar{w}}_{{li}}\\right)}^{\\frac{1}{3}}}{{k}_{i}\\left({k}_{i}-1\\right)}$$\\end{document}</tex-math><mml:math id=\"M124\"><mml:msub><mml:mrow><mml:mi>C</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mn>2</mml:mn><mml:mo>×</mml:mo><mml:msub><mml:mrow><mml:mo mathsize=\"big\">∑</mml:mo></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>,</mml:mo><mml:mi>l</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi></mml:mrow></mml:msub><mml:msup><mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>w</mml:mi></mml:mrow><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>w</mml:mi></mml:mrow><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mi>l</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>w</mml:mi></mml:mrow><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi>l</mml:mi><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced></mml:mrow><mml:mrow><mml:mfrac><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow></mml:mfrac></mml:mrow></mml:msup></mml:mrow><mml:mrow><mml:msub><mml:mrow><mml:mi>k</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi>k</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfenced></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq57\"><alternatives><tex-math id=\"M125\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${k}_{i}$$\\end{document}</tex-math><mml:math id=\"M126\"><mml:msub><mml:mrow><mml:mi>k</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq58\"><alternatives><tex-math id=\"M127\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M128\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq59\"><alternatives><tex-math id=\"M129\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{w}$$\\end{document}</tex-math><mml:math id=\"M130\"><mml:mover accent=\"true\"><mml:mrow><mml:mi>w</mml:mi></mml:mrow><mml:mo>¯</mml:mo></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq60\"><alternatives><tex-math id=\"M131\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\gamma$$\\end{document}</tex-math><mml:math id=\"M132\"><mml:mi>γ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq61\"><alternatives><tex-math id=\"M133\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda$$\\end{document}</tex-math><mml:math id=\"M134\"><mml:mi>λ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ7\"><label>7</label><alternatives><tex-math id=\"M135\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\gamma =\\frac{{C}_{p}^{{real}}}{{C}_{p}^{{rand}}}$$\\end{document}</tex-math><mml:math id=\"M136\"><mml:mi>γ</mml:mi><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msubsup><mml:mrow><mml:mi>C</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow><mml:mrow><mml:mi>r</mml:mi><mml:mi>e</mml:mi><mml:mi>a</mml:mi><mml:mi>l</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mrow><mml:msubsup><mml:mrow><mml:mi>C</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow><mml:mrow><mml:mi>r</mml:mi><mml:mi>a</mml:mi><mml:mi>n</mml:mi><mml:mi>d</mml:mi></mml:mrow></mml:msubsup></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ8\"><label>8</label><alternatives><tex-math id=\"M137\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda =\\frac{{L}_{p}^{{real}}}{{L}_{p}^{{rand}}}$$\\end{document}</tex-math><mml:math id=\"M138\"><mml:mi>λ</mml:mi><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msubsup><mml:mrow><mml:mi>L</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow><mml:mrow><mml:mi>r</mml:mi><mml:mi>e</mml:mi><mml:mi>a</mml:mi><mml:mi>l</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mrow><mml:msubsup><mml:mrow><mml:mi>L</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow><mml:mrow><mml:mi>r</mml:mi><mml:mi>a</mml:mi><mml:mi>n</mml:mi><mml:mi>d</mml:mi></mml:mrow></mml:msubsup></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq62\"><alternatives><tex-math id=\"M139\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${C}_{p}^{{rand}}$$\\end{document}</tex-math><mml:math id=\"M140\"><mml:msubsup><mml:mrow><mml:mi>C</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow><mml:mrow><mml:mi>r</mml:mi><mml:mi>a</mml:mi><mml:mi>n</mml:mi><mml:mi>d</mml:mi></mml:mrow></mml:msubsup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq63\"><alternatives><tex-math id=\"M141\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${L}_{p}^{{rand}}$$\\end{document}</tex-math><mml:math id=\"M142\"><mml:msubsup><mml:mrow><mml:mi>L</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow><mml:mrow><mml:mi>r</mml:mi><mml:mi>a</mml:mi><mml:mi>n</mml:mi><mml:mi>d</mml:mi></mml:mrow></mml:msubsup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq64\"><alternatives><tex-math id=\"M143\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${C}_{p}$$\\end{document}</tex-math><mml:math id=\"M144\"><mml:msub><mml:mrow><mml:mi>C</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq65\"><alternatives><tex-math id=\"M145\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${L}_{p}$$\\end{document}</tex-math><mml:math id=\"M146\"><mml:msub><mml:mrow><mml:mi>L</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq66\"><alternatives><tex-math id=\"M147\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\gamma > 1$$\\end{document}</tex-math><mml:math id=\"M148\"><mml:mi>γ</mml:mi><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq67\"><alternatives><tex-math id=\"M149\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda \\approx 1$$\\end{document}</tex-math><mml:math id=\"M150\"><mml:mi>λ</mml:mi><mml:mo>≈</mml:mo><mml:mn>1</mml:mn></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq68\"><alternatives><tex-math id=\"M151\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma$$\\end{document}</tex-math><mml:math id=\"M152\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ9\"><label>9</label><alternatives><tex-math id=\"M153\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma =\\frac{\\gamma }{\\lambda }$$\\end{document}</tex-math><mml:math id=\"M154\"><mml:mi>σ</mml:mi><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mi>γ</mml:mi></mml:mrow><mml:mrow><mml:mi>λ</mml:mi></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq69\"><alternatives><tex-math id=\"M155\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma$$\\end{document}</tex-math><mml:math id=\"M156\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ10\"><label>10</label><alternatives><tex-math id=\"M157\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{nE}}_{{glob}}\\left(i\\right)=\\frac{{\\sum }_{j\\in G,j\\ne i}{d}_{{ij}}^{-1}}{N-1}$$\\end{document}</tex-math><mml:math id=\"M158\"><mml:msub><mml:mrow><mml:mi>n</mml:mi><mml:mi>E</mml:mi></mml:mrow><mml:mrow><mml:mi>g</mml:mi><mml:mi>l</mml:mi><mml:mi>o</mml:mi><mml:mi>b</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mo mathsize=\"big\">∑</mml:mo></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi><mml:mo>,</mml:mo><mml:mi>j</mml:mi><mml:mo>≠</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:msubsup><mml:mrow><mml:mi>d</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow><mml:mrow><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq70\"><alternatives><tex-math id=\"M159\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${d}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M160\"><mml:msub><mml:mrow><mml:mi>d</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq71\"><alternatives><tex-math id=\"M161\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M162\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq72\"><alternatives><tex-math id=\"M163\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M164\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ11\"><label>11</label><alternatives><tex-math id=\"M165\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{nE}}_{{loc}}\\left(i\\right)={E}_{{glob}}\\left({G}_{i}\\right)$$\\end{document}</tex-math><mml:math id=\"M166\"><mml:msub><mml:mrow><mml:mi>n</mml:mi><mml:mi>E</mml:mi></mml:mrow><mml:mrow><mml:mi>l</mml:mi><mml:mi>o</mml:mi><mml:mi>c</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:mfenced><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mi>E</mml:mi></mml:mrow><mml:mrow><mml:mi>g</mml:mi><mml:mi>l</mml:mi><mml:mi>o</mml:mi><mml:mi>b</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi>G</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ12\"><label>12</label><alternatives><tex-math id=\"M167\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${k}_{i}=\\mathop{\\sum} \\limits_{j\\in N}{w}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M168\"><mml:msub><mml:mrow><mml:mi>k</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mo>∑</mml:mo></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>∈</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:munder><mml:msub><mml:mrow><mml:mi>w</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq73\"><alternatives><tex-math id=\"M169\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M170\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ13\"><label>13</label><alternatives><tex-math id=\"M171\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${b}_{i}=\\frac{1}{(n-1)(n-2)} \\mathop{\\sum} \\limits_{{j,k\\in G}\\atop{j\\ne k,k\\ne i,i\\ne j}}\\frac{{\\rho }_{{jk}}(i)}{{\\rho }_{{jk}}}$$\\end{document}</tex-math><mml:math id=\"M172\"><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>n</mml:mi><mml:mo>−</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>n</mml:mi><mml:mo>−</mml:mo><mml:mn>2</mml:mn></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:mfrac><mml:munder><mml:mrow><mml:mo>∑</mml:mo></mml:mrow><mml:mrow><mml:mfrac linethickness=\"0\"><mml:mrow><mml:mi>j</mml:mi><mml:mo>,</mml:mo><mml:mi>k</mml:mi><mml:mo>∈</mml:mo><mml:mi>G</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>≠</mml:mo><mml:mi>k</mml:mi><mml:mo>,</mml:mo><mml:mi>k</mml:mi><mml:mo>≠</mml:mo><mml:mi>i</mml:mi><mml:mo>,</mml:mo><mml:mi>i</mml:mi><mml:mo>≠</mml:mo><mml:mi>j</mml:mi></mml:mrow></mml:mfrac></mml:mrow></mml:munder><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mi>ρ</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mi>k</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>i</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow><mml:mrow><mml:msub><mml:mrow><mml:mi>ρ</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mi>k</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfrac></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq74\"><alternatives><tex-math id=\"M173\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\rho }_{{jk}}$$\\end{document}</tex-math><mml:math id=\"M174\"><mml:msub><mml:mrow><mml:mi>ρ</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mi>k</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq75\"><alternatives><tex-math id=\"M175\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M176\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq76\"><alternatives><tex-math id=\"M177\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$k$$\\end{document}</tex-math><mml:math id=\"M178\"><mml:mi>k</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq77\"><alternatives><tex-math id=\"M179\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\rho }_{{jk}}(i)$$\\end{document}</tex-math><mml:math id=\"M180\"><mml:msub><mml:mrow><mml:mi>ρ</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mi>k</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>i</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq78\"><alternatives><tex-math id=\"M181\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M182\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq79\"><alternatives><tex-math id=\"M183\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$k$$\\end{document}</tex-math><mml:math id=\"M184\"><mml:mi>k</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq80\"><alternatives><tex-math id=\"M185\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M186\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq81\"><alternatives><tex-math id=\"M187\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\pm \\,$$\\end{document}</tex-math><mml:math id=\"M188\"><mml:mo>±</mml:mo></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ14\"><label>14</label><alternatives><tex-math id=\"M189\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${y}_{{ij}}= \t \\,{\\beta }_{0}+{b}_{i}+\\left({\\beta }_{{age}}+{b}_{{age},i}\\right){{age}}_{{ij}}+{\\beta }_{{sex}}{{sex}}_{i} \\\\ \t +{\\beta }_{{tbv}}{{tbv}}_{{ij}}+{\\beta }_{{centre}}{{centre}}_{i}+{\\varepsilon }_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M190\"><mml:msub><mml:mrow><mml:mi>y</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi><mml:mo>,</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:msub><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>t</mml:mi><mml:mi>b</mml:mi><mml:mi>v</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>t</mml:mi><mml:mi>b</mml:mi><mml:mi>v</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>c</mml:mi><mml:mi>e</mml:mi><mml:mi>n</mml:mi><mml:mi>t</mml:mi><mml:mi>r</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>c</mml:mi><mml:mi>e</mml:mi><mml:mi>n</mml:mi><mml:mi>t</mml:mi><mml:mi>r</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>ε</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq82\"><alternatives><tex-math id=\"M191\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${y}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M192\"><mml:msub><mml:mrow><mml:mi>y</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq83\"><alternatives><tex-math id=\"M193\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M194\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq84\"><alternatives><tex-math id=\"M195\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M196\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq85\"><alternatives><tex-math id=\"M197\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M198\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq86\"><alternatives><tex-math id=\"M199\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${b}_{{age},i}$$\\end{document}</tex-math><mml:math id=\"M200\"><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi><mml:mo>,</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq87\"><alternatives><tex-math id=\"M201\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M202\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq88\"><alternatives><tex-math id=\"M203\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{age}}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M204\"><mml:msub><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq89\"><alternatives><tex-math id=\"M205\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M206\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq90\"><alternatives><tex-math id=\"M207\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M208\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq91\"><alternatives><tex-math id=\"M209\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{tbv}}_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M210\"><mml:msub><mml:mrow><mml:mi>t</mml:mi><mml:mi>b</mml:mi><mml:mi>v</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq92\"><alternatives><tex-math id=\"M211\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{centre}}_{i}$$\\end{document}</tex-math><mml:math id=\"M212\"><mml:msub><mml:mrow><mml:mi>c</mml:mi><mml:mi>e</mml:mi><mml:mi>n</mml:mi><mml:mi>t</mml:mi><mml:mi>r</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq93\"><alternatives><tex-math id=\"M213\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${{sex}}_{i}$$\\end{document}</tex-math><mml:math id=\"M214\"><mml:msub><mml:mrow><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq94\"><alternatives><tex-math id=\"M215\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\varepsilon }_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M216\"><mml:msub><mml:mrow><mml:mi>ε</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq95\"><alternatives><tex-math id=\"M217\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M218\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq96\"><alternatives><tex-math id=\"M219\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$j$$\\end{document}</tex-math><mml:math id=\"M220\"><mml:mi>j</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ15\"><label>15</label><alternatives><tex-math id=\"M221\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${y}_{{ij}}= \t \\,{\\beta }_{0}+{b}_{i}+\\left({\\beta }_{{{age}}^{2}}+{b}_{{{age}}^{2},i}\\right){{{age}}_{{ij}}}^{2}+\\left({\\beta }_{{age}}+{b}_{{age},i}\\right){{age}}_{{ij}}\\\\ \t +{\\beta }_{{sex}}{{sex}}_{i}+{\\beta }_{{tbv}}{{tbv}}_{{ij}}+{\\beta }_{{centre}}{{centre}}_{i}+{\\varepsilon }_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M222\"><mml:msub><mml:mrow><mml:mi>y</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:msup><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:msup><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:msup><mml:mrow><mml:msub><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi><mml:mo>,</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:msub><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>t</mml:mi><mml:mi>b</mml:mi><mml:mi>v</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>t</mml:mi><mml:mi>b</mml:mi><mml:mi>v</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>c</mml:mi><mml:mi>e</mml:mi><mml:mi>n</mml:mi><mml:mi>t</mml:mi><mml:mi>r</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>c</mml:mi><mml:mi>e</mml:mi><mml:mi>n</mml:mi><mml:mi>t</mml:mi><mml:mi>r</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>ε</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq97\"><alternatives><tex-math id=\"M223\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{{age}}^{2}}$$\\end{document}</tex-math><mml:math id=\"M224\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:msup><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq98\"><alternatives><tex-math id=\"M225\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${b}_{{{age}}^{2},i}$$\\end{document}</tex-math><mml:math id=\"M226\"><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:msup><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq99\"><alternatives><tex-math id=\"M227\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i$$\\end{document}</tex-math><mml:math id=\"M228\"><mml:mi>i</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ16\"><label>16</label><alternatives><tex-math id=\"M229\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${y}_{{ij}}= \t \\,{\\beta }_{0}+{b}_{i}+\\left({\\beta }_{{age}}+{b}_{{age},i}\\right){{age}}_{{ij}}+{\\beta }_{{sex}}{{sex}}_{i}\\\\ \t +{\\beta }_{{age}* {sex}}\\left({{age}}_{{ij}}* {{sex}}_{i}\\right) +{\\beta }_{{tbv}}{{tbv}}_{{ij}}+{\\beta }_{{centre}}{{centre}}_{i}+{\\varepsilon }_{{ij}}$$\\end{document}</tex-math><mml:math id=\"M230\"><mml:msub><mml:mrow><mml:mi>y</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mspace width=\"0.25em\"/><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>b</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi><mml:mo>,</mml:mo><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:msub><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi><mml:mo></mml:mo><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo></mml:mo><mml:msub><mml:mrow><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>x</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfenced><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>t</mml:mi><mml:mi>b</mml:mi><mml:mi>v</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>t</mml:mi><mml:mi>b</mml:mi><mml:mi>v</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>c</mml:mi><mml:mi>e</mml:mi><mml:mi>n</mml:mi><mml:mi>t</mml:mi><mml:mi>r</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi>c</mml:mi><mml:mi>e</mml:mi><mml:mi>n</mml:mi><mml:mi>t</mml:mi><mml:mi>r</mml:mi><mml:mi>e</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mrow><mml:mi>ε</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mi>j</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq100\"><alternatives><tex-math id=\"M231\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M232\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq101\"><alternatives><tex-math id=\"M233\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M234\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq102\"><alternatives><tex-math id=\"M235\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M236\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq103\"><alternatives><tex-math id=\"M237\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M238\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq104\"><alternatives><tex-math id=\"M239\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M240\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq105\"><alternatives><tex-math id=\"M241\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\times$$\\end{document}</tex-math><mml:math id=\"M242\"><mml:mo>×</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq106\"><alternatives><tex-math id=\"M243\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\times$$\\end{document}</tex-math><mml:math id=\"M244\"><mml:mo>×</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq107\"><alternatives><tex-math id=\"M245\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M246\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq108\"><alternatives><tex-math id=\"M247\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M248\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq109\"><alternatives><tex-math id=\"M249\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M250\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq110\"><alternatives><tex-math id=\"M251\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\times$$\\end{document}</tex-math><mml:math id=\"M252\"><mml:mo>×</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq111\"><alternatives><tex-math id=\"M253\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\beta }_{{age}}$$\\end{document}</tex-math><mml:math id=\"M254\"><mml:msub><mml:mrow><mml:mi>β</mml:mi></mml:mrow><mml:mrow><mml:mi>a</mml:mi><mml:mi>g</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>" ]	[]	[]	[]	[]	[ "<supplementary-material content-type=\"local-data\" id=\"MOESM1\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM2\"></supplementary-material>" ]	[ "<fn-group><fn><p><bold>Publisher’s note</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn><fn><p>These authors contributed equally: Guozheng Feng, Rui Chen.</p></fn><fn><p><bold>Change history</bold></p><p>1/11/2024</p><p>A Correction to this paper has been published: 10.1038/s42003-024-05771-z</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"42003_2023_5647_Fig1_HTML\" id=\"d32e540\"/>", "<graphic xlink:href=\"42003_2023_5647_Fig2_HTML\" id=\"d32e554\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq1.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq2.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq3.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq4.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq5.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq6.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq7.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq8.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq9.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq10.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq11.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq12.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Fig3_HTML\" id=\"d32e849\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq13.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq14.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq15.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq16.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq17.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq18.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq19.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq20.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq21.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq22.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq23.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq24.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq25.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Fig4_HTML\" id=\"d32e1246\"/>", "<graphic xlink:href=\"42003_2023_5647_Fig5_HTML\" id=\"d32e1295\"/>", "<graphic xlink:href=\"42003_2023_5647_Fig6_HTML\" id=\"d32e1426\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq26.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq27.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq28.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq29.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq30.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq31.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq32.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq33.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq34.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq35.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ1.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq36.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq37.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq38.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq39.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq40.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq41.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq42.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq43.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ2.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq44.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq45.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ3.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq46.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq47.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq48.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq49.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq50.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq51.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ4.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq52.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq53.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq54.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ5.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq55.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq56.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ6.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq57.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq58.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq59.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq60.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq61.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ7.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ8.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq62.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq63.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq64.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq65.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq66.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq67.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq68.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ9.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq69.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ10.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq70.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq71.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq72.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ11.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ12.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq73.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ13.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq74.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq75.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq76.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq77.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq78.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq79.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq80.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq81.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ14.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq82.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq83.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq84.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq85.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq86.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq87.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq88.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq89.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq90.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq91.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq92.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq93.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq94.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq95.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq96.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ15.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq97.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq98.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq99.gif\"/>", "<graphic xlink:href=\"42003_2023_5647_Article_Equ16.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq100.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq101.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq102.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq103.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq104.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq105.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq106.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq107.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq108.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq109.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq110.gif\"/>", "<inline-graphic xlink:href=\"42003_2023_5647_Article_IEq111.gif\"/>" ]	[ "<media xlink:href=\"42003_2023_5647_MOESM1_ESM.pdf\"><caption><p>Supplementary Information</p></caption></media>", "<media xlink:href=\"42003_2023_5647_MOESM2_ESM.pdf\"><caption><p>Reporting summary</p></caption></media>" ]	[{"label": ["37."], "surname": ["Xia"], "given-names": ["Y"], "article-title": ["Development of functional connectome gradients during childhood and adolescence"], "source": ["Sci. Bull."], "year": ["2022"], "volume": ["67"], "fpage": ["1049"], "lpage": ["1061"], "pub-id": ["10.1016/j.scib.2022.01.002"]}, {"label": ["44."], "surname": ["Tao"], "given-names": ["S"], "article-title": ["Intelligence development and school adjustment of school-age children and adolescents: a follow-up cohort study"], "source": ["Psychol. Commun."], "year": ["2019"], "volume": ["2"], "fpage": ["88"], "lpage": ["90"]}, {"label": ["50."], "mixed-citation": ["Feng, G. et al. Spatial and temporal pattern of structure-function coupling of human brain connectome with development. "], "italic": ["bioRxiv"]}, {"label": ["53."], "surname": ["Akaike"], "given-names": ["H"], "article-title": ["A new look at the statistical identification model"], "source": ["IEEE Trans. Automat. Control"], "year": ["1974"], "volume": ["19"], "fpage": ["716"], "lpage": ["723"], "pub-id": ["10.1109/TAC.1974.1100705"]}, {"label": ["66."], "mixed-citation": ["Lotter, L. D., Dukart, J. & Fulcher, B. D. ABAnnotate: A toolbox for ensemble-based multimodal gene-category enrichment analysis of human neuroimaging data. "], "italic": ["Zenodo"]}, {"label": ["67."], "mixed-citation": ["Fulcher, B. D., Arnatkeviciute, A. & Fornito, A. Overcoming false-positive gene-category enrichment in the analysis of spatially resolved transcriptomic brain atlas data. "], "italic": ["Nat. Commun."], "bold": ["12"]}, {"label": ["108."], "surname": ["Oguz"], "given-names": ["I"], "article-title": ["DTIPrep: quality control of diffusion-weighted images"], "source": ["Front. Neuroinf."], "year": ["2014"], "volume": ["8"], "fpage": ["4"], "pub-id": ["10.3389/fninf.2014.00004"]}, {"label": ["112."], "surname": ["Onnela", "Saramaki", "Kertesz", "Kaski"], "given-names": ["JP", "J", "J", "K"], "article-title": ["Intensity and coherence of motifs in weighted complex networks"], "source": ["Phys. Rev. E"], "year": ["2005"], "volume": ["71"], "fpage": ["065103"], "pub-id": ["10.1103/PhysRevE.71.065103"]}, {"label": ["116."], "mixed-citation": ["Freeman, L. C. Centrality in social networks conceptual clarification. "], "italic": ["Soc. Netw"], "bold": ["1"]}, {"label": ["122."], "mixed-citation": ["Feng, G. FelixFengCN/WM-connectome-development: v1.0.0. "], "italic": ["Zenodo"]}]	{ "acronym": [], "definition": [] }	122	CC BY	no	2024-01-13 23:36:42	Commun Biol. 2023 Dec 12; 6:1257	oa_package/70/9c/PMC10716168.tar.gz
PMC10728222	38110766	[ "<title>Introduction</title>", "<p id=\"Par2\">Mining activity produces significant amounts of waste materials, causing a disruptive and negative impact on the environment (Hoskin, ##UREF##9##2000##). Mining and flotation tailings related to the exploitation of non-ferrous metal ores are a source of heavy metal pollution, especially due to the transport of post-flotation tailings and the erosion of landfill (Conesa et al., ##REF##16820188##2007##; Li, ##REF##15992864##2006##; Wang et al., ##UREF##35##2009##). Aeolian erosion, which intensifies in periods of low precipitation, is an unfavorable factor that poses a significant threat to the environment. Forests in the vicinity of tailings ponds show signs of pollution and their growth is clearly weakened. The reclamation of post-flotation tailings ponds is extremely difficult due to the high concentration of metals contained in them, alongside their low nutrient levels, high pH values, and the low water retention capacity of the soil (Cano-Reséndiz et al., ##REF##21411226##2011##; Conesa et al., ##REF##16820188##2007##; Krzaklewski & Pietrzykowski, ##UREF##18##2002##; Ye et al., ##REF##12137044##2002##). The lack of nutrients, or their low availability, is an important selection factor that limits the development of vegetation (Kazakou et al., ##REF##18823392##2008##; Turnau et al., ##UREF##33##2010##). Most post-flotation tailings pond landfills are devoid of vegetation cover, and the natural emergence of pioneer plants is quite exceptional (Monterroso et al., ##UREF##26##2014##). The problems of nutrient deficiency and lack of vegetation can be solved by covering the post-flotation tailings with a top layer of fertile soil, which must often be transported over long distances, significantly increasing costs, especially in the case of large tailings ponds (Kasowska et al., ##REF##29063407##2018##). Because post-flotation waste is a potential source for the recycling and recovery of non-ferrous metals, tailing ponds are not subject to full reclamation, rather only temporary revegetation and technical and biological stabilization (Cheng et al., ##REF##25450917##2015##; Krzaklewski & Pietrzykowski, ##UREF##18##2002##). An environmentally friendly and inexpensive technology is phytoremediation, which uses plants to neutralize pollutants without extracting them (Novo et al., ##UREF##28##2013##). The most important factor in phytoremediation technology is the appropriate selection of plants characterized by rapid growth, high biomass gain, high tolerance to excess metals, and intensive growth in conditions of nutrient deficiency (Deng et al., ##REF##16828210##2007##; Pottier et al., ##UREF##29##2015##). Within the pool of species that can be used in phytoremediation, trees are highly effective in stabilizing heavy metals (Mendez & Maier, ##UREF##25##2008##).</p>", "<p id=\"Par3\">Due to the participation of many heavy metals in redox reactions, and their function as cofactors or enzyme activators, the tolerance range of plants toward metals varies depending on the tree species, type, concentration, and chemical form of the metal, as well as the composition and pH of the soil. Exceeding the limit values of their concentrations negatively affects the growth of trees and is toxic to cells, tissues, and entire plants (Asgari Lajayer et al., ##REF##28759767##2017##, ##REF##30712209##2019##; Chandel et al., ##UREF##3##2023##; Dimkpa et al., ##UREF##5##2009##; Kraj & Zarek, ##UREF##17##2021##). However, there is a group of metal ions such as cadmium (Cd), mercury (Hg), lead (Pb), and arsenic (As) that are biologically irrelevant and highly toxic even at low concentrations in various biochemical and physiological processes (Asgari Lajayer et al., ##REF##28759767##2017##, ##REF##30712209##2019##; Hristozkova et al., ##UREF##10##2016##). Heavy metals are therefore an important stress factor (Fryzova et al., ##REF##29032515##2018##). Elements such as Cd and Pb are trace elements and have no nutritional or physiological function in plants (Schützendübel & Polle, ##UREF##30##2001##). Due to its high mobility in the soil–plant system, Cd has been classified as the fourth most toxic element to higher plants (Qayyum et al., ##REF##28189896##2017##). Heavy metals and salinity are examples of abiotic stress factors, a common effect of which (in addition to limiting shoot and root growth) is an imbalance between the generation and capture of potentially cell-damaging reactive oxygen species (ROSs). The accumulation of ROSs leads to oxidative stress (Sidhu et al., ##REF##27744137##2017##). The emerging imbalance of the redox state in cells is caused, on one hand, by an increase in the content of superoxide ions (O<sub>2</sub>•–), hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), and thiobarbituric-acid-reactive substances (TBARSs)––an indicator of membrane lipid peroxidation. This results from the activation of oxidases located in the membranes and the interruption of the electron transport chain in the photosynthetic system in chloroplasts and the respiratory chain in the mitochondria, causing oxidation and inhibition of the activity of cellular proteins. On the other hand, based on the lower ability to synthesize small molecule antioxidants (primarily ascorbic acid and glutathione), the decreasing activity of antioxidant enzymes such as superoxide dismutase, catalase, and enzymes of the Foyer-Halliwell-Asada cycle, plants show lower activity of the cellular antioxidant system (Abbas et al., ##UREF##0##2017##; Yongqi et al., ##UREF##36##2016##). Plants protect themselves against the adverse effects of ROSs by increasing the synthesis and activity of small-molecular and enzymatic antioxidants, with plant stress tolerance being strongly related to the activity of the antioxidant system of cells (Kraj & Slepaczuk, ##UREF##16##2022##; Sidhu et al., ##REF##27214085##2016##). The growth of plants under stress conditions is part of their life, and determining the limits of their tolerance and acclimatization abilities to these conditions is of practical importance in predicting the adaptive potential of individuals (Isebrands et al., ##UREF##11##2000##).</p>", "<p id=\"Par4\">The seedlings of some tree species can successfully develop in areas polluted by heavy metals. Research on these species is important in the context of exploring the potential for introducing tree species to achieve the permanent biological stabilization and reclamation of post-flotation tailings, especially after the final recycling of trace metals, but where concentrations remain much higher than in natural soils. To better understand the adaptation and reaction to plant stress induced by heavy metal ions of <italic>Betula pendula</italic> Roth., <italic>Pinus sylvestris</italic> L., and <italic>Larix decidua</italic> Mill. seedlings caused by tailings waste highly contaminated by trace elements, the relationships between: the concentration of heavy metals in the soil substrate, the ability to their accumulation, and the biometric parameters of the seedlings were determined. We also estimated the threshold content of heavy metals in the roots above which the oxidative burst, an early plant response to heavy metal content increase is triggered. We assume that there are certain limit concentrations of heavy metals in the soil and fine roots, which depend on the tree species and beyond which the plant responds strongly to stress. We believe that the tolerance limits and the ability of forest tree seedlings to acclimatize under stressful conditions depend on the species. Additionally, there are certain ranges of heavy metal concentrations in the soil at which the physiological response is the greatest.</p>" ]	[ "<title>Materials and methods</title>", "<title>Study sites and field study</title>", "<p id=\"Par5\">The experiment was carried out between March and October in the Olkusz Forestry Nursery, Poland. The average annual air temperature was 7.7°C and the average total precipitation during the experiment was 562 mm (the average annual precipitation was 741 mm). Stimulated contamination of the substrate by sludge taken from a post-flotation tailings ponds was used. Different concentrations of trace metals were obtained by mixing the nursery substrate with a volumetric ratio of post-flotation tailings taken from the tailing ponds (Table ##TAB##0##1##).</p>", "<p id=\"Par6\">One-year-old seedlings of silver birch (<italic>Betula pendula</italic> Roth), Scots pine (<italic>Pinus sylvestris</italic> L.), and European larch (<italic>Larix decidua</italic> Mill.) were tested in the experiment. Light-demanding species were selected for the study, which when placed in an open area will tolerate strong sunlight well. Pine is one of the main forest-forming species in Europe and is characterized by low habitat requirements. Pine trees occur in various soil conditions with a wide range of humidity conditions. <italic>Betula</italic> trees have a shallow, extensive root system that can effectively absorb heavy metals from the soil. Moreover, <italic>Betula</italic> is often a succesional species. <italic>Larix</italic> has a strong tap root system with numerous lateral roots. <italic>Larix</italic> is characterized by very rapid growth when young. Each seedling was planted in a container with a capacity of 5 dm<sup>3</sup>. For each substrate variant and species, 10 seedlings were planted in March (120 seedlings in total). In June (date 1) and October 2021 (date 2), 60 seedlings were collected, in which the content of macro- and selected microelements (Cd, Pb, Zn) were analyzed.</p>", "<title>Laboratory analyses</title>", "<p id=\"Par7\">In the substrate samples, pH was measured potentiometrically in 1 M potassium chloride (KCl). The N content was measured using the dry combustion method using a TruMac® CNS analyzer. The total contents of magnesium (Mg), (potassium) K, phosphorus (P), (cadmium) Cd, (lead) Pb, and (zinc) Zn were measured using inductively coupled plasma–optical emission spectroscopy (ICP–OES) (iCAP™ 6000 series) after extraction in a mixture of nitric (HNO<sub>3</sub>) and perchloric (HClO<sub>4</sub>) acids at a ratio of 3:1. Trace elements (Cd, Pb, Zn) were extracted using 1M ammonium acetate (CH<sub>3</sub>COONH<sub>4</sub>) and determined using ICP–OES.</p>", "<p id=\"Par8\">After extraction from the substrate, the seedlings were transported to the laboratory and washed in distilled water. The cuttings were divided into roots, shoots, and leaves. The root systems were scanned and analyzed using WinRHIZO software, which allows determination of the total root length and average root diameter. The roots, shoots, and leaves were dried at 65°C and weighed to an accuracy of 0.01 g on a laboratory balance. The elements (Mg, K, P, Cd, Pb, and Zn) in the roots, stems, and leaves were measured using a spectrophotometer after wet combustion in a mixture of HNO<sub>3</sub> and HClO<sub>4</sub> at a ratio of 4:1. The total N content was measured using the dry combustion method and a TruMac analyzer.</p>", "<title>Oxidative stress marker determination</title>", "<p id=\"Par9\">The intensity of oxidative stress caused by the uptake and accumulation of heavy metals was determined based on the content of H<sub>2</sub>O<sub>2</sub> and the level of the biochemical marker of lipid peroxidation (TBARS) in the roots, shoots, and assimilation organs. The ability to scavenge the H<sub>2</sub>O<sub>2</sub>, and indirectly the ROS, transformed into this compound was determined by analyzing the total ascorbic acid (tAsA) content and the percentage of its oxidized form as dehydroascorbic acid (DHA).</p>", "<p id=\"Par10\">Seedlings intended for the analysis of oxidative stress markers and the H<sub>2</sub>O<sub>2</sub> scavenging rate were rinsed of substrate, divided into their organs (leaves/needles, shoots, and roots), frozen in liquid N, and then ground into powder. H<sub>2</sub>O<sub>2</sub> content was determined using the Amplex Red oxidation method (Cayman Chemical, Ann Arbor, MI, USA), as described by Kraj, (##UREF##15##2016##). Briefly, H<sub>2</sub>O<sub>2</sub> was extracted in 50 mM sodium phosphate buffer (pH 7.4) containing Triton X-100 (0.2%). The Amplex Red oxidation was carried out in the dark at 30°C for 30 min. The components of the reaction mixture (0.1 mM Amplex Red and 0.2 U/ml horseradish peroxidase (Sigma, St. Louis, MO, USA)) were dissolved in sodium phosphate buffer, and then this solution was mixed with the H<sub>2</sub>O<sub>2</sub> extract in a 1:1 ratio. The absorbance was read at 560 nm, and the H<sub>2</sub>O<sub>2</sub> concentration was determined from the standard curve for the range of 0–8 μM.</p>", "<p id=\"Par11\">The degree of lipid peroxidation was determined by analyzing the TBARS content according to the method of Dhindsa et al. (##UREF##4##1981##). TBARS extraction was performed with 5% trichloroacetic acid (TCA). The reaction mixture containing the extract and a 20% solution of TCA plus thiobarbituric acid (TBA) (Sigma, St. Louis, MO, USA) was heated at 95°C for 30 min and then quickly cooled in ice. The TBARS concentration was calculated using an extinction coefficient of 155 mM<sup>−1</sup> cm<sup>−1</sup> based on the difference in absorbance at 532 nm and non-specific absorbance at 600 nm.</p>", "<title>Ascorbate and dehydroascorbate determination</title>", "<p id=\"Par12\">The total content of ascorbic acid (tAsA) and the content of its reduced form were determined according to the method of Gillespie and Ainsworth, (##UREF##8##2007##). Ascorbic acid extract in 6% TCA was obtained. To analyze the total content of ascorbic acid, the oxidized form of this compound was reduced by adding 10 mM dithiothreitol (DTT). The solution was incubated at 37°C for 20 min. To remove DTT excess 0.5% N-ethylmaleimide (NEM) was added. The reduced form of ascorbic acid was determined without the DTT or NEM. A reaction mixture containing TCA, phosphoric acid (H<sub>3</sub>PO<sub>4</sub>), 2,2'-dipyridyl, and iron chloride (FeCl<sub>3</sub>) was added to the ascorbic acid extract. The reaction was carried out at 37°C for 60 min. The absorbance at 550 nm was read, and the content of ascorbic acid was determined on the basis of a standard curve plotted for concentrations of 0.15–10 mM. The content of the oxidized form of ascorbic acid (DHA) was calculated as the difference between the total and reduced forms of the compound and expressed as a % of its total content.</p>", "<p id=\"Par13\">All absorbance readings were taken using a Microplate Reader Synergy-2 (Biotek, Winooski, VT, USA).</p>", "<title>Statistical procedures</title>", "<p id=\"Par14\">Statistical analysis included the implementation of generalized additive models (GAMs). The GAM method with an identical binding function was used for prognostic calculations. One-way analysis of variance (ANOVA) was used to check the differences in mean values of the soil properties. Two-way ANOVA was used to check the differences in mean values of the biometric parameters, the total content of Mg, K, P, Cd, Pb, and Zn, and determine the oxidative stress marker. This was followed by a multiple comparison procedure using the RIR–Tukey test (at <italic>p</italic> < 0.05). The statistical analysis was performed using Statistica 13.3 software (StatSoft, Inc.).</p>" ]	[ "<title>Results</title>", "<title>Basic properties of the substrates</title>", "<p id=\"Par15\">The post-flotation tailings used to prepare the substrates were slightly alkaline (pH 7.61). The nitrogen (N) content was 0.009%, and the content of exchangeable cations was calcium (Ca<sup>2+</sup>) 7.99, potassium (K<sup>+</sup>) 0.01, magnesium (Mg<sup>2+</sup>) 0.87, and sodium (Na<sup>+</sup>) 0.02 all in cmol∙kg<sup>−1</sup>. The total concentration of Cd was 0.08 mg∙g<sup>−1</sup>, whereas the concentrations of Pb and zinc (Zn) were 1.96 and 8.23 mg∙g<sup>−1</sup>, respectively.</p>", "<p id=\"Par16\">The substrates used in the experiment differed in their physicochemical properties. The SA substrate was very strongly acidic (pH 4.98), whereas the remaining substrates were neutral, the higher the PFS content (Table ##TAB##0##1##). The high pH is related to the properties of the ore-bearing rocks from which the sediments were formed. Zinc–Pb ores in Poland occur mainly in Middle Triassic dolomites, marly dolomites, ore-bearing limestones, and marly limestones, which, due to their high Ca and Mg carbonate (CO<sub>3</sub>) contents, affect the alkalization of the substrates. Most trace metals in this pH range show relatively low mobility (Krzaklewski & Pietrzykowski, ##UREF##18##2002##). The content of macronutrients in the substrates was inversely related to the percentage of PFS. The substrate without the addition of PFS had the highest N content (6.10 mg∙g<sup>−1</sup>), whereas the SA + 50% PFS substrate contained the least N (0.46 mg∙g<sup>−1</sup>). The decrease in N content in substrates containing a higher proportion of PFS resulted from the lack of this element in the post-flotation tailings. The N content in the post-flotation tailings taken from the tailing ponds was 0.09 mg·g<sup>−1</sup>. Similar results were obtained for Ca, K, Mg, and Na (Table ##TAB##1##2##). The content of heavy metals (Cd, Pb, Zn) increased with an increasing share of PFS in the substrate, except for Pb, the content of which was comparable with the substrates SA + 25% PFS and SA + 50% PFS (approximately 0.55 mg∙g<sup>−1</sup>) (Table ##TAB##1##2##).</p>", "<title>Biometric parameters and chemistry of the seedlings</title>", "<p id=\"Par17\">The tested species differed in their shoot, root, and leaves biomass. <italic>Betula</italic> was characterized by having the lowest leaves biomass (0.9 g). By contrast, <italic>Pinus</italic> had the lowest shoot (1.7 g) and root biomass (1.0 g). The average root diameter was the smallest in the <italic>Betula</italic> seedlings (0.4 mm), larger in <italic>Pinus</italic> (0.5 mm), and largest in <italic>Larix</italic> (0.6 mm). The seedlings growing in the SA + 50% PFS variant were characterized by a shorter root length and a larger root diameter than the seedlings growing in the other variants. The average root length for the seedlings growing in the SA variant was 1274.4 mm, whereas, in the SA + 50% PFS variant, it was about 50% shorter, at 623.1 mm. The average root diameter for seedlings growing in the SA + 50% PFS variant was 0.7 mm, and 0.5 mm for seedlings growing in the other variants (Table ##TAB##2##3##).</p>", "<p id=\"Par18\">The N content in the <italic>Betula</italic> leaves was higher than in the <italic>Pinus</italic> and <italic>Larix</italic> needles. A higher content of N and K was found in the leaves of the seedlings growing in the SA variant. The N supply of the shoots did not differ across species. The seedlings growing in different test substrates did not differ in their content of P in the roots, shoots, or leaves. The supply of Mg to the leaves of the tested seedlings was the highest for <italic>Betula</italic> in the SA + 10% PFS and SA + 25% PFS variants (Table ##TAB##3##4##).</p>", "<p id=\"Par19\">The Cd, Pb, and Zn contents in the <italic>Betula</italic>, <italic>Larix</italic>, and <italic>Pinus</italic> seedlings depended on the tree species and the substrate. The highest concentration of cadmium was found in fine pine roots and birch leaves and shoots. The highest lead concentration was found in fine roots and pine shoots. The concentration of lead in pine and larch needles did not differ and was higher than the concentration of lead in birch leaves. The highest concentration of zinc was found in fine pine roots. The concentration of zinc was highest in birch shoots and leaves (Table ##TAB##4##5##). The bioaccumulation factors of Cd, Pb, and Zn by the roots, leaves, and shoots were, in most cases, lower than 0.1. Bioaccumulation factors above 1 were found in the roots of the seedlings grown in uncontaminated substrates</p>", "<p id=\"Par20\">The correlation coefficient between the concentration of trace elements (Pb, Cd, Zn) in the soil and the biometric parameters of the seedlings (leaves weight, shoot weight, root weight, root length, root diameter) revealed a significant negative correlation between the trace elements and the root length in the first period of growth (from the beginning of the experiment until June). The correlation coefficients between root length and Cd, Pb, and Zn were −0.48, −0.60, and −0.45, respectively. To better understand the effect of trace-element concentrations on root length using a GAM, a model was developed to explain the relationship between the soil concentration of Cd, Pb, and Zn and root length. An important factor influencing root length was the concentration of Cd, with an increase in Cd concentration from 0 to 0.015 mg∙g<sup>−1</sup> causing a several-fold decrease in root length.</p>", "<title>Influence of heavy metal concentration on the level of oxidative stress</title>", "<p id=\"Par21\">The intensity of oxidative stress caused by the uptake and accumulation of heavy metals in the organs (roots, shoots, and leaves/needles) of <italic>Betula</italic>, <italic>Pinus</italic>, and <italic>Larix</italic> seedlings, and their ability to scavenge ROSs, depended on the content of heavy metals (Cd, Pb, Zn) in the seedlings. The reaction of the plants to the time of growth in the substrates containing heavy metals was determined, taking into account the seedling species and organ. The seedling species differed in the degree of lipid peroxidation in the roots, shoots, and leaves/needles, and the content of H<sub>2</sub>O<sub>2</sub> in the leaves/needles. A significantly higher TBARS content was found in the organs of <italic>Larix</italic> compared to those of the <italic>Pinus</italic> and <italic>Betula</italic> seedlings (Table ##TAB##5##6##).</p>", "<p id=\"Par22\">The highest TBARS content was found with the lowest content of Cd<italic>.</italic> An increase in Cd content in the roots growing on substrates with an increasing share of flotation sludge resulted in a decrease in the degree of lipid peroxidation (Table ##TAB##6##7##). A different reaction in the roots was found for Zn and Pb, which caused either an increase or a constant content of TBARS, respectively, with an increase in the metal content. The remaining organs of the seedlings, except for Pb ions in the leaves/needles, did not show a clear relationship between the increasing content of metals and the level of lipid peroxidation (Table ##TAB##6##7##). The needles of the <italic>Larix</italic> seedlings showed a significantly greater increase in the H<sub>2</sub>O<sub>2</sub> content in response to the uptake of heavy metals relative to the <italic>Betula</italic> seedlings, and a slightly smaller increase relative to the <italic>Pinus</italic> seedlings. The increasing Cd content in the <italic>Larix</italic> needles caused an increase in the H<sub>2</sub>O<sub>2</sub> content (Table ##TAB##6##7##). At the same time, no other correlation was found between the increasing content of the other metals and the intensity of the oxidative stress.</p>", "<p id=\"Par23\">Similarly to the markers of oxidative stress, there were significant interspecies differences in the markers indicating activity in the antioxidant system (i.e., tAsA) and the proportion of its oxidized form (% DHA) in the organs of the seedlings. The highest level of tAsA was found in the <italic>Betula</italic> seedlings, whereas significantly less was found in the coniferous <italic>Pinus</italic> and <italic>Larix</italic> seedlings. The tree seedlings growing on substrates containing heavy metals differed in their profiles of tAsA content change. It was found that all the organs of <italic>Betula</italic> seedlings were characterized by a continuous decrease in the content of this compound. By contrast, in response to the increasing content of heavy metals, the <italic>Pinus</italic> and <italic>Larix</italic> seedlings initially showed an increase in tAsA content, which reached its maximum in June, and then were characterized by a rapid decrease in this compound with increasing heavy metal content. The greatest decrease in tAsA during the vegetation period was found in the <italic>Pinus</italic> seedlings, with the decrease being less in the <italic>Larix</italic> and <italic>Betula</italic> seedlings (Table ##TAB##5##6##). In response to the oxidative stress caused by the presence of the heavy metals, the seedlings showed an increase in the share of the tAsA in its oxidized form (Table ##TAB##5##6##). The smallest increase in the share of DHA (relative to the tAsA) was found in the <italic>Betula</italic> organs. A significantly greater increase in the percentage of DHA was found in the organs of the <italic>Larix</italic> and <italic>Pinus</italic> seedlings. The roots of the coniferous seedlings showed a significantly higher degree of oxidation of ascorbic acid compared with the <italic>Betula</italic> seedlings. It was also found that the greatest increase in the share of DHA took place in the roots of the coniferous seedlings, with only a slight increase of this compound in the roots of the <italic>Betula</italic> seedlings. Significant differences were found in the concentrations of the markers of oxidative stress and forms of ascorbic acid in the organs of the <italic>Betula</italic>, <italic>Larix</italic>, and <italic>Pinus</italic> seedlings. These differences depended on the date of seedling sampling and how much time they had been growing on the substrates containing heavy metals. The TBARS content in the roots was significantly lower in September than in June for all three species. A similar tendency was found for the TBARSs in the shoots of the seedlings. However, the leaves showed a significant increase in the degree of lipid peroxidation in September, compared to the beginning of the vegetation period. The H<sub>2</sub>O<sub>2</sub> content showed a significant increase in the roots and leaves/needles of the seedling species during the sampling period. While the increase in H<sub>2</sub>O<sub>2</sub> content in the <italic>Betula</italic> roots was higher (by about 50%) in September than in June, its increase in the <italic>Pinus</italic> and <italic>Larix</italic> was several times higher than that (Table ##TAB##5##6##). The tAsA content showed a significant decrease in the roots of the seedlings. It was higher in the coniferous seedlings than in the <italic>Betula</italic> seedlings. The growth of the seedlings under stress conditions on the substrates containing heavy metals resulted in an increase in the share of the oxidized form of ascorbic acid in the organs of all the seedling species. The greatest increase in this share was in the roots of the coniferous tree seedlings, whereas it was significantly lower in their shoots and needles (Table ##TAB##5##6##).</p>" ]	[ "<title>Discussion</title>", "<p id=\"Par24\">The growth of the <italic>Betula</italic>, <italic>Larix</italic>, and <italic>Pinus</italic> seedlings was significantly inhibited in the contaminated substrates. One of the factors limiting their growth was the high concentrations of Pb, Zn, and Cd in the tested substrates. Kabata-Pendias & Pendias, (##UREF##13##2001##) reported that concentrations of 0.1–0.4 mg∙g<sup>−1</sup> Pb and 0.07–0.4 mg∙g<sup>−1</sup> Zn in soil are considered toxic to plants. Levy et al., (##UREF##22##1999##) showed that the phytotoxic concentration of Pb is 0.03–0.3 mg∙g<sup>−1</sup>, and above 0.1 mg∙g<sup>−1</sup> for Zn. Differences in biomass reduction and root length reflect differences in the tolerance of seedlings to high concentrations of heavy metals in soils (Shi et al., ##UREF##32##2011##). The first signs of heavy metal toxicity in trees include a decrease in growth parameters, such as root elongation, root hair formation, and biomass production (Kahle, ##UREF##14##1993##). The seedlings of woody plants exposed to high concentrations of Cd have shown a reduction in root length (Arduini et al., ##UREF##1##1994##) or both root length and the root system biomass (Kahle, ##UREF##14##1993##; Lunackova et al., ##UREF##24##2003##). In a similar study, an increase in Cd concentration in the soil, from 0.59 to 2.4 mg∙kg<sup>−1</sup>, has been found to result in a 20% reduction in root length (Domínguez et al., ##REF##19375778##2009##). In tree seedlings grown on contaminated soils, the rapid development of the root system is crucial for their survival, especially during periods of summer drought. In our study, the effect on root elongation was small at low or moderate levels of Cd in the soil, but a fourfold increase in the concentration of Cd caused a threefold reduction in the mass of the oak roots.</p>", "<p id=\"Par25\">An important criterion for assessing the adaptability of forest tree seedlings to various habitat conditions is the physiological response of plants to the content of macroelements in their leaves (Lõhmus et al., ##UREF##23##2006##; Vares et al., ##UREF##34##2004##). Seedlings grown in the SA, SA + 10% PFS, and SA + 25% PFS variants were sufficiently supplied with N and Mg, while the substrate containing 50% PFS caused N, Mg, and K deficiency. A decrease in the supply of N and P, coupled with a simultaneous increase in the demand for these elements by plants, contributes to a reduction of the concentrations of these elements in the leaves (Lambers & Oliveira, ##UREF##21##2019##). Several authors have argued that the efficiency of nutrient use increases with decreasing nutrient availability in the soil. The lower concentration of P in the leaves, relative to optimal conditions, is probably due to the high pH of the growth medium and its consequent low availability for plants. The chemical composition of the leaves of <italic>Pinus</italic> and <italic>Betula</italic> seedlings grown on alkaline soils has been found to be 2.12% N, 0.18% P, 0.97% K, and 0.51% Mg for <italic>Betula</italic>, and 1.15% N, 0.11% P, 0.74% K, and 0.20% Mg for <italic>Pinus</italic> (Kuznetsova et al., ##UREF##20##2010##).</p>", "<p id=\"Par26\">Metal accumulations in roots, shoots, and leaves are significantly lower than other trace-element hyperaccumulators (Shi et al., ##UREF##32##2011##). The metal contents in the tested seedlings may have result mainly from the period of growth in the contaminated soil (4 and 8 months). The high concentration of heavy metals in the roots indicates a high efficiency in immobilizing heavy metals, and a significant phytostabilization potential of the tested forest tree seedlings (Mertens et al., ##REF##15142776##2004##). The bioaccumulation index––the ability of plants to accumulate heavy metals––was below 1 for most of the variants in our study, and the translocation of metals from the roots to the shoots and leaves seems to have been strongly limited. The roots accumulated a much higher content of heavy metals than the shoots and leaves, which indicates both the high availability of the metals and limited mobility inside the plant (Deng et al., ##REF##15276271##2004##; Fitzgerald et al., ##REF##12663206##2003##). The efficiency of heavy metal accumulation is reflected in the values of the bioaccumulation index, depending on the plant species, their tolerance to high concentrations of trace metals, and the concentrations of the trace metals in the soil (Jeyakumar et al., ##UREF##12##2010##; Pourrut et al., ##REF##21871650##2011##). Our results are similar to the values obtained for other forest tree species occurring in polluted areas, where the bioaccumulation factor of the heavy metals was also determined to be below 1 for shoots and leaves (Brunner et al., ##REF##17707113##2008##; Mertens et al., ##REF##15142776##2004##; Nadgórska-Socha et al., ##REF##28570890##2017##; Sebastiani et al., ##UREF##31##2004##). It is normally assumed that the values of the bioaccumulation index for a given metal are above 1 in plants suitable for phytoextraction, but that values below 1 are tolerable for the phytostabilization of heavy metals (Bech et al., ##UREF##2##2012##; Pourrut et al., ##REF##21871650##2011##). The limited translocation of metals from roots to shoots suggests that shoot harvesting would not effectively remove metals from contaminated tailings (Shi et al., ##UREF##32##2011##).</p>", "<p id=\"Par27\">The most important and common effect of the uptake of heavy metal ions by plants, including Cd, Pb, and Zn ions, and a symptom of their toxicity, is the formation of free radicals and ROSs, such as superoxide ions, H<sub>2</sub>O<sub>2</sub>, and lipid peroxidation products. This causes cell redox imbalance, oxidative stress, lipid peroxidation, and an increase in membrane leakage (Ashraf et al., ##REF##30878808##2019##; Sandalio et al., ##REF##11604450##2001##). In this study, it was confirmed by the increase in the content of oxidative stress markers (i.e., TBARSs and H<sub>2</sub>O<sub>2</sub> in the roots, shoots, and leaves of the seedlings). The highest accumulation of heavy metals in the roots during the initial period of seedling growth (June) on the contaminated substrates resulted in the highest intensity of oxidative stress. As reactive particles become more abundant in plant cells, the cellular antioxidant system is activated, the task of which is to scavenge free radicals and ROSs and keeping their content at an appropriate level (Dubey et al., ##UREF##6##2018##; Kraj & Zarek, ##UREF##17##2021##; Singh et al., ##REF##19233306##2009##). Although the formation of ROSs and their accumulation above physiologically acceptable levels are harmful, at low concentrations, these particles play a signaling role and activate the antioxidant system (Dubey et al., ##UREF##6##2018##). One of the main water-soluble cellular antioxidants is ascorbic acid (Kraj, ##UREF##15##2016##; Noctor & Foyer, ##UREF##27##1998##). Its basic function is to maintain the redox state of cells and protect them against stress factors by capturing H<sub>2</sub>O<sub>2</sub> formed under the influence of stress factors, including the presence of heavy metals. The Foyer–Halliwell–Asada cycle plays a special role in maintaining an appropriate content of H<sub>2</sub>O<sub>2</sub> in cells (Foyer et al., ##UREF##7##1994##; Noctor & Foyer, ##UREF##27##1998##), and its operation depends not only on the activity of APX––one of the enzymes catalyzing the decomposition of H<sub>2</sub>O<sub>2</sub>––but also on the tAsA content and the share of its reduced form (DHA) (Bielen et al., ##REF##23519107##2013##). Therefore, decreasing the ascorbate content and increasing the ratios of its oxidized to reduced forms are often used as indicators of oxidative stress (Kukavica & Jovanovic, ##UREF##19##2004##).</p>", "<p id=\"Par28\">Differences in the TBARS content in the seedlings’ organs between the initial (June) and final (September) growth periods testify to the gradually decreasing intensity of lipid peroxidation in the roots, while the intensity of this process increased in the leaves. The migration of heavy metals to the aboveground parts of the seedlings resulted in a species-dependent increase in damage to the leaves cell membranes. In contrast to changes in the cell membranes, the accumulation of H<sub>2</sub>O<sub>2</sub> significantly increased both in the leaves and roots of the seedlings, especially in <italic>Larix</italic>. The increase in H<sub>2</sub>O<sub>2</sub> content was significantly influenced not only by the uptake of metal ions, but also by their negative effect on the tAsA content and the increasing share of its oxidized form, which was not regenerated under stress conditions on the substrates containing harmful Cd, Pb, and Zn ions due to oxidative stress. This resulted in a deficiency of the reduced form of ascorbic acid, which is necessary as a substrate in the Foyer–Halliwell–Asad cycle that reduces the levels of H<sub>2</sub>O<sub>2</sub> in cells (Bielen et al., ##REF##23519107##2013##).</p>" ]	[]	[ "<p id=\"Par1\">The seedlings of some tree species can successfully develop in areas polluted by heavy metals. Research on such species is important in order to explore the possibility of introducing tree species for the permanent biological stabilization and reclamation of post-flotation tailings, especially after the final recycling of trace metals, but where concentrations remain much higher than in natural soils. To better understand the adaptation and reaction of <italic>Betula pendula</italic> Roth., <italic>Pinus sylvestris</italic> L., and <italic>Larix decidua</italic> Mill. seedlings to heavy metals pollution caused by tailings waste highly contaminated by trace elements: 1) the relationships between the concentration of heavy metals in the soil substrate, the efficiency of heavy metal ions accumulation in plant organs, and the biometric parameters of the seedlings; and 2) the threshold content of heavy metals in the roots above which the plant physiological response is triggered was determined. We assume that there are certain limit concentrations of heavy metals in the soil and fine roots, which depend on the tree species and beyond which the plant responds strongly to stressThe obtained results showed that <italic>Betula</italic> is a suitable species for the phytostabilization of post-flotation tailings due to its rapid growth rate and production of root biomass. The accumulation of metals in <italic>Betula</italic> roots was found to be much greater than in Pinus and <italic>Larix</italic>. Despite the high concentrations of heavy metals in the prepared substrates, there was only a slight transfer of these elements to the aboveground parts of the plant. At high soil concentrations, the heavy metals adversely affected the cellular and physiological processes of plants. In plants growing in such conditions, the activity of the antioxidant system depended both on the species and organ of the plant, as well as on the type and metal concentration.</p>", "<title>Keywords</title>" ]	[ "<title>Summary</title>", "<p id=\"Par29\">The results of this study showed that <italic>Betula</italic> seedlings are suitable for the phytostabilization of post-flotation tailings due to their faster growth rate and higher production of root biomass than the seedlings of <italic>Pinus</italic> and <italic>Larix</italic>. Moreover, the quantity of metals accumulated in the <italic>Betula</italic> roots was much higher. Despite the high concentrations of heavy metals in the prepared substrates, the transfer of these elements to the aboveground parts of the plants was only slight. The correlation coefficient between the concentration of trace elements in the soil (Pb, Cd, Zn) and the biometric parameters of the seedlings (weight of the leaves, shoots, and roots; weight, length, and diameter of the roots) showed a significantly negative correlation between trace elements and root length in the first period of growth (from the beginning of the experiment until June). An important factor affecting root length was the concentration of Cd in the soil, with an increase causing a several-fold decrease in root length. The high concentration of heavy metals in the soil adversely affects the biochemical and physiological processes in plants and causes a reduction in the activity of the antioxidant system, depending on the species and organ as well as the type and concentration of metals. The conducted research has shown that in order to effectively bioremediate contaminated areas, it is necessary to remove entire plants, because the roots are mainly responsible for the bioaccumulation of heavy metals. Restoring stable forest ecosystems in urbanized areas will be important in the context of ongoing environmental degradation, and roots may act as a key indicator of the level of environmental pollution. The research results may be the basis for selecting appropriate tree species for use in the remediation and phytostabilization processes of heavily polluted post-industrial facilities.</p>" ]	[ "<title>Data availability statement</title>", "<p>The data that support the findings of this study are available from the corresponding author upon reasonable request.</p>", "<title>Author contributions</title>", "<p>Conceptualization: Bartłomiej Świątek, Marcin Pietrzykowski, Wojciech Kraj; Methodology: Bartłomiej Świątek, Marcin Pietrzykowski, Wojciech Kraj; Software: Bartłomiej Świątek, Marcin Pietrzykowski; Validation: Bartłomiej Świątek, Marcin Pietrzykowski, Wojciech Kraj; Formal Analysis: Bartłomiej Świątek, Marcin Pietrzykowski, Wojciech Kraj; Investigation: Bartłomiej Świątek, Marcin Pietrzykowski; Resources: Bartłomiej Świątek, Marcin Pietrzykowski Wojciech Kraj; Data Curation: Bartłomiej Świątek; Writing— original draft preparation: Bartłomiej Świątek, Marcin Pietrzykowski Wojciech Kraj; Writing—review and editing: Bartłomiej Świątek, Marcin Pietrzykowski, Wojciech Kraj; Visualization: Bartłomiej Świątek, Marcin Pietrzykowski; Supervision: Bartłomiej Świątek, Marcin Pietrzykowski; Project Administration: Bartłomiej Świątek. All authors have read and agreed to the published version of the manuscript.</p>", "<title>Funding</title>", "<p>This study was financed by the National Science Centre, Poland (Grant no. 2019/33/N/ST10/02509).</p>", "<title>Declarations</title>", "<title>Ethical approval</title>", "<p id=\"Par30\">Not applicable</p>", "<title>Consent to participate</title>", "<p id=\"Par31\">Not applicable</p>", "<title>Consent to publication</title>", "<p id=\"Par32\">Not applicable</p>", "<title>Competing interests</title>", "<p id=\"Par33\">The authors declare no competing interests.</p>" ]	[]	[ "<table-wrap id=\"Tab1\"><label>Table 1</label><caption><p>Experimental substrate</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th>Substrate</th><th>Volumetric share of nursery substrate</th><th>Volumetric share of flotation tailings</th></tr></thead><tbody><tr><td>SA</td><td>100%</td><td>0%</td></tr><tr><td>SA+10%PFS</td><td>90%</td><td>10%</td></tr><tr><td>SA+25%PFS</td><td>75%</td><td>25%</td></tr><tr><td>SA+50%PFS</td><td>50%</td><td>50%</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab2\"><label>Table 2</label><caption><p>One-way ANOVA for the basic soil properties (mean ± standard errors)</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th>Soil properties</th><th>Units</th><th>SA</th><th>SA+10% PFS</th><th>SA+25% PFS</th><th>SA+50% PFS</th></tr></thead><tbody><tr><td>pH KCl</td><td/><td>4.98±0.19<sup>a</sup></td><td>7.05±0.14<sup>c</sup></td><td>7.20±0.07<sup>bc</sup></td><td>7.29±0.05<sup>b</sup></td></tr><tr><td>N<sub>tot</sub></td><td>mg g<sup>−1</sup></td><td>6.1±0.19<sup>a</sup></td><td>1.86±0.11<sup>b</sup></td><td>1.07±0.08<sup>c</sup></td><td>0.46±0.02<sup>d</sup></td></tr><tr><td>C<sub>tot</sub></td><td>mg g<sup>−1</sup></td><td>372.76±11.78<sup>a</sup></td><td>162.04±6.57<sup>b</sup></td><td>126.36±4.87<sup>c</sup></td><td>97.13±1.82<sup>d</sup></td></tr><tr><td>Ca<sup>2+</sup></td><td>cmol kg<sup>−1</sup></td><td>29.74±1.59<sup>a</sup></td><td>30.18±2.88<sup>a</sup></td><td>19.57±1.17<sup>b</sup></td><td>11.09±0.88<sup>c</sup></td></tr><tr><td>K<sup>+</sup></td><td>cmol kg<sup>−1</sup></td><td>0.18±0.01<sup>a</sup></td><td>0.08±0.01<sup>b</sup></td><td>0.05±0.00<sup>c</sup></td><td>0.02±0.00<sup>d</sup></td></tr><tr><td>Mg<sup>2+</sup></td><td>cmol kg<sup>−1</sup></td><td>19.35±0.86<sup>a</sup></td><td>8.65±0.79<sup>b</sup></td><td>4.25±0.41<sup>c</sup></td><td>1.35±0.29<sup>d</sup></td></tr><tr><td>Na<sup>+</sup></td><td>cmol kg<sup>−1</sup></td><td>0.24±0.06<sup>a</sup></td><td>0.08±0.02<sup>b</sup></td><td>0.04±0.02<sup>c</sup></td><td>0.02±0.01<sup>c</sup></td></tr><tr><td>Cd</td><td>mg kg<sup>−1</sup></td><td>0.26±0.05<sup>d</sup></td><td>9.15±0.76<sup>b</sup></td><td>14.07±0.75<sup>a</sup></td><td>11.83±0.46<sup>c</sup></td></tr><tr><td>Pb</td><td>mg kg<sup>−1</sup></td><td>2.66±1<sup>c</sup></td><td>263.58±12.29<sup>b</sup></td><td>460.46±28.01<sup>a</sup></td><td>475.99±28.11<sup>a</sup></td></tr><tr><td>Zn</td><td>mg kg<sup>−1</sup></td><td>6.67±1.24<sup>c</sup></td><td>180.62±14.08<sup>b</sup></td><td>235.92±12.56<sup>a</sup></td><td>194.35±8.72<sup>b</sup></td></tr><tr><td>Cd<sub>tot</sub></td><td>mg kg<sup>−1</sup></td><td>1.25±0.20<sup>d</sup></td><td>55.08±0.63<sup>c</sup></td><td>74.32±0.54<sup>b</sup></td><td>80.56±2.41<sup>a</sup></td></tr><tr><td>Pb<sub>tot</sub></td><td>mg kg<sup>−1</sup></td><td>126.4±13.24<sup>b</sup></td><td>2274.5±65.40<sup>a</sup></td><td>2407.7±106.98<sup>a</sup></td><td>2456.1±166.85<sup>a</sup></td></tr><tr><td>Zn<sub>tot</sub></td><td>mg kg<sup>−1</sup></td><td>217.4±21.87<sup>d</sup></td><td>5716.3±71.10<sup>c</sup></td><td>7015.4±55.60<sup>b</sup></td><td>7399.3±91.99<sup>a</sup></td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab3\"><label>Table 3</label><caption><p>Biometric parameters of birch, larch and pine seedlings growing in the tested substrates</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th rowspan=\"2\"/><th colspan=\"3\">Lenght roots [mm]</th><th colspan=\"3\">Avg diameter roots [mm]</th><th colspan=\"3\">Mass stem [g]</th><th colspan=\"3\">Mass roots [g]</th><th colspan=\"3\">Mass leaves [g]</th></tr><tr><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th></tr></thead><tbody><tr><td>SA</td><td>1821.1±337<sup>a</sup></td><td>1141.9±150.2<sup>ab</sup></td><td>952±302.5<sup>ab</sup></td><td>0.3±0.0<sup>b</sup></td><td>0.5±0.0<sup>a</sup></td><td>0.6±0.1<sup>a</sup></td><td>3.0±1.2<sup>a</sup></td><td>1.4±0.2<sup>b</sup></td><td>3.0±0.8<sup>a</sup></td><td>1.5±0.4<sup>a</sup></td><td>0.9±0.2<sup>b</sup></td><td>1.7±0.6<sup>a</sup></td><td>0.7±0.2<sup>b</sup></td><td>2.4±0.4<sup>a</sup></td><td>2.9±0.4<sup>a</sup></td></tr><tr><td>SA+10%PFS</td><td>1602.3±131.4<sup>a</sup></td><td>1207.4±104.4<sup>a</sup></td><td>544.5±180.1<sup>b</sup></td><td>0.4±0.1<sup>a</sup></td><td>0.5±0.0<sup>a</sup></td><td>0.5±0<sup>a</sup></td><td>3.3±0.5<sup>a</sup></td><td>1.7±0.3<sup>b</sup></td><td>2.5±0.6<sup>ab</sup></td><td>1.7±0.3<sup>a</sup></td><td>1.1±0.1<sup>b</sup></td><td>1.2±0.5<sup>b</sup></td><td>0.9±0.2<sup>b</sup></td><td>2.4±0.4<sup>a</sup></td><td>3.0±0.1<sup>a</sup></td></tr><tr><td>SA+25%PFS</td><td>1139±123.6<sup>a</sup></td><td>922.1±77.8<sup>ab</sup></td><td>744±241.1<sup>b</sup></td><td>0.4±0.1<sup>b</sup></td><td>0.5±0.0<sup>ab</sup></td><td>0.6±0.1<sup>a</sup></td><td>2.7±0.7<sup>ab</sup></td><td>1.9±0.2<sup>b</sup></td><td>4.4±1.3<sup>a</sup></td><td>1.2±0.3<sup>b</sup></td><td>1.1±0.2<sup>b</sup></td><td>1.9±0.5<sup>a</sup></td><td>0.7±0.2<sup>b</sup></td><td>2.6±0.2<sup>a</sup></td><td>2.7±1.2<sup>a</sup></td></tr><tr><td> SA+50%PFS</td><td>983.8±197.9<sup>a</sup></td><td>489.1±53.7<sup>b</sup></td><td>423.4±91.2<sup>b</sup></td><td>0.5±0.1<sup>b</sup></td><td>0.7±0.0<sup>a</sup></td><td>0.7±0.1<sup>a</sup></td><td>4.8±1.3<sup>a</sup></td><td>1.9±0.4<sup>b</sup></td><td>2.3±0.8<sup>b</sup></td><td>1.8±0.5<sup>a</sup></td><td>0.8±0.1<sup>b</sup></td><td>0.9±0.3<sup>b</sup></td><td>1.1±0.5<sup>b</sup></td><td>2.7±0.4<sup>a</sup></td><td>1.3±0.6<sup>b</sup></td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab4\"><label>Table 4</label><caption><p>Two-way ANOVA for the N, P, K, and Mg contents (mean values ± standard errors) in seedlings studied tree species growing on different substrates</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th rowspan=\"2\"/><th rowspan=\"2\"/><th colspan=\"3\">N [mg g<sup>−1</sup>]</th><th colspan=\"3\">P [mg g<sup>−1</sup>]</th><th colspan=\"3\">K [mg g<sup>−1</sup>]</th><th colspan=\"3\">Mg [mg g<sup>−1</sup>]</th></tr><tr><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th></tr></thead><tbody><tr><td rowspan=\"4\">Roots</td><td>SA</td><td>6.4±0.3<sup>bA</sup></td><td>7.3±0.3<sup>aB</sup></td><td>5.1±0.0<sup>b</sup></td><td>0.7±0.1<sup>aA</sup></td><td>0.7±0.0<sup>aA</sup></td><td>0.6±0.0<sup>bA</sup></td><td>2.6±0.0<sup>aA</sup></td><td>3.6±0.2<sup>aA</sup></td><td>2.8±0.0<sup>aA</sup></td><td>1.3±0.1<sup>aA</sup></td><td>1.3±0.0<sup>aA</sup></td><td>1.2±0.0<sup>aB</sup></td></tr><tr><td>SA+10%PFS</td><td>4.5±0.2<sup>bB</sup></td><td>6.3±0.0<sup>aC</sup></td><td>5.8±0.1<sup>a</sup></td><td>0.5±0.0<sup>aA</sup></td><td>0.5±0.0<sup>aA</sup></td><td>0.5±0.0<sup>aA</sup></td><td>2.6±0.0<sup>aA</sup></td><td>2.8±0.1<sup>aA</sup></td><td>2.7±0.2<sup>aA</sup></td><td>1.3±0.0<sup>bA</sup></td><td>1.7±0.0<sup>aA</sup></td><td>1.6±0.2<sup>aA</sup></td></tr><tr><td>SA+25%PFS</td><td>6.1±0.4<sup>aAB</sup></td><td>6.5±0.2<sup>aC</sup></td><td>4.7±0.1<sup>b</sup></td><td>0.6±0.1<sup>aA</sup></td><td>0.5±0.0<sup>aA</sup></td><td>0.6±0.0<sup>aA</sup></td><td>2.9±0.2<sup>aA</sup></td><td>2.8±0.0<sup>aA</sup></td><td>2.9±0.2<sup>aA</sup></td><td>1.4±0.1<sup>bA</sup></td><td>1.7±0.1<sup>aA</sup></td><td>2.0±0.1<sup>aA</sup></td></tr><tr><td>SA+50%PFS</td><td>5.6±0.3<sup>bAB</sup></td><td>7.7±0.3<sup>aA</sup></td><td>5.6±0.3<sup>b</sup></td><td>0.6±0.1<sup>aA</sup></td><td>0.6±0.1<sup>aA</sup></td><td>0.7±0.0<sup>aA</sup></td><td>2.7±0.2<sup>aA</sup></td><td>3.0±0.4<sup>aA</sup></td><td>2.9±0.2<sup>aA</sup></td><td>1.4±0.0<sup>bA</sup></td><td>1.9±0.2<sup>aA</sup></td><td>1.9±0.1<sup>aA</sup></td></tr><tr><td rowspan=\"4\">Leaves</td><td>SA</td><td>18.0±0.0<sup>aA</sup></td><td>11.5±0.3<sup>bA</sup></td><td>10.6±0.0<sup>bA</sup></td><td>1.1±0.0<sup>aA</sup></td><td>0.6±0.1<sup>bA</sup></td><td>0.7±0.0<sup>bA</sup></td><td>6.2±0.0<sup>aA</sup></td><td>4.4±0.3<sup>bA</sup></td><td>4.7±0.0<sup>bA</sup></td><td>3.8±0.0<sup>aB</sup></td><td>1.6±0.1<sup>cB</sup></td><td>2.2±0.0<sup>bA</sup></td></tr><tr><td>SA+10%PFS</td><td>13.8±0.0<sup>aC</sup></td><td>8.7±0.1<sup>bB</sup></td><td>9.9±0.0<sup>bA</sup></td><td>1.1±0.0<sup>aA</sup></td><td>0.5±0.0<sup>bA</sup></td><td>0.7±0.0<sup>bAB</sup></td><td>5.3±0.0<sup>aAB</sup></td><td>2.9±0.2<sup>bB</sup></td><td>3.0±0.0<sup>bB</sup></td><td>4.7±0.0<sup>aA</sup></td><td>1.5±0.1<sup>cB</sup></td><td>2.0±0.0<sup>bA</sup></td></tr><tr><td>SA+25%PFS</td><td>15.9±0.0<sup>aB</sup></td><td>8.3±0.3<sup>bB</sup></td><td>9.5±0.0<sup>bA</sup></td><td>0.9±0.0<sup>aA</sup></td><td>0.5±0.0<sup>bA</sup></td><td>0.9±0.0<sup>aBC</sup></td><td>4.9±0.0<sup>aAB</sup></td><td>3.2±0.3<sup>bB</sup></td><td>3.3±0.0<sup>bB</sup></td><td>4.7±0.0<sup>aA</sup></td><td>1.5±0.1<sup>cB</sup></td><td>1.9±0.0<sup>bA</sup></td></tr><tr><td>SA+50%PFS</td><td>16.5±0.0<sup>aAB</sup></td><td>8.6±0.7<sup>cB</sup></td><td>10.6±0.0<sup>b</sup></td><td>1.0±0.0<sup>aA</sup></td><td>0.6±0.1<sup>bA</sup></td><td>1.3±0.0<sup>aC</sup></td><td>4.3±0.0<sup>aB</sup></td><td>2.5±0.3<sup>bB</sup></td><td>3.5±0.0<sup>abB</sup></td><td>4.0±0.0<sup>aB</sup></td><td>1.9±0.1<sup>bA</sup></td><td>2.1±0.0<sup>bA</sup></td></tr><tr><td rowspan=\"4\">Stems</td><td>SA</td><td>5.5±0.1<sup>aA</sup></td><td>5.3±0.3<sup>aAB</sup></td><td>6.0±0.6<sup>aB</sup></td><td>0.5±0.0<sup>aA</sup></td><td>0.5±0.0<sup>aA</sup></td><td>0.5±0.0<sup>aB</sup></td><td>2.6±0.3<sup>bB</sup></td><td>3.6±0.1<sup>aA</sup></td><td>3.5±0.0<sup>aA</sup></td><td>0.9±0.0<sup>bA</sup></td><td>1.4±0.0<sup>aA</sup></td><td>1.1±0.0<sup>bB</sup></td></tr><tr><td>SA+10%PFS</td><td>5.5±0.0<sup>aA</sup></td><td>4.0±0.1<sup>aC</sup></td><td>6.9±1.5<sup>bA</sup></td><td>0.5±0.0<sup>bA</sup></td><td>0.4±0.0<sup>bA</sup></td><td>0.8±0.1<sup>aA</sup></td><td>2.2±0.1<sup>bB</sup></td><td>3.1±0.2<sup>aAB</sup></td><td>1.9±0.1<sup>bC</sup></td><td>0.9±0.0<sup>bA</sup></td><td>1.4±0.0.0<sup>aA</sup></td><td>1.1±0.1<sup>bB</sup></td></tr><tr><td>SA+25%PFS</td><td>5.4±0.0<sup>aA</sup></td><td>4.4±0.1<sup>bBC</sup></td><td>4.1±0.7<sup>cC</sup></td><td>0.5±0.0<sup>aA</sup></td><td>0.4±0.0<sup>aA</sup></td><td>0.5±0.1<sup>aB</sup></td><td>2.5±0.0<sup>bB</sup></td><td>2.7±0.2<sup>aB</sup></td><td>2.8±0.6<sup>aB</sup></td><td>0.9±0.1<sup>bA</sup></td><td>1.3±0.1<sup>aA</sup></td><td>1.0±0.1<sup>bB</sup></td></tr><tr><td>SA+50%PFS</td><td>4.4±0.1<sup>aB</sup></td><td>5.5±0.1<sup>bA</sup></td><td>5.8±0.7<sup>cB</sup></td><td>0.4±0.0<sup>bA</sup></td><td>0.5±0.0<sup>bA</sup></td><td>0.8±0.1<sup>aA</sup></td><td>1.9±0.1<sup>bA</sup></td><td>3.2±0.2<sup>aA</sup></td><td>2.6±0.3<sup>abB</sup></td><td>0.7±0.0<sup>bB</sup></td><td>1.3±0.1<sup>aA</sup></td><td>1.3±0.2<sup>aA</sup></td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab5\"><label>Table 5</label><caption><p>Two-way ANOVA for the Cd, Pb, and Zn contents (mean values ± standard errors) in seedlings studied tree species growing on different substrates</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th rowspan=\"2\"/><th rowspan=\"2\"/><th colspan=\"3\">Cd [mg kg<sup>−1</sup>]</th><th colspan=\"3\">Pb [mg kg<sup>−1</sup>]</th><th colspan=\"3\">Zn [mg kg<sup>−1</sup>]</th></tr><tr><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th><th><italic>Betula</italic></th><th><italic>Pinus</italic></th><th><italic>Larix</italic></th></tr></thead><tbody><tr><td rowspan=\"4\">Roots</td><td>SA</td><td>5.24±1.27<sup>aB</sup></td><td>1.87±0.43<sup>aC</sup></td><td>1.46±0.00<sup>aC</sup></td><td>198.13±66.67<sup>aD</sup></td><td>60.26±19.65<sup>bD</sup></td><td>34.64±0<sup>bD</sup></td><td>227.76±2.89<sup>aC</sup></td><td>105.33±17.85<sup>aC</sup></td><td>61.64±0.00<sup>bC</sup></td></tr><tr><td>SA+10%PFS</td><td>11.17±1.05<sup>aB</sup></td><td>15±0.48<sup>aB</sup></td><td>7.97±2.71<sup>aBC</sup></td><td>573.88±39.88<sup>bC</sup></td><td>1017.34±44.37<sup>aC</sup></td><td>385.7±148.3<sup>cC</sup></td><td>402.7±54.97<sup>abBC</sup></td><td>514.99±48.39<sup>aB</sup></td><td>282.97±63.72<sup>bC</sup></td></tr><tr><td>SA+25%PFS</td><td>22.12±0.35<sup>aAB</sup></td><td>27.47±0.83<sup>aB</sup></td><td>26.32±1.63<sup>aAB</sup></td><td>1051.64±41.56<sup>cB</sup></td><td>1657.06±31.53<sup>aB</sup></td><td>1198.96±51.07<sup>bB</sup></td><td>619.44±60.17<sup>bAB</sup></td><td>780.39±62.25<sup>aB</sup></td><td>642.17±28.22<sup>abB</sup></td></tr><tr><td>SA+50%PFS</td><td>31.16±0.42<sup>bA</sup></td><td>53.44±6.15<sup>aA</sup></td><td>36.11±2.78<sup>abA</sup></td><td>1556.36±81.32<sup>cA</sup></td><td>2794.31±38.57<sup>aA</sup></td><td>1726.56±53.28<sup>bA</sup></td><td>723.45±60.05<sup>bA</sup></td><td>1310.94±17.22<sup>aA</sup></td><td>946.37±28.83<sup>cA</sup></td></tr><tr><td rowspan=\"4\">Leaves</td><td>SA</td><td>0.74±0.00<sup>aC</sup></td><td>0.79±0.16<sup>aC</sup></td><td>0.27±0.00<sup>aB</sup></td><td>25.38±0.00<sup>aA</sup></td><td>35.75±9.53<sup>aB</sup></td><td>10.5±0.00<sup>aB</sup></td><td>134.04±0.00<sup>aB</sup></td><td>99.01±11.46<sup>aB</sup></td><td>27.54±0.00<sup>aB</sup></td></tr><tr><td>SA+10%PFS</td><td>5.09±0.00<sup>aB</sup></td><td>1.83±0.25<sup>bB</sup></td><td>1.34±0.00<sup>bB</sup></td><td>69.27±0.00<sup>aA</sup></td><td>62.21±11.67<sup>aB</sup></td><td>52.87±0.00<sup>aAB</sup></td><td>414.39±0.00<sup>aA</sup></td><td>145.44±17.33<sup>bB</sup></td><td>70.04±0.00<sup>bB</sup></td></tr><tr><td>SA+25%PFS</td><td>11.41±0.00<sup>aA</sup></td><td>3.36±0.52<sup>bB</sup></td><td>4.35±0.00<sup>bA</sup></td><td>89.13±0.00<sup>aA</sup></td><td>123.76±27.44<sup>aB</sup></td><td>175.86±0.00<sup>aAB</sup></td><td>458.34±0.00<sup>aA</sup></td><td>201.37±35.88<sup>bB</sup></td><td>131.29±0.00<sup>bAB</sup></td></tr><tr><td>SA+50%PFS</td><td>4.95±0.00<sup>aB</sup></td><td>5.88±0.95<sup>aA</sup></td><td>5.36±0.00<sup>aA</sup></td><td>41.68±0.00<sup>bA</sup></td><td>290.14±75.57<sup>aA</sup></td><td>224.11±0.00<sup>abA</sup></td><td>364.89±0.00<sup>aA</sup></td><td>400.72±92.09<sup>aA</sup></td><td>187.64±0.00<sup>aA</sup></td></tr><tr><td rowspan=\"4\">Stems</td><td>SA</td><td>0.68±0.12<sup>aD</sup></td><td>1.17±0.14<sup>aD</sup></td><td>0.87±0.15<sup>aD</sup></td><td>8.07±1.56<sup>bC</sup></td><td>52.34±6.27<sup>aC</sup></td><td>33.91±6.96<sup>aC</sup></td><td>155.97±20.38<sup>aC</sup></td><td>116.8±12.85<sup>aC</sup></td><td>61.44±10.33<sup>bB</sup></td></tr><tr><td>SA+10%PFS</td><td>4.39±1.3<sup>aC</sup></td><td>3.21±0.44<sup>bC</sup></td><td>2.13±0.21<sup>bC</sup></td><td>96.87±53.05<sup>aA</sup></td><td>69.85±16.55<sup>bC</sup></td><td>59.55±17.21<sup>bBC</sup></td><td>219.98±55.51<sup>aB</sup></td><td>164.04±17.13<sup>bB</sup></td><td>93.9±19.11<sup>cB</sup></td></tr><tr><td>SA+25%PFS</td><td>7.99±0.22<sup>aA</sup></td><td>4.9±0.35<sup>bB</sup></td><td>4.0±0.53<sup>bB</sup></td><td>42.48±0.51<sup>bB</sup></td><td>108.56±15<sup>aB</sup></td><td>85.57±18.27<sup>aB</sup></td><td>262.24±32.8<sup>aA</sup></td><td>193.12±20.31<sup>bB</sup></td><td>98.57±20.73<sup>cB</sup></td></tr><tr><td>SA+50%PFS</td><td>6.75±0.77<sup>aB</sup></td><td>6.09±0.27<sup>bA</sup></td><td>5.94±1.19<sup>bA</sup></td><td>98.24±44.93<sup>bA</sup></td><td>205.19±22.77<sup>aA</sup></td><td>208.09±51.61<sup>aA</sup></td><td>224.65±29.55<sup>aB</sup></td><td>252.37±23.8<sup>aA</sup></td><td>199.38±40.2<sup>aA</sup></td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab6\"><label>Table 6</label><caption><p>Contents of TBARS, H<sub>2</sub>O<sub>2</sub> and the reduced form of ascorbic acid (tAsA) and the share of its oxidized form (%DHA) in the organs of birch, pine, and larch seedlings</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th/><th colspan=\"2\"><italic>Betula</italic></th><th rowspan=\"2\">% changes</th><th colspan=\"2\"><italic>Pinus</italic></th><th rowspan=\"2\">% changes</th><th colspan=\"2\">Larix</th><th rowspan=\"2\">% changes</th></tr><tr><th/><th>Term 1</th><th>Term 2</th><th>Term 1</th><th>Term 2</th><th>Term 1</th><th>Term 2</th></tr></thead><tbody><tr><td>Root TBARS</td><td>436.23</td><td>316.17</td><td>−27.52%</td><td>810.4</td><td>369.68</td><td>−54.38%</td><td>994.71</td><td>541.82</td><td>-45.53%</td></tr><tr><td>Shoot TBARS</td><td>277.13</td><td>218.39</td><td>−21.20%</td><td>445.2</td><td>389.66</td><td>−12.48%</td><td>623.26</td><td>334.68</td><td>-46.30%</td></tr><tr><td>Leaf TBARS</td><td>217.48</td><td/><td/><td>322.67</td><td>672.28</td><td>108.35%</td><td>348.51</td><td>1500.89</td><td>330.66%</td></tr><tr><td>Root H<sub>2</sub>O<sub>2</sub></td><td>0.58</td><td>0.86</td><td>48.28%</td><td>0.3</td><td>1.35</td><td>350.00%</td><td>0.39</td><td>0.96</td><td>146.15%</td></tr><tr><td>Shoot H<sub>2</sub>O<sub>2</sub></td><td>0.25</td><td>0.28</td><td>12.00%</td><td>0.27</td><td>0.13</td><td>−51.85%</td><td>0.22</td><td>0.4</td><td>81.82%</td></tr><tr><td>Leaf H<sub>2</sub>O<sub>2</sub></td><td>0.09</td><td/><td/><td>0.23</td><td>0.69</td><td>200.00%</td><td>0.15</td><td>1.32</td><td>780.00%</td></tr><tr><td>Root tAsA</td><td>262.4</td><td>255.35</td><td>−2.69%</td><td>390.89</td><td>241.32</td><td>−38.26%</td><td>578.63</td><td>372.79</td><td>-35.57%</td></tr><tr><td>Shoot tAsA</td><td>91.97</td><td>71.74</td><td>−22.00%</td><td>203.42</td><td>128.96</td><td>−36.60%</td><td>111.56</td><td>86.08</td><td>-22.84%</td></tr><tr><td>Leaf tAsA</td><td>155.72</td><td/><td/><td>152.57</td><td>88.85</td><td>−41.76%</td><td>301.31</td><td>229.54</td><td>-23.82%</td></tr><tr><td>Root %DHA</td><td>0.38</td><td>0.44</td><td>15.79%</td><td>0.02</td><td>0.43</td><td>2050.00%</td><td>0.04</td><td>0.49</td><td>1125.00%</td></tr><tr><td>Shoot % DHA</td><td>0.1</td><td>0.48</td><td>380.00%</td><td>0.15</td><td>0.5</td><td>233.33%</td><td>0.08</td><td>0.49</td><td>512.50%</td></tr><tr><td>Leaf % DHA</td><td>0.18</td><td/><td/><td>0.15</td><td>0.49</td><td>226.67%</td><td>0.3</td><td>0.52</td><td>73.33%</td></tr></tbody></table></table-wrap>", "<table-wrap id=\"Tab7\"><label>Table 7</label><caption><p>The influence of increasing contents of Cd, Zn, and Pb in the organs of <italic>B. pendula</italic>, <italic>P. sylvestris</italic>, and <italic>L. decidua</italic> seedlings on the content TBARS, H<sub>2</sub>O<sub>2</sub>, and the reduced form of ascorbic acid (tAsA) and the share of its oxidized form (%DHA)</p></caption><table frame=\"hsides\" rules=\"groups\"><thead><tr><th>Związek</th><th>Organ</th><th>Cd</th><th>Zn</th><th>Pb</th><th><italic>R</italic><sup>2</sup></th></tr></thead><tbody><tr><td rowspan=\"3\">TBARS</td><td>Root</td><td>↘</td><td>↗</td><td>↔</td><td>75%</td></tr><tr><td>Shoot</td><td>N</td><td>↔</td><td>N</td><td>72%</td></tr><tr><td>Leaf</td><td>N</td><td>↔</td><td>↗</td><td>88%</td></tr><tr><td rowspan=\"3\">H<sub>2</sub>O<sub>2</sub></td><td>Root</td><td>↘</td><td>N</td><td>↗</td><td>65%</td></tr><tr><td>Shoot</td><td>↗</td><td>↔</td><td>↔</td><td>71%</td></tr><tr><td>Leaf</td><td>↗</td><td>N</td><td>↔</td><td>84%</td></tr><tr><td rowspan=\"3\">tAsA</td><td>Root</td><td>↔</td><td>↔</td><td>↔</td><td>84%</td></tr><tr><td>Shoot</td><td>↔</td><td>N</td><td>N</td><td>75%</td></tr><tr><td>Leaf</td><td>↘</td><td>↗</td><td>↗</td><td>95%</td></tr><tr><td rowspan=\"3\">% DHA</td><td>Root</td><td>↗</td><td>↔</td><td>N</td><td>69%</td></tr><tr><td>Shoot</td><td>N</td><td>N</td><td>N</td><td>N</td></tr><tr><td>Leaf</td><td>↗</td><td>↔</td><td>↔</td><td>94%</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><p><italic>SA</italic> Nursery substrate; <italic>PFS</italic> flotation tailings</p></table-wrap-foot>", "<table-wrap-foot><p>Different letters indicate significant differences between the variants substrate. <italic>C</italic><sub><italic>tot</italic></sub> Contents of carbon; <italic>N</italic><sub><italic>tot</italic></sub> contents of nitrogen; <italic>Ca</italic><sup><italic>2+</italic></sup> exchangeable calcium; <italic>K</italic><sup><italic>+</italic></sup> exchangeable potassium; <italic>Mg</italic><sup><italic>2+</italic></sup> exchangeable magnesium; <italic>Na</italic><sup><italic>+</italic></sup> exchangeable sodium; <italic>Cd</italic> exchangeable cadmium; <italic>Pb</italic> exchangeable lead; <italic>Zn</italic> exchangeable zinc, <italic>Cd</italic><sub><italic>tot</italic></sub> contents of cadmium; <italic>Pb</italic><sub><italic>tot</italic></sub> contents of lead; <italic>Zn</italic><sub><italic>tot</italic></sub> contents of zinc</p></table-wrap-foot>", "<table-wrap-foot><p>Different letters indicate significant differences between the species</p></table-wrap-foot>", "<table-wrap-foot><p>Different letters (a, b, c, d) indicate significant differences between the studied species (for the same substrate). Different capital letters (A, B) indicate significant differences between the studied types of parent materials (on the same trees species)</p></table-wrap-foot>", "<table-wrap-foot><p>Different letters indicate significant differences between the variants substrate</p></table-wrap-foot>", "<table-wrap-foot><p>↗Content increase, ↘decrease in content, ↔no content changes, <italic>N</italic> negligible effect of the increase in metal content</p></table-wrap-foot>", "<fn-group><fn><p><bold>Publisher’s Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group>" ]	[]	[]	[{"surname": ["Abbas", "Saqib", "Akhtar", "Murtaza"], "given-names": ["G", "M", "J", "G"], "article-title": ["Physiological and biochemical characterization of "], "italic": ["Acacia stenophylla", "Acacia albida"], "source": ["Canadian Journal of Forest Research"], "year": ["2017"], "volume": ["47"], "fpage": ["1293"], "lpage": ["1301"], "pub-id": ["10.1139/cjfr-2016-0499"]}, {"surname": ["Arduini", "Godbold", "Onnis"], "given-names": ["I", "DL", "A"], "article-title": ["Cadmium and copper change root growth and morphology of "], "italic": ["Pinus pinea", "Pinus pinaster"], "source": ["Physiologia Plantarum"], "year": ["1994"], "volume": ["92"], "fpage": ["675"], "lpage": ["680"], "pub-id": ["10.1111/j.1399-3054.1994.tb03039.x"]}, {"surname": ["Bech", "Roca", "Barcel\u00f3", "Duran", "Tume", "Poschenrieder"], "given-names": ["J", "N", "J", "P", "P", "C"], "article-title": ["Soil and plant contamination by lead mining in Bellmunt (Western Mediterranean area)"], "source": ["Journal of Geochemical Exploration"], "year": ["2012"], "volume": ["113"], "fpage": ["94"], "lpage": ["99"], "pub-id": ["10.1016/j.gexplo.2011.10.001"]}, {"surname": ["Chandel", "Dar", "Singh", "Thakur", "Kaur", "Singh", "Pandey"], "given-names": ["S", "RA", "D", "S", "R", "K", "VC"], "article-title": ["Plant assisted bioremediation of heavy metal polluted soils"], "source": ["Bio-Inspired Land Remediation. Environmental Contamination Remediation and Management"], "year": ["2023"], "publisher-name": ["Springer"], "fpage": ["85"], "lpage": ["114"]}, {"mixed-citation": ["Dhindsa, R. S., Plumb-Dhindsa, P., Thorpe, T. A. (1981). Leaf senescence: correlated with increased levels of membrane permeability and lipid peroxidation, and\u00a0decreased levels of superoxide dismutase and catalase.\u00a0"], "italic": ["Journal of Experimental Botany, 32"]}, {"surname": ["Dimkpa", "Merten", "Svatos", "B\u00fcchel", "Kothe"], "given-names": ["CHO", "D", "A", "G", "E"], "article-title": ["Metal-induced oxidative stress impacting plant growth in contaminated soil is alleviated by microbial siderophores"], "source": ["Soil Biology and Biochemistry"], "year": ["2009"], "volume": ["41"], "fpage": ["154"], "lpage": ["162"], "pub-id": ["10.1016/j.soilbio.2008.10.01"]}, {"surname": ["Dubey", "Shri", "Gupta", "Rani", "Chakrabarty"], "given-names": ["S", "M", "A", "V", "D"], "article-title": ["Toxicity and detoxification of heavy metals during plant growth and metabolism"], "source": ["Environmental Chemistry Letters"], "year": ["2018"], "volume": ["16"], "fpage": ["1169"], "lpage": ["1192"], "pub-id": ["10.1007/s10311-018-0741-8"]}, {"surname": ["Foyer", "Lelandais", "Kunert"], "given-names": ["CH", "M", "KJ"], "article-title": ["Photooxidative stress in plants"], "source": ["Physiologia Plantarum"], "year": ["1994"], "volume": ["92"], "fpage": ["696"], "lpage": ["717"], "pub-id": ["10.1111/j.1399-3054.1994.tb03042.x"]}, {"mixed-citation": ["Gillespie, K. M., Ainsworth, E. A. (2007). Measurement of reduced, oxidized and total ascorbate content in plants. "], "italic": ["Nature Protocols, 2"]}, {"surname": ["Hoskin"], "given-names": ["W"], "italic": ["Hazardous materials management at mine sites: Lessons learned from recent accidents"], "year": ["2000"], "publisher-name": ["Third Asia Pacific Training Workshop on Hazardous Waste Management in Mining"]}, {"surname": ["Hristozkova", "Geneva", "Stancheva", "Boychinova", "Djonova"], "given-names": ["M", "M", "I", "M", "E"], "article-title": ["Contribution of arbuscular mycorrhizal fungi in attenuation of heavy metal impact on "], "italic": ["Calendula officinalis"], "source": ["Applied Soil Ecology"], "year": ["2016"], "volume": ["101"], "fpage": ["57"], "lpage": ["63"], "pub-id": ["10.1016/j.apsoil.2016.01.008"]}, {"surname": ["Isebrands", "Dickson", "Rebbeck", "Karnosky"], "given-names": ["JG", "RE", "J", "DF"], "article-title": ["Interacting effects of multiple stresses on growth and physiological processes in northern forest trees"], "italic": ["Responses of Northern U.S. Forests to Environmental Change. Ecological Studies"], "year": ["2000"], "publisher-name": ["Springer"], "fpage": ["149"], "lpage": ["180"]}, {"surname": ["Jeyakumar", "Loganathan", "Sivakumaran", "Anderson", "McLaren"], "given-names": ["P", "P", "S", "CWN", "RG"], "article-title": ["Bioavailability of copper and zinc to poplar and microorganisms in a biosolids-amended soil"], "source": ["Australian Journal of Soil Research"], "year": ["2010"], "volume": ["48"], "fpage": ["459"], "lpage": ["469"], "pub-id": ["10.1071/SR09169"]}, {"surname": ["Kabata-Pendias", "Pendias"], "given-names": ["A", "H"], "italic": ["Trace elements in soils and plants"], "year": ["2001"], "edition": ["third ed."], "publisher-name": ["CRC"]}, {"surname": ["Kahle"], "given-names": ["H"], "article-title": ["Response of roots of trees to heavy metals"], "source": ["Environmental and Experimental Botany"], "year": ["1993"], "volume": ["33"], "fpage": ["99"], "lpage": ["119"], "pub-id": ["10.1016/0098-8472(93)90059-O"]}, {"surname": ["Kraj"], "given-names": ["W"], "article-title": ["Reactive oxygen species and antioxidant levels as the factors of autumn senescence in phenological forms of beech ("], "italic": ["Fagus sylvatica"], "source": ["Acta Physiologiae Plantarum"], "year": ["2016"], "volume": ["38"], "fpage": ["32"], "pub-id": ["10.1007/s11738-015-2052-z"]}, {"surname": ["Kraj", "Slepaczuk"], "given-names": ["W", "A"], "article-title": ["Morphophysiological acclimation of developed and senescing beech leaves to different light conditions"], "source": ["Forests"], "year": ["2022"], "volume": ["13"], "fpage": ["1333"], "pub-id": ["10.3390/f13081333"]}, {"surname": ["Kraj", "Zarek"], "given-names": ["W", "M"], "article-title": ["Biochemical basis of altitude adaptation and antioxidant system activity during autumn leaves senescence in beech populations"], "source": ["Forests"], "year": ["2021"], "volume": ["12"], "fpage": ["529"], "pub-id": ["10.3390/f12050529"]}, {"surname": ["Krzaklewski", "Pietrzykowski"], "given-names": ["W", "M"], "article-title": ["Selected physico-chemical properties of zinc and lead ore tailings and their biological stabilisation"], "source": ["Water, Air, & Soil Pollution"], "year": ["2002"], "volume": ["141"], "fpage": ["125"], "lpage": ["141"], "pub-id": ["10.1023/A:1021302725532"]}, {"surname": ["Kukavica", "Jovanovic"], "given-names": ["B", "SV"], "article-title": ["Senescence-related changes in the antioxidant status of ginkgo and birch leaves during autumn yellowing"], "source": ["Physiologia Plantarum"], "year": ["2004"], "volume": ["122"], "fpage": ["321"], "lpage": ["327"], "pub-id": ["10.1111/j.1399-3054.2004.00410.x"]}, {"surname": ["Kuznetsova", "Rosenvald", "Ostonen", "Helmisaari", "Mandre", "L\u00f5hmus"], "given-names": ["T", "K", "I", "H", "M", "K"], "article-title": ["Survival of black alder ("], "italic": ["Alnus glutinosa", "Betula pendula", "Pinus sylvestris"], "source": ["Ecological Engineering"], "year": ["2010"], "volume": ["36"], "fpage": ["495"], "lpage": ["502"], "pub-id": ["10.1016/j.ecoleng.2009.11.019"]}, {"surname": ["Lambers", "Oliveira"], "given-names": ["H", "RS"], "italic": ["Plant physiological ecology"], "year": ["2019"], "edition": ["third ed."], "publisher-name": ["Springer"]}, {"surname": ["Levy", "Redente", "Uphoff"], "given-names": ["DB", "EF", "GD"], "article-title": ["Evaluating the phytotoxicity of Pb-Zn tailings to big bluesteam ("], "italic": ["Andropogon gerardii", "Panicum virgatum"], "source": ["Soil Science"], "year": ["1999"], "volume": ["164"], "fpage": ["363"], "lpage": ["375"], "pub-id": ["10.1097/00010694-199906000-00001"]}, {"surname": ["L\u00f5hmus", "Truu", "Truu", "Kaar", "Ostonen", "Alama", "Kuznetsova", "Rosenvald", "Vares", "Uri", "Mander", "Brebba", "Mander"], "given-names": ["K", "J", "M", "E", "I", "S", "T", "K", "A", "V", "\u00dc", "CA", "\u00dc"], "article-title": ["Black alder as a perspective deciduous species for reclaiming of oil shale mining areas"], "italic": ["Brownfields III. Prevention, Assessment, Rehabilitation and Development of Brownfield Sites"], "year": ["2006"], "publisher-name": ["Wessex Institute of Technology Press"], "fpage": ["87"], "lpage": ["97"]}, {"surname": ["Lunackova", "Sottnikova", "Masarovicova", "Lux", "Stresko"], "given-names": ["L", "A", "E", "A", "V"], "article-title": ["Comparison of cadmium effect on willow and poplar in response to different cultivation conditions"], "source": ["Biologia Plantarum"], "year": ["2003"], "volume": ["47"], "fpage": ["403"], "lpage": ["411"], "pub-id": ["10.1023/B:BIOP.0000023884.54709.09"]}, {"surname": ["Mendez", "Maier"], "given-names": ["MO", "RM"], "article-title": ["Phytoremediation of mine tailings in temperate and arid environments"], "source": ["Reviews in Environmental Science and Biotechnology"], "year": ["2008"], "volume": ["7"], "fpage": ["47"], "lpage": ["59"], "pub-id": ["10.1007/s11157-007-9125-4"]}, {"surname": ["Monterroso", "Rodr\u00edguez", "Chaves", "Diez", "Becerra-Castro", "Kidd", "Mac\u00edas"], "given-names": ["C", "F", "R", "J", "C", "PS", "F"], "article-title": ["Heavy metal distribution in mine-soils and plants growing in a Pb/Zn-mining area in NW Spain"], "source": ["Applied Geochemistry"], "year": ["2014"], "volume": ["44"], "fpage": ["3"], "lpage": ["11"], "pub-id": ["10.1016/j.apgeochem.2013.09.001"]}, {"surname": ["Noctor", "Foyer"], "given-names": ["G", "CH"], "article-title": ["Ascorbate and glutathione: Keeping active oxygen under control"], "source": ["Annual Review of Plant Physiology and Plant Molecular Biology"], "year": ["1998"], "volume": ["49"], "fpage": ["249"], "lpage": ["279"], "pub-id": ["10.1146/annurev.arplant.49.1.249"]}, {"surname": ["Novo", "Covelo", "Gonz\u00e1lez"], "given-names": ["LAB", "EF", "L"], "article-title": ["Phytoremediation of amended copper mine tailings with "], "italic": ["Brassica juncea"], "source": ["International Journal of Mining, Reclamation and Environment"], "year": ["2013"], "volume": ["27"], "fpage": ["215"], "lpage": ["226"], "pub-id": ["10.1080/17480930.2013.779061"]}, {"surname": ["Pottier", "Garc\u00eda de la Torre", "Victor", "David", "Chalot", "Thomine"], "given-names": ["M", "VS", "C", "LC", "M", "S"], "article-title": ["Genotypic variations in the dynamics of metal concentrations in poplar leaves: A field study with a perspective on phytoremediation"], "source": ["Environmental Pollution"], "year": ["2015"], "volume": ["199"], "fpage": ["72"], "lpage": ["83"], "pub-id": ["10.1016/j.envpol.2015.01.010"]}, {"surname": ["Sch\u00fctzend\u00fcbel", "Polle"], "given-names": ["A", "A"], "article-title": ["Plant responses to abiotic stresses: Heavy metal-induced oxidative stress and protection by mycorrhization"], "source": ["Journal of Experimental Botany"], "year": ["2001"], "volume": ["53"], "fpage": ["1351"], "lpage": ["1365"], "pub-id": ["10.1093/jexbot/53.372.1351"]}, {"surname": ["Sebastiani", "Scebba", "Tognetti"], "given-names": ["L", "F", "R"], "article-title": ["Heavy metal accumulation and growth responses in poplar clones Eridano ("], "italic": ["Populus deltoides \u00d7 maximowiczii", "P. \u00d7 euramericana"], "source": ["Environmental and Experimental Botany"], "year": ["2004"], "volume": ["52"], "fpage": ["79"], "lpage": ["88"], "pub-id": ["10.1016/j.envexpbot.2004.01.003"]}, {"surname": ["Shi", "Zhang", "Chen", "Chen", "Wang", "Shan"], "given-names": ["X", "X", "G", "Y", "L", "X"], "article-title": ["Seedling growth and metal accumulation of selected woody species in copper and lead/zinc mine tailings"], "source": ["Journal of Environmental Sciences"], "year": ["2011"], "volume": ["23"], "fpage": ["266"], "lpage": ["274"], "pub-id": ["10.1016/S1001-0742(10)60402-0"]}, {"surname": ["Turnau", "Ostachowicz", "Wojtczak", "Anielska", "Sobczyk"], "given-names": ["K", "B", "G", "T", "\u0141"], "article-title": ["Metal uptake by xerothermic plants introduced into Zn-Pb industrial wastes"], "source": ["Plant and Soil"], "year": ["2010"], "volume": ["337"], "fpage": ["299"], "lpage": ["311"], "pub-id": ["10.1007/s11104-010-0527-7"]}, {"surname": ["Vares", "L\u00f5hmus", "Truu", "Truu", "Tullus", "Kanal"], "given-names": ["A", "K", "M", "J", "H", "A"], "article-title": ["Productivity of black alder ("], "italic": ["Alnus glutinosa"], "source": ["Oil Shale"], "year": ["2004"], "volume": ["21"], "fpage": ["43"], "lpage": ["58"], "pub-id": ["10.3176/oil.2004.1.05"]}, {"surname": ["Wang", "Liao", "Yu", "Liao", "Shu"], "given-names": ["SL", "WB", "FQ", "B", "WS"], "article-title": ["Hyperaccumulation of lead, zinc, and cadmium in plants growing on a lead/zinc outcrop in Yunnan Province, China"], "source": ["Environmental Geology"], "year": ["2009"], "volume": ["58"], "fpage": ["471"], "lpage": ["476"], "pub-id": ["10.1007/s00254-008-1519-2"]}, {"mixed-citation": ["Yongqi, H., Jinping, C., Xiaodan, L., Peng, Z., Bin, Y., Hongsheng, Z., & Zhoufei, W. (2016). Acquisition of desiccation tolerance during seed development is associated with oxidative processes in rice. "], "italic": ["Botany, 94"]}]	{ "acronym": [], "definition": [] }	62	CC BY	no	2024-01-13 23:35:10	Environ Monit Assess. 2024 Dec 18; 196(1):52	oa_package/76/3f/PMC10728222.tar.gz
PMC10730649	38131039	[ "<title>Introduction</title>", "<p id=\"Par2\">We are interested in the local Hölder regularity of weak solutions to a class of parabolic equations involving a fractional <italic>p</italic>-Laplacian type operator:where for some open set and some , and the nonlocal operator is defined byfor some . Here, denotes the principle value of the integral, whereas the kernel is a measurable function satisfying the following condition uniformly in <italic>t</italic>:for some positive , and .</p>", "<p id=\"Par3\">Throughout this note, the parameters are termed the <italic>data</italic>, and we use as a generic positive constant in various estimates that can be determined by the data only.</p>", "<p id=\"Par4\">The formal definition of weak solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) and notation can be found in Sect. <xref rid=\"Sec3\" ref-type=\"sec\">1.2</xref>. We proceed to present our main result as follows.</p>", "<title>Theorem 1.1</title>", "<p id=\"Par5\">Let <italic>u</italic> be a locally bounded, local, weak solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) in with .Then <italic>u</italic> is locally Hölder continuous in . More precisely, there exist constants and that can be determined a priori only in terms of the data, such that for any , there holdsprovided the cylinders are included in , where</p>", "<title>Remark 1.1</title>", "<p id=\"Par6\">Theorem <xref ref-type=\"sec\" rid=\"FPar1\">1.1</xref> has been formulated independent of any initial/boundary data. While local, the oscillation estimate bears global information via the <italic>tail</italic> of <italic>u</italic>; see (##FORMU##75##1.9##). In particular, a solution is allowed to grow at infinity. Whereas if <italic>u</italic> is globally bounded in , then can be taken as the global bound. This occurs if, for instance, proper initial/boundary data are prescribed, cf. [##UREF##3##4##, ##UREF##5##6##]. In addition, if <italic>u</italic> is globally bounded in , then <italic>u</italic> is, <italic>a fortiori</italic>, a constant by the oscillation estimate.</p>", "<title>Remark 1.2</title>", "<p id=\"Par7\">Theorem <xref ref-type=\"sec\" rid=\"FPar1\">1.1</xref> continues to hold for more general structures. For instance, one can consider the kernel satisfyingAlso, proper lower order terms can be considered, cf. [##UREF##7##8##]. However, we will concentrate on the actual novelty and leave possible generalizations to the motivated reader.</p>", "<title>Remark 1.3</title>", "<p id=\"Par8\">Our approach only has a minimal requirement regarding fractional calculus; all relevant results are collected in Appendix A. However, DiBenedetto’s intrinsic scaling method is quite involved; monographs [##UREF##8##9##, ##UREF##10##11##, ##UREF##24##25##] provide a good account of the method. It would be instructive to first practice our arguments in the elliptic setting or in the linear parabolic setting.</p>", "<title>Novelty and significance</title>", "<p id=\"Par9\">The nonlocal elliptic operator as in (##FORMU##5##1.2##) with a kernel like (##FORMU##9##1.3##), especially when , has been a classical topic in Probability, Potential theory, Harmonic Analysis, etc. In addition, nonlocal partial differential equations arise from continuum mechanics and phase transition, from population dynamics, and from optimal control and game theory. We refer to [##UREF##4##5##, ##UREF##13##14##] for a source of motivations and applications.</p>", "<p id=\"Par10\">Local regularity for the nonlocal elliptic operator with merely measurable kernels is well studied, cf. [##UREF##7##8##, ##UREF##11##12##, ##UREF##12##13##, ##UREF##16##17##, ##UREF##21##22##]—just to mention a few. In [##UREF##11##12##, ##UREF##12##13##], localization techniques are developed in order to establish Hölder regularity and Harnack’s inequality for the elliptic operator. A logarithmic estimate plays a key role in [##UREF##11##12##, ##UREF##12##13##]. Whereas [##UREF##7##8##] further improves these results to functions in certain DeGiorgi classes and the logarithmic estimate is dispensed with.</p>", "<p id=\"Par11\">The parabolic nonlocal problem (##FORMU##0##1.1##) has witnessed a growing interest recently; see [##UREF##1##2##–##UREF##3##4##, ##UREF##5##6##, ##UREF##14##15##, ##UREF##15##16##, ##UREF##17##18##, ##UREF##18##19##, ##UREF##20##21##, ##UREF##22##23##, ##UREF##23##24##, ##UREF##25##26##, ##UREF##26##27##]—just to mention a few. Coming to the local regularity, while the case has been subject to extensive studies, the case is largely open. Local regularity of supersolutions is studied in [##UREF##1##2##, ##UREF##2##3##]. Some local boundedness estimates are reported in [##UREF##14##15##, ##UREF##22##23##]. Meanwhile, it is tried in [##UREF##14##15##] to adapt techniques of [##UREF##11##12##] and to show Hölder regularity for (##FORMU##0##1.1##) with . However, we are unable to verify [##UREF##14##15##, (5.23)], which is based on a logarithmic estimate. When the kernel <italic>K</italic>(<italic>x</italic>, <italic>y</italic>, <italic>t</italic>) is exactly for , explicit Hölder exponents are obtained in [##UREF##3##4##].</p>", "<p id=\"Par12\">Our contribution lies in establishing Hölder regularity for the parabolic fractional <italic>p</italic>-Laplace type equation with merely measurable kernels for all . The approach is structural, in the sense that we dispense with any kind of comparison principle and do not reply on solving PDEs. More generally, we find that the Hölder regularity is in fact encoded in a family of energy estimates in Corollary <xref ref-type=\"sec\" rid=\"FPar9\">2.1</xref>, and tools like logarithmic estimates or exponential change of variables play no role in our arguments.<xref ref-type=\"fn\" rid=\"Fn1\">1</xref> This differs from the Moser approach, which keeps using the PDE with different testing functions. As such, the arguments are new even for and hold the promise of a wider applicability, for instance, in Calculus of Variations.</p>", "<p id=\"Par14\">Unlike the elliptic operator or the parabolic operator with , the local behavior of a solution to the parabolic <italic>p</italic>-Laplacian is markedly different: it has to be read in its own <italic>intrinsic geometry</italic>. This is the guiding idea in the local operator theory, cf. [##UREF##6##7##, ##UREF##8##9##–##UREF##10##11##, ##UREF##24##25##]. In terms of oscillation estimates, this idea leads to the construction of geometric sequences and connected by the intrinsic relationThe nonlocal theory developed here is no exception. However, the nonlocal character of (##FORMU##0##1.1##) needs to be carefully handled in this intrinsic scaling scenario. A new component brought by the nonlocality of the operator is a proper control of the so-called <italic>tail</italic>—a nonlocal integral of the solution (see (##FORMU##75##1.9##)). Precisely, we havewhere denotes the supremum/infimum of <italic>u</italic> over . In other words, the nonlocal tail is controlled by the local oscillation, if the intrinsic relation (##FORMU##41##1.4##) is verified. The tail estimate (##FORMU##42##1.5##) in turn allows us to reduce the oscillation in the next step, and so on. This induction procedure can be illustrated byThe local regularity theory for the nonlocal parabolic problem (##FORMU##0##1.1##) with is still at its inception. We believe the techniques developed in this note are flexible enough and provide a handy toolkit that can be used to fruitfully attack more general nonlocal parabolic equations.</p>", "<title>Definitions and notation</title>", "<title>Function spaces</title>", "<p id=\"Par15\">For and , we introduce the fractional Sobolev space bywhich is endowed with the normSimilarly, the fractional Sobolev space for a domain can be defined. Moreover, we denoteThese spaces admit imbedding into proper Lebesgue spaces; we collect some in Appendix A.</p>", "<title>Notion of weak solution</title>", "<p id=\"Par16\">A measurable function satisfyingis a local, weak sub(super)-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##), if for every compact set and every sub-interval , we haveandwherefor all non-negative testing functionsA function <italic>u</italic> that is both a local weak sub-solution and a local weak super-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) is a local weak solution.</p>", "<title>Remark 1.4</title>", "<p id=\"Par17\">As we are developing a local theory, the function space in (##FORMU##62##1.8##) can be taken smaller. Namely, the notion of can be replaced by functions with a compact support in for a.e. <italic>t</italic>.</p>", "<title>Remark 1.5</title>", "<p id=\"Par18\">To ensure the convergence of the global integral in (##FORMU##60##1.7##), it suffices to weaken the norm appearing in the condition (##FORMU##59##1.6##) by the norm. However, in deriving the energy estimate of Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref>, the condition (##FORMU##59##1.6##) is needed already.</p>", "<title>Some notation</title>", "<p id=\"Par19\">Throughout this note, we will use to denote the ball of radius and center in , and the symbolsto denote (backward) cylinders with the indicated positive parameters. When the context is unambiguous, we will omit the vertex from the symbols for simplicity. When , it is also omitted.</p>", "<p id=\"Par20\">A nonlocal integral of <italic>u</italic>—termed the <italic>tail </italic> of <italic>u</italic>—inevitably appears in the theory, which we define asFor any , the finiteness of this tail is guaranteed by (##FORMU##59##1.6##).</p>" ]	[]	[]	[]	[]	[ "<p>Communicated by Jan Kristensen.</p>", "<p id=\"Par1\">Local Hölder regularity is established for certain weak solutions to a class of parabolic fractional <italic>p</italic>-Laplace equations with merely measurable kernels. The proof uses DeGiorgi’s iteration and refines DiBenedetto’s intrinsic scaling method. The control of a nonlocal integral of solutions in the reduction of oscillation plays a crucial role and entails delicate analysis in this intrinsic scaling scenario. Dispensing with any logarithmic estimate and any comparison principle, the proof is new even for the linear case.</p>", "<title>Mathematics Subject Classification</title>" ]	[ "<title>Energy estimates</title>", "<p id=\"Par21\">This section is devoted to energy estimates satisfied by local weak sub(super)-solutions to (##FORMU##0##1.1##)–(##FORMU##9##1.3##). We first introduce, for any , the truncated functionsIn what follows, when we state <italic>“u is a sub(super)-solution...”</italic> and use or afterwards, we mean the sub-solution corresponds to the upper sign and the super-solution corresponds to the lower sign in the statement.</p>", "<title>Proposition 2.1</title>", "<p id=\"Par22\">Let <italic>u</italic> be a local weak sub(super)-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) in . There exists a constant , such that for all cylinders , every , and every non-negative, piecewise smooth cutoff function compactly supported in for all , there holdsHere, we have denoted for simplicity.</p>", "<title>Proof</title>", "<p id=\"Par23\">We will only deal with the case of sub-solution as the other case is similar. Using as a testing function in the weak formulation modulo a proper time mollification (cf. Appendix B), the last terms on the right/left-hand side of the energy estimate are rather standard. We only treat the integral resulting from the fractional diffusion part, which, due to the support of and symmetry of the integrand, can be split into two parts, that is,where we have used for simplicity.</p>", "<p id=\"Par24\">Let us manipulate the first integral, which is the leading term. To this end, we denote for fixed . Observe that if while , one obtainsfor some proper . Whereas if , we claim thatTo prove the claim, we may assume that due to symmetry and writeIf , the above display (##FORMU##103##2.3##) is estimated below byand hence the claim follows. If, instead , then (##FORMU##103##2.3##) can be written asTo proceed, we need an elementary inequality:This simply follows from the mean value theorem and Young’s inequality:We may apply (##FORMU##108##2.4##) with , andto obtainCombining the last two estimates in (##FORMU##103##2.3##), we obtain (##FORMU##101##2.2##) in the case also.</p>", "<p id=\"Par25\">Employing (##FORMU##98##2.1##) and (##FORMU##101##2.2##) and properly adjusting <italic>c</italic> if necessary, the first integral is estimated byNow let us treat the second integral , which yields the only nonlocal integral in the energy estimate. Indeed, we first estimateAs a result, we may estimate by the condition (##FORMU##9##1.3##) on the kernel <italic>K</italic>,Note that the finiteness of the above nonlocal integral is guaranteed by (##FORMU##59##1.6##). This term will evolve into the tail term (##FORMU##75##1.9##) in the forthcoming theory.</p>", "<p id=\"Par26\">Finally, we can put all these estimates together and use the condition (##FORMU##9##1.3##) on the kernel <italic>K</italic> to conclude. </p>", "<p>The above energy estimate can be written in for any . As usual, this will lead to an estimate in the time variable on the left, due to the arbitrariness of <italic>t</italic>. Further, by choosing a proper cutoff function , we derive the following two types of energy estimates from Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref>, which encode all the information needed to show Theorem <xref ref-type=\"sec\" rid=\"FPar1\">1.1</xref>.</p>", "<title>Corollary 2.1</title>", "<p id=\"Par28\">Let <italic>u</italic> be a local weak sub(super)-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) in . There exists a constant , such that for all cylinders , and every , there holdsandHere, we have denoted for simplicity.</p>", "<title>Preliminary tools</title>", "<p id=\"Par29\">In this section, we collect the main modules of the proof of Hölder regularity. An important feature is that the tail term appears in these modules via an either-or form. This feature clarifies the role of the tail and greatly facilitates the delicate intrinsic scaling arguments to be unfolded in the next two sections. To streamline, we derive them from the energy estimates in Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref>. Nevertheless, it will be clear from their proofs that Corollary <xref ref-type=\"sec\" rid=\"FPar9\">2.1</xref> actually suffices. We also stress that the arguments in this section are given in a unified fashion for all .</p>", "<p id=\"Par30\">Throughout this section, let be a cylinder included in . We introduce numbers and satisfyingThe first result concerns a DeGiorgi type lemma. For simplicity, we omit the vertex from .</p>", "<title>Lemma 3.1</title>", "<p id=\"Par31\">Let <italic>u</italic> be a locally bounded, local weak sub(super)-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) in . For some set and assume . There exists a constant depending only on the data and , such that ifthen eitherorMoreover, we have the dependence for some depending on <italic>p</italic> and <italic>N</italic>.</p>", "<title>Proof</title>", "<p id=\"Par32\">It suffices to show the case of super-solution with . As a restatement,<xref ref-type=\"fn\" rid=\"Fn2\">2</xref> we will show that there exists , such that ifand ifthenWe stress that only depends on the data and , but independent of .</p>", "<p id=\"Par34\">Upon a translation, we may assume and define for ,It is helpful to observe thatIntroduce the cutoff function in , vanishing outside and equal to the identity in , such thatLet us examine the energy estimate of Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref> in this setting:Recalling , we treat the three terms on the right-hand side of the energy estimate as follows. For the first term, we estimatewhere we have defined .</p>", "<p id=\"Par35\">For the second term, we observe that for and , there holdsconsequently, recalling also a.e. in by assumption, we estimateIn the last line, we have enforcedFor the third term, it is quite standard to obtainCollecting these estimates on the right-hand side of the energy estimate, we arrive atNow set to be a cutoff function in , which vanishes outside , equals the identity in and satisfies . An application of the Hölder inequality and the Sobolev imbedding (cf. Proposition <xref ref-type=\"sec\" rid=\"FPar23\">A.3</xref> with ) gives thatfor some . To obtain the last line, we used the triangle inequalityfor some , such thatPlugging this into the second-to-last line and employing the above energy estimate, the last line follows. Notice also from Proposition <xref ref-type=\"sec\" rid=\"FPar23\">A.3</xref> there holdsIn terms of , this estimate leads to the recursive inequalityfor some generic constant . Hence, by the fast geometric convergence, cf. [##UREF##8##9##, Chapter I, Lemma 4.1], there exists a positive constant depending only on the data, such that if we require that . </p>", "<p>The next lemma is a variant of the previous one, involving quantitative initial data.</p>", "<title>Lemma 3.2</title>", "<p id=\"Par37\">Let <italic>u</italic> be a locally bounded, local weak sub(super)-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) in . Let . There exists a positive constant depending only on the data and independent of , such that ifthen eitherorprovided the cylinders are included in .</p>", "<title>Proof</title>", "<p id=\"Par38\">Assume . It suffices to show the case of super-solutions with . Let us first examine the energy estimate of Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref> in for some to be determined. Note that the time level in Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref> corresponds to here. Let be a time independent, piecewise smooth, cutoff function in that vanishes on . If we take the level , the spatial integral at (i.e. the term at the time level in Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref>) vanishes due to the assumption that a.e. in . The term involving also vanishes since is independent of <italic>t</italic>. As a result, the energy estimate readsIntroduce , , , , , , , and as in Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref>. The only difference is that the cylinders , , and are now of forward type, i.e. , , and . Note that while shrinking the base balls , , and along , the height of the cylinders is fixed. For the piecewise smooth function in , we choose it to vanish outside , be equal to 1 in , and satisfy . By a similar treatment of the right-hand side as in Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref>, after enforcingwe may obtain thatwhere .</p>", "<p id=\"Par39\">Then we may proceed as in Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref> to obtain the recursive inequalitywhere and the constants depend only on the data. Hence, by the fast geometric convergence, cf. [##UREF##8##9##, Chapter I, Lemma 4.1], there exists a positive constant depending only on the data, such that ifthen . To finish the proof, we choose . </p>", "<p>The following lemma propagates measure theoretical information forward in time.</p>", "<title>Lemma 3.3</title>", "<p id=\"Par41\">Let <italic>u</italic> be a locally bounded, local weak sub(super)-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) in . Introduce parameters and in (0, 1). There exist and in (0, 1), depending only on the data and , such that ifthen eitherorprovided this cylinder is included in . Moreover, we may trace the dependences by and .</p>", "<title>Proof</title>", "<p id=\"Par42\">We only show the case of super-solutions with . Assume without loss of generality. Use the energy estimate in Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref> in the cylinder , with the truncationChoose a standard non-negative cutoff function independent of time that equals 1 on with to be chosen later and vanishes outside satisfying ; in such a case, the energy estimate presents that, for all , there holdsThe first term on the right-hand side is estimated byAs for the second term, we observe that for and , there holdstherefore, we estimateHere, in the last line we have enforcedTherefore, combining all these estimates in the energy estimate, we have for all , thatThe left-hand side in the last display is estimated from below bywhere we have definedNotice also a simple fact thatUsing the last two estimates, together with the energy estimate, we have for all , thatTo conclude the proof, we choose various parameters , and to satisfy:In this way, we obtainfor all , which is a restatement of the desired measure estimate. </p>", "<p>The following measure shrinking lemma is usually a delicate part in the theory of the parabolic <italic>p</italic>-Laplacian. However, the term that involves mixed positive/negative truncations in the energy estimate greatly simplifies the argument. For ease of notation, we omit the vertex from .</p>", "<title>Lemma 3.4</title>", "<p id=\"Par44\">Let <italic>u</italic> be a locally bounded, local weak sub(super)-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) in . Suppose that for some , and in , there holdsLet . There exists depending only on the data and independent of , such that eitherorprovided is included in .</p>", "<title>Proof</title>", "<p id=\"Par45\">It suffices to show the case of super-solutions with . For simplicity, we assume . Let us employ the energy estimate of Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref> in with the truncationand introduce a cutoff function in (independent of <italic>t</italic>) that is equal to 1 in and vanishes outside , such that . Then, we obtain from Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref> thatThe first term on the right-hand side is estimated bynoticing that in the last line. As for the second term, observe that for and , there holdsconsequently, we estimateHere, in the last line we have enforcedand used . Whereas the third term is standard:recalling that and noticing that .</p>", "<p id=\"Par46\">Combining the above estimate we see that the right-hand side of the energy estimate is bounded byprovided the tail estimate is enforced. We stress that depends only on the data and is independent of .</p>", "<p id=\"Par47\">The left-hand side is estimated by extending the integrals over smaller sets and by using the given measure theoretical information:Combining these estimates and properly adjusting relevant constants, we conclude the proof. </p>", "<title>Proof of theorem <xref ref-type=\"sec\" rid=\"FPar1\">1.1</xref>: </title>", "<title>Expansion of positivity</title>", "<p id=\"Par48\">Suppose the cylinder and the numbers and are defined as in Sect. <xref rid=\"Sec8\" ref-type=\"sec\">3</xref>. The key ingredient of the reduction of oscillation lies in the following expansion of positivity, which is valid for .</p>", "<title>Proposition 4.1</title>", "<p id=\"Par49\">Let <italic>u</italic> be a locally bounded, local, weak sub(super)-solution to (##FORMU##0##1.1##)–(##FORMU##9##1.3##) in , with . Suppose for some constants , there holdsThen there exist constants depending only on the data and , such that eitherorprovidedMoreover, we have and for some depending on the data .</p>", "<title>Proof</title>", "<p id=\"Par50\">Assuming and for simplicity, it suffices to deal with super-solutions. As a restatement, we need to show that there exist and , such that ifand ifthenWe stress that and depend only on the data and , but independent of .</p>", "<p id=\"Par51\">Rewriting the measure theoretical information at the initial time in the larger ball and replacing by , we can enforceand apply Lemma <xref ref-type=\"sec\" rid=\"FPar14\">3.3</xref> to obtain depending only on the data and , such thatThis measure theoretical information for each slice of the time interval in turn allows us to apply Lemma <xref ref-type=\"sec\" rid=\"FPar16\">3.4</xref> in the cylinders with an arbitrary , and with and there replaced by and . This is viable because and ; consequently, we havewhen ranges over the given interval. Note also this step used the fact that .</p>", "<p id=\"Par52\">Letting be determined in Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref> in terms of the data and , we further choose according to Lemma <xref ref-type=\"sec\" rid=\"FPar16\">3.4</xref> to satisfyThis choice is possible because of Lemma <xref ref-type=\"sec\" rid=\"FPar16\">3.4</xref> is independent of . Further enforcingsuch a choice of permits us to apply Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref> in the cylinders with an arbitrary , and with there replaced by . Therefore, by arbitrariness of we conclude thatThe proof is completed by defining and properly adjusting relevant constants in dependence of the data and . </p>", "<p>Based on Proposition <xref ref-type=\"sec\" rid=\"FPar18\">4.1</xref>, the remaining part is devoted to the proof of Theorem <xref ref-type=\"sec\" rid=\"FPar1\">1.1</xref> for . All constants determined in the course of the proof are stable as .</p>", "<title>The first step</title>", "<p id=\"Par54\">For some we introduceand . By properly shrinking <italic>R</italic>, we may assume that and setWithout loss of generality, we take .</p>", "<p id=\"Par55\">Then the following intrinsic relation holds true:The choice of the reference cylinder is made to verify (##FORMU##429##4.1##), on which the subsequent arguments are based.</p>", "<p id=\"Par56\">Let be determined in Proposition <xref ref-type=\"sec\" rid=\"FPar18\">4.1</xref> with . For some to be chosen, defineand consider two alternativesAssuming , one of the two alternatives must hold. Whereas the case will be trivially incorporated into the forthcoming oscillation estimate (##FORMU##444##4.3##).</p>", "<p id=\"Par57\">Let us suppose the first alternative holds for instance. An appeal to Proposition <xref ref-type=\"sec\" rid=\"FPar18\">4.1</xref> with , and determines and yields that eitherorwhich, thanks to (##FORMU##429##4.1##), gives the reduction of oscillationThe number <italic>c</italic> is chosen to ensure that (##FORMU##442##4.2##) does not happen. Indeed, we may first estimateThis can be seen by the definitions of and the tail,Then, using (##FORMU##445##4.4##) we choosesuch that (##FORMU##442##4.2##) does not occur. Note that (##FORMU##448##4.5##) is not the final choice of <italic>c</italic> yet and it is subject to a further smallness requirement.</p>", "<p id=\"Par58\">Next, we set for some to verify the set inclusionAs a result of this inclusion and (##FORMU##444##4.3##) we obtainwhich plays the role of (##FORMU##429##4.1##) in the next stage.</p>", "<title>The induction</title>", "<p id=\"Par59\">Now we may proceed by induction.</p>", "<p id=\"Par60\">Suppose up to , we have builtThe induction argument will show that the above oscillation estimate continues to hold for the -th step.</p>", "<p id=\"Par61\">Let be fixed as before, whereas is subject to a further choice. To reduce the oscillation in the next stage, we basically repeat what has been done in the first step, now with , , , , etc. In fact, we defineand consider two alternativesLike in the first step, we may assume , so that one of the two alternatives must hold. Otherwise, the case can be trivially incorporated into the forthcoming oscillation estimate (##FORMU##473##4.8##).</p>", "<p id=\"Par62\">Let us suppose the first case holds for instance. An application of Proposition <xref ref-type=\"sec\" rid=\"FPar18\">4.1</xref> in , with , and yields (for the same as before) that eitherorwhich, thanks to the <italic>j</italic>-th induction assumption, gives the reduction of oscillationThe final choice of <italic>c</italic> is made to ensure that (##FORMU##471##4.7##) does not happen, independent of <italic>j</italic>. This hinges upon the following tail estimateTo prove this, we first rewrite the tail as follows:Here, we denoted for short. The first integral is estimated by using the definition of . Namely, for any ,Whereas the second integral is estimated by using the simple fact that, for ,Namely, for any ,Combine them and further estimate the tail byThe summation in the last display is bounded by if we restrict the choice of byConsequently, the tail estimate (##FORMU##474##4.9##) is proven and (##FORMU##471##4.7##) does not happen, if we choose <italic>c</italic> to verifyThe final choice of <italic>c</italic> is made out of the smaller one of (##FORMU##448##4.5##) and (##FORMU##488##4.10##).</p>", "<p id=\"Par63\">Let for some to verify the set inclusionNote that the choice of in the last display may have been adjusted from the previous one in (##FORMU##451##4.6##) due to the possible change of <italic>c</italic> made in (##FORMU##488##4.10##). The final choice of isAs a result of the inclusion (##FORMU##491##4.11##) and (##FORMU##473##4.8##) we obtainwhich completes the induction argument. From now on, the deduction of a Hölder modulus of continuity becomes quite standard; cf. [##UREF##8##9##, Chapter III, Proposition 3.1].</p>", "<title>Proof of theorem <xref ref-type=\"sec\" rid=\"FPar1\">1.1</xref>: </title>", "<p id=\"Par64\">As in the previous section, we first introduce ,and for and some to be determined. By properly shrinking <italic>R</italic>, we may assume that and setWithout loss of generality, we take .</p>", "<p id=\"Par65\">Then the following intrinsic relation holds:As before, the choice of is made to ensure (##FORMU##505##5.1##), on which the subsequent arguments are based.</p>", "<p id=\"Par66\">Unlike the case , an expansion of positivity for the case requires additional technical complication. To deal with this case, we instead refine DiBenedetto’s argument in [##UREF##9##10##]: On one hand, the tail needs a great care in this intrinsic scaling scenario; on the other hand, we dispense with any kind of logarithmic estimate and just rely on the energy estimate.</p>", "<title>The first alternative</title>", "<p id=\"Par67\">In this section, we work with <italic>u</italic> as a super-solution near its infimum. Furthermore, we assumeThe other case , will be considered later.</p>", "<p id=\"Par68\">Suppose verify that for the moment (which will be confirmed in (##FORMU##538##5.11##) and (##FORMU##540##5.12##)), and for some , there holdswhere is the constant determined in Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref> (with ) in terms of the data. According to Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref> with , and , we have eitherorTo proceed, we restrict <italic>c</italic> so that (##FORMU##520##5.4##) does not happen. Indeed, since, according to the definition of , the tail can be easily estimated by (cf. (##FORMU##445##4.4##))we imposeNote that this is not the final choice of <italic>c</italic> yet and it is subject to further smallness requirements in the course of the proof.</p>", "<p id=\"Par69\">The pointwise estimate in (##FORMU##521##5.5##) at allows us to apply Lemma <xref ref-type=\"sec\" rid=\"FPar12\">3.2</xref> with and obtain that for some free parameter , eitherorThe number is chosen to fulfillIn this way, the estimate (##FORMU##529##5.8##) can be claimed up to and yields the reduction of oscillationNote that in the dependence of , the constants <italic>a</italic> and <italic>c</italic> are still to be determined. For the moment, let us suppose <italic>c</italic> has been fixed. We then select <italic>a</italic> to ensure (##FORMU##528##5.7##) does not occur. In fact, since the tail is bounded by as before, we imposewhere we have employed the selection of in (##FORMU##531##5.9##). Consequently, the above display yields the relation of <italic>a</italic> and <italic>c</italic>, that is,Hence, by this choice, the estimate (##FORMU##528##5.7##) does not occur and the reduction of oscillation (##FORMU##533##5.10##) actually holds.</p>", "<p id=\"Par70\">Moreover, the assumption made at the beginning is verified, if we use (##FORMU##538##5.11##) and further restrict <italic>c</italic> byThe number <italic>a</italic> will be eventually fixed via (##FORMU##538##5.11##), once we determine <italic>c</italic> in the end.</p>", "<title>The second alternative</title>", "<p id=\"Par71\">In this section, we work with <italic>u</italic> as a sub-solution near its supremum. Suppose (##FORMU##514##5.3##) does not hold for any . Due to (##FORMU##509##5.2##), this can be rephrased asBased on this, it is not hard to find some , such thatIndeed, if the above inequality were not to hold for any <italic>s</italic> in the given interval, thenwhich would yield a contradiction.</p>", "<p id=\"Par72\">Starting from this measure theoretical information, we may apply Lemma <xref ref-type=\"sec\" rid=\"FPar14\">3.3</xref> (with and ) to obtain and depending on the data and , such that, for some free parameter , eitherorThe number is chosen to satisfyIn this way, the measure theoretical information (##FORMU##553##5.14##) can be claimed up to the time level . Whereas the constant <italic>c</italic> is again chosen so small that (##FORMU##552##5.13##) does not happen. Indeed, according to the definition of , just like in (##FORMU##445##4.4##) the tail can be easily estimated byA simple calculation as before then givesConsequently, the measure theoretical information (##FORMU##553##5.14##) yieldsthanks to the arbitrariness of .</p>", "<p id=\"Par73\">Given (##FORMU##560##5.16##), we want to apply Lemma <xref ref-type=\"sec\" rid=\"FPar16\">3.4</xref> with , and next. To this end, we first let be fixed in Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref> (with ) and choose to satisfyThis choice is possible because of Lemma <xref ref-type=\"sec\" rid=\"FPar16\">3.4</xref> is independent of . Then we use (##FORMU##538##5.11##) and restrict <italic>c</italic> further to satisfyIn this way, the measure theoretical information (##FORMU##560##5.16##) gives thatwhich allows us to implement Lemma <xref ref-type=\"sec\" rid=\"FPar16\">3.4</xref>. Namely, we have eitherorBy Lemma <xref ref-type=\"sec\" rid=\"FPar10\">3.1</xref> (with ), the last display yieldswhich in turn gives the reduction of oscillationOnce again, we may restrict the choice of <italic>c</italic> to ensure that (##FORMU##573##5.18##) does not happen.Indeed, according to the definition of , just like in (##FORMU##445##4.4##) the tail can be easily estimated byBy a similar calculation as before, this amounts to requiringCombining (##FORMU##533##5.10##) and (##FORMU##577##5.19##), we arrive atwhereNow, set and . To prepare the induction, we need to verify the set inclusionThis, by the choice of <italic>a</italic> in (##FORMU##538##5.11##), amounts to further requiring the smallness of <italic>c</italic>.</p>", "<p id=\"Par74\">As a result of this inclusion and (##FORMU##581##5.21##), we obtainwhich takes the place of (##FORMU##505##5.1##) in the next stage. Note that this oscillation estimate also takes into account the reverse case of (##FORMU##509##5.2##).</p>", "<title>The induction</title>", "<p id=\"Par75\">Now we may proceed by induction.</p>", "<p id=\"Par76\">Suppose up to , we have builtThe induction argument will show that the above oscillation estimate continues to hold for the -th step.</p>", "<p id=\"Par77\">Like in the proof for , we can repeat all the previous arguments, which now are adapted with , , , , , etc. In the end, we have a reduction of oscillation parallel with (##FORMU##581##5.21##), that is,Now, setting and , it is straightforward to verify the set inclusionwhich, by (##FORMU##596##5.22##), impliesA key step lies in determining <italic>c</italic> as done in (##FORMU##524##5.6##), (##FORMU##559##5.15##), (##FORMU##540##5.12##), (##FORMU##571##5.17##) and (##FORMU##580##5.20##), such that the alternative involving the tail, along the course of the arguments, does not really occur and hence (##FORMU##596##5.22##) can be reached. This hinges upon the following estimate of the tail:The computations leading to the above tail estimate can be performed as those leading to (##FORMU##474##4.9##). We omit the details to avoid repetition. After the number <italic>c</italic> is determined independent of <italic>j</italic>, the number <italic>a</italic> is finally chosen via the relation (##FORMU##538##5.11##). Hence the induction is completed and the derivation of a Hölder modulus of continuity follows.</p>" ]	[ "<title>Appendix A. Fractional Sobolev inequalities</title>", "<p id=\"Par80\">Note that the definition of the space in Sect. <xref rid=\"Sec3\" ref-type=\"sec\">1.2</xref> is also valid for , though we will not use it. An elementary proof of the following result can be retrieved from [##UREF##13##14##, Theorem 6.5].</p>", "<title>Proposition A.1</title>", "<p id=\"Par81\">Let and satisfying . For any measurable and compactly supported function , there holdsfor some positive constant .</p>", "<p>It is our intention to circumvent a more advanced theory of function spaces, extension domains, etc. and keep this section as elementary as possible.</p>", "<p>The following local version is a direct consequence of Proposition <xref ref-type=\"sec\" rid=\"FPar20\">A.1</xref>. Here and in the sequel, we omit the reference to the center of a ball .</p>", "<title>Proposition A.2</title>", "<p id=\"Par84\">Let and . For any function that is compactly supported in with some , there holdsfor some positive constant , where</p>", "<title>Proof</title>", "<p id=\"Par85\">It suffices to show the inequality for , thanks to its scaling invariance in <italic>R</italic>. Since <italic>u</italic> is compactly supported in , we may view it as a function in upon zero extension. This fact is verified by a simple calculation (similar to what follows). First consider the case . According to Proposition <xref ref-type=\"sec\" rid=\"FPar20\">A.1</xref>, we estimateIn the last line, we used the fact that (recalling ) and . Consequently, the desired inequality for any in the interval follows from an application of Hölder’s inequality. Note also the constant <italic>C</italic> is actually independent of in this case.</p>", "<p id=\"Par86\">Next, we consider the case . A first observation is that for any . Quantitatively, we estimateNow we select , which verifies , and apply (##FORMU##623##A.1##) in , together with the above observation, to conclude. </p>", "<p>Based on Proposition <xref ref-type=\"sec\" rid=\"FPar21\">A.2</xref>, the following parabolic imbedding is in order. It plays an essential role in proving DeGiorgi type lemmas.</p>", "<title>Proposition A.3</title>", "<p id=\"Par88\">Let , andFor any functionwhich is compactly supported in for some and for a.e. , there holdsfor some positive constant , where</p>", "<title>Proof</title>", "<p id=\"Par89\">The inequality is scaling invariant in <italic>R</italic>. Hence, it suffices to show it for . An application of Hölder’s inequality, followed by Proposition <xref ref-type=\"sec\" rid=\"FPar21\">A.2</xref> and the choice of , yields thatThis finishes the proof. </p>", "<title>Appendix B: Time mollification</title>", "<p id=\"Par90\">The time derivative of a weak solution in general does not exist in the Sobolev sense. On the other hand, it is desirable to use the solution in a testing function when we derive the energy estimate in Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref>. To overcome this well-organized difficulty, we find the following mollifier quite convenient. Namely, we introduce for any ,Properties of this mollification can for instance be found in [##UREF##19##20##, Lemma 2.2]. In particular, by direct differentiation, we obtain the following identities:They are paired by the identityAnother fact, we will rely on is that, if for some , then , and moreover, as we haveNow we take on a rigorous justification of formal calculations in Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref>. By working with a closed interval in (0, <italic>T</italic>), we may assume with no loss of generality. For ease of notation, we denoteLet the cutoff function be as in Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref> and introduce to be a Lipschitz approximation of . Namely, in , outside , while linearly interpolated otherwise. In the weak formulation (##FORMU##60##1.7##), we take the testing functionwe obtainThe first term in (##FORMU##670##B.3##) can be written as, recalling (##FORMU##653##B.1##),On the right-hand side of the last display, the second term is discarded due to its non-negative contribution, whereas the third term converges to 0 as owing to (##FORMU##659##B.2##). For the first term, we integrate by parts in time, let and then let , to obtainThese are the last terms on the left/right-hand side of the energy estimate in Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref>.</p>", "<p id=\"Par91\">The next goal is to show that the second integral in (##FORMU##670##B.3##) converges toif we send , whereOnce this is shown, we will justify the formal calculations in the proof of Proposition <xref ref-type=\"sec\" rid=\"FPar7\">2.1</xref>.</p>", "<p id=\"Par92\">For this purpose, we take the difference between the two integrals and split the obtained integral into two parts, that is,Note that we used for in defining . We then show that and converge to 0 after sending .</p>", "<p id=\"Par93\">For , we first claim thatfor some constant . This uniform bound allows us to extract a weakly convergent subsequence (still labeled by <italic>h</italic>). Since, up to a subsequence, a.e. in , we obtain that, up to a subsequence,Consequently, we have in view of this weak convergence and the fact thatTo prove (##FORMU##687##B.4##), the numerator of the integrand needs to be controlled. Using the triangle inequality and the fact that and are bounded by 1, we computefor some proper . Next, we estimate the first term on the right-hand side of the last display by Hölder’s inequality:A time integration of the above estimate, followed by Fubini’s theorem, gives thatThus we deduce thatAnalogously, for the second term, we may first estimateand then,Combining (##FORMU##700##B.5##) and (##FORMU##702##B.6##), we have shown (##FORMU##687##B.4##).</p>", "<p id=\"Par94\">To deal with , we first notice that for and . Hence, we estimateNow we easily see that as due to (##FORMU##659##B.2##).</p>", "<title>Acknowledgements</title>", "<p>This work was supported by the FWF-Project P36272-N “On the Stefan type problems\" and the FWF-Project P31956-N32 \"Doubly nonlinear evolution equations”.</p>", "<title>Funding</title>", "<p>Open access funding provided by Paris Lodron University of Salzburg.</p>", "<title>Data availability</title>", "<p>Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.</p>" ]	[]	[]	[ "<disp-formula id=\"Equ1\"><label>1.1</label><alternatives><tex-math id=\"M1\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\partial _t u + \\mathscr {L} u=0\\quad \\text {weakly in}\\> E_T, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M2\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mi>u</mml:mi><mml:mo>+</mml:mo><mml:mi mathvariant=\"script\">L</mml:mi><mml:mi>u</mml:mi><mml:mo>=</mml:mo><mml:mn>0</mml:mn><mml:mspace width=\"1em\"/><mml:mtext>weakly in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq1\"><alternatives><tex-math id=\"M3\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T=E\\times (0,T]$$\\end{document}</tex-math><mml:math id=\"M4\"><mml:mrow><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mi>E</mml:mi><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq2\"><alternatives><tex-math id=\"M5\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E\\subset \\mathbb {R}^N$$\\end{document}</tex-math><mml:math id=\"M6\"><mml:mrow><mml:mi>E</mml:mi><mml:mo>⊂</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq3\"><alternatives><tex-math id=\"M7\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$T>0$$\\end{document}</tex-math><mml:math id=\"M8\"><mml:mrow><mml:mi>T</mml:mi><mml:mo>></mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq4\"><alternatives><tex-math id=\"M9\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathscr {L}$$\\end{document}</tex-math><mml:math id=\"M10\"><mml:mi mathvariant=\"script\">L</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ2\"><label>1.2</label><alternatives><tex-math id=\"M11\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathscr {L}u(x,t)=\\mathrm{P.V.}\\int _{\\mathbb {R}^N} K(x,y,t)\\big \|u(x,t) - u(y,t)\\big \|^{p-2} \\big (u(x,t) - u(y,t)\\big )\\,\\textrm{d}y, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M12\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi mathvariant=\"script\">L</mml:mi><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mi mathvariant=\"normal\">P</mml:mi><mml:mo>.</mml:mo><mml:mi mathvariant=\"normal\">V</mml:mi><mml:mo>.</mml:mo></mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq5\"><alternatives><tex-math id=\"M13\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p>1$$\\end{document}</tex-math><mml:math id=\"M14\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq6\"><alternatives><tex-math id=\"M15\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathrm{P.V.}$$\\end{document}</tex-math><mml:math id=\"M16\"><mml:mrow><mml:mi mathvariant=\"normal\">P</mml:mi><mml:mo>.</mml:mo><mml:mi mathvariant=\"normal\">V</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq7\"><alternatives><tex-math id=\"M17\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K:\\mathbb {R}^N\\times \\mathbb {R}^N\\times (0,T]\\rightarrow [0,\\infty )$$\\end{document}</tex-math><mml:math id=\"M18\"><mml:mrow><mml:mi>K</mml:mi><mml:mo>:</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo>×</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:mo stretchy=\"false\">→</mml:mo><mml:mrow><mml:mo stretchy=\"false\">[</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>∞</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ3\"><label>1.3</label><alternatives><tex-math id=\"M19\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\frac{C_o}{\|x-y\|^{N+sp}}\\le K(x,y,t)\\equiv K(y,x,t)\\le \\frac{C_1}{\|x-y\|^{N+sp}}\\quad \\text {a.e.}\\> x,\\,y\\in \\mathbb {R}^N, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M20\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mfrac><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>≤</mml:mo><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≡</mml:mo><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"1em\"/><mml:mtext>a.e.</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mi>y</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq8\"><alternatives><tex-math id=\"M21\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$C_o$$\\end{document}</tex-math><mml:math id=\"M22\"><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq9\"><alternatives><tex-math id=\"M23\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$C_1$$\\end{document}</tex-math><mml:math id=\"M24\"><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq10\"><alternatives><tex-math id=\"M25\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$s\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M26\"><mml:mrow><mml:mi>s</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq11\"><alternatives><tex-math id=\"M27\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M28\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq12\"><alternatives><tex-math id=\"M29\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma }$$\\end{document}</tex-math><mml:math id=\"M30\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq13\"><alternatives><tex-math id=\"M31\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M32\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq14\"><alternatives><tex-math id=\"M33\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p>1$$\\end{document}</tex-math><mml:math id=\"M34\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq15\"><alternatives><tex-math id=\"M35\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M36\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq16\"><alternatives><tex-math id=\"M37\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma }>1$$\\end{document}</tex-math><mml:math id=\"M38\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq17\"><alternatives><tex-math id=\"M39\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\beta \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M40\"><mml:mrow><mml:mi>β</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq18\"><alternatives><tex-math id=\"M41\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0<\\varrho<R<\\widetilde{R}$$\\end{document}</tex-math><mml:math id=\"M42\"><mml:mrow><mml:mn>0</mml:mn><mml:mo><</mml:mo><mml:mi>ϱ</mml:mi><mml:mo><</mml:mo><mml:mi>R</mml:mi><mml:mo><</mml:mo><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ54\"><alternatives><tex-math id=\"M43\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{(x_o,t_o)+Q_{\\varrho }({\\varvec{\\omega }}^{2-p})} u\\le {\\varvec{\\gamma }} {\\varvec{\\omega }} \\left( \\frac{\\varrho }{R}\\right) ^{\\beta }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M44\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mi>β</mml:mi></mml:msup><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq19\"><alternatives><tex-math id=\"M45\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)+Q_{R}(\\varvec{\\omega }^{2-p})\\subset (x_o,t_o)+Q_{\\widetilde{R}}$$\\end{document}</tex-math><mml:math id=\"M46\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq20\"><alternatives><tex-math id=\"M47\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M48\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ55\"><alternatives><tex-math id=\"M49\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\omega }=2\\mathop {\\mathrm{ess\\,sup}}\\limits _{(x_o,t_o)+Q_{\\widetilde{R}}}\|u\| +\\textrm{Tail}\\big (u; (x_o,t_o)+Q_{\\widetilde{R}}\\big ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M50\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>=</mml:mo><mml:mn>2</mml:mn><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:mrow></mml:munder><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>;</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq21\"><alternatives><tex-math id=\"M51\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathbb {R}^N\\times (0,T)$$\\end{document}</tex-math><mml:math id=\"M52\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq22\"><alternatives><tex-math id=\"M53\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M54\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq23\"><alternatives><tex-math id=\"M55\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathbb {R}^N\\times (-\\infty ,T)$$\\end{document}</tex-math><mml:math id=\"M56\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>∞</mml:mi><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ56\"><alternatives><tex-math id=\"M57\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\frac{C_o \\chi _{\\{\|x-y\|\\le 1\\}}}{\|x-y\|^{N+sp}}\\le K(x,y,t)\\equiv K(y,x,t)\\le \\frac{C_1}{\|x-y\|^{N+sp}}\\quad \\text {a.e.}\\> x,\\,y\\in \\mathbb {R}^N. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M58\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mfrac><mml:mrow><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msub><mml:mi>χ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>≤</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>≤</mml:mo><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≡</mml:mo><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"1em\"/><mml:mtext>a.e.</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mi>y</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq24\"><alternatives><tex-math id=\"M59\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathscr {L}$$\\end{document}</tex-math><mml:math id=\"M60\"><mml:mi mathvariant=\"script\">L</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq25\"><alternatives><tex-math id=\"M61\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p=2$$\\end{document}</tex-math><mml:math id=\"M62\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq26\"><alternatives><tex-math id=\"M63\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p=2$$\\end{document}</tex-math><mml:math id=\"M64\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq27\"><alternatives><tex-math id=\"M65\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p\\ne 2$$\\end{document}</tex-math><mml:math id=\"M66\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>≠</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq28\"><alternatives><tex-math id=\"M67\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p>2$$\\end{document}</tex-math><mml:math id=\"M68\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>></mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq29\"><alternatives><tex-math id=\"M69\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$ 2\|x-y\|^{-N-sp}$$\\end{document}</tex-math><mml:math id=\"M70\"><mml:msup><mml:mrow><mml:mn>2</mml:mn><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:mi>N</mml:mi><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq30\"><alternatives><tex-math id=\"M71\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p\\ge 2$$\\end{document}</tex-math><mml:math id=\"M72\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>≥</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq31\"><alternatives><tex-math id=\"M73\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p>1$$\\end{document}</tex-math><mml:math id=\"M74\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq32\"><alternatives><tex-math id=\"M75\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p=2$$\\end{document}</tex-math><mml:math id=\"M76\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq33\"><alternatives><tex-math id=\"M77\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p=2$$\\end{document}</tex-math><mml:math id=\"M78\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq34\"><alternatives><tex-math id=\"M79\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{R_i\\}$$\\end{document}</tex-math><mml:math id=\"M80\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq35\"><alternatives><tex-math id=\"M81\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{\\varvec{\\omega }_{i}\\}$$\\end{document}</tex-math><mml:math id=\"M82\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ4\"><label>1.4</label><alternatives><tex-math id=\"M83\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{array}{c} \\displaystyle \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{R_{i}}(\\varvec{\\omega }_{i}^{2-p})}u\\le \\varvec{\\omega }_{i}. \\end{array} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M84\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ5\"><label>1.5</label><alternatives><tex-math id=\"M85\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\textrm{Tail}\\big (\\big (u - \\varvec{\\mu }_i^{\\pm }\\big )_{\\pm }; Q_{R_{i}}\\big (\\varvec{\\omega }_{i}^{2-p}\\big )\\big ) \\le \\varvec{\\gamma }\\varvec{\\omega }_i, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M86\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>i</mml:mi><mml:mo>±</mml:mo></mml:msubsup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq36\"><alternatives><tex-math id=\"M87\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$ \\varvec{\\mu }_i^{\\pm }$$\\end{document}</tex-math><mml:math id=\"M88\"><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>i</mml:mi><mml:mo>±</mml:mo></mml:msubsup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq37\"><alternatives><tex-math id=\"M89\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_{R_{i}}(\\varvec{\\omega }_{i}^{2-p})$$\\end{document}</tex-math><mml:math id=\"M90\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ57\"><alternatives><tex-math id=\"M91\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} (1.4)_{i}^{i+1}\\> \\leftrightarrows \\> (1.5)_{i}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M92\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1.4</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>i</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mspace width=\"0.222222em\"/><mml:mo>⇆</mml:mo><mml:mspace width=\"0.222222em\"/><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1.5</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>i</mml:mi></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq38\"><alternatives><tex-math id=\"M93\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p\\ne 2$$\\end{document}</tex-math><mml:math id=\"M94\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>≠</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq39\"><alternatives><tex-math id=\"M95\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p>1$$\\end{document}</tex-math><mml:math id=\"M96\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq40\"><alternatives><tex-math id=\"M97\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$s\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M98\"><mml:mrow><mml:mi>s</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq41\"><alternatives><tex-math id=\"M99\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$W^{s,p}(\\mathbb {R}^N)$$\\end{document}</tex-math><mml:math id=\"M100\"><mml:mrow><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ58\"><alternatives><tex-math id=\"M101\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} W^{s,p}(\\mathbb {R}^N):=\\bigg \\{v \\in L^p(\\mathbb {R}^N):\\, \\int _{\\mathbb {R}^N}\\int _{\\mathbb {R}^N}\\frac{\|v(x) - v(y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y<\\infty \\bigg \\}, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M102\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>v</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>:</mml:mo><mml:mspace width=\"0.166667em\"/><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>v</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>v</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mo><</mml:mo><mml:mi>∞</mml:mi><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ59\"><alternatives><tex-math id=\"M103\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Vert v\\Vert _{W^{s,p}(\\mathbb {R}^N)}:=\\left( \\int _{\\mathbb {R}^N}\|v\|^p\\,\\textrm{d}x\\right) ^{\\frac{1}{p}} + \\left( \\int _{\\mathbb {R}^N}\\int _{\\mathbb {R}^N}\\frac{\|v(x)-v(y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\right) ^{\\frac{1}{p}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M104\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mrow><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>v</mml:mi><mml:mo stretchy=\"false\">‖</mml:mo></mml:mrow><mml:mrow><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>v</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced><mml:mfrac><mml:mn>1</mml:mn><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:mo>+</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>v</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>v</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced><mml:mfrac><mml:mn>1</mml:mn><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq42\"><alternatives><tex-math id=\"M105\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$W^{s,p}(E)$$\\end{document}</tex-math><mml:math id=\"M106\"><mml:mrow><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>E</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq43\"><alternatives><tex-math id=\"M107\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E\\subset \\mathbb {R}^N$$\\end{document}</tex-math><mml:math id=\"M108\"><mml:mrow><mml:mi>E</mml:mi><mml:mo>⊂</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ60\"><alternatives><tex-math id=\"M109\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} W^{s,p}_o(E):=\\bigg \\{v\\in W^{s,p}(\\mathbb {R}^N):\\, v=0\\>\\>\\text {a.e. in}\\>\\mathbb {R}^N\\setminus E \\bigg \\}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M110\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msubsup><mml:mi>W</mml:mi><mml:mi>o</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>E</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>v</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>:</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mi>v</mml:mi><mml:mo>=</mml:mo><mml:mn>0</mml:mn><mml:mspace width=\"0.222222em\"/><mml:mspace width=\"0.222222em\"/><mml:mtext>a.e. in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:mi>E</mml:mi><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq44\"><alternatives><tex-math id=\"M111\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$u:\\,\\mathbb {R}^N\\times (0,T]\\rightarrow \\mathbb {R}$$\\end{document}</tex-math><mml:math id=\"M112\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>:</mml:mo><mml:mspace width=\"0.166667em\"/><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:mo stretchy=\"false\">→</mml:mo><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ61\"><alternatives><tex-math id=\"M113\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u\\in C_{{\\text {loc}}}\\big (0,T;L^2_{{\\text {loc}}}(E)\\big )\\cap L^p_{{\\text {loc}}}\\big (0,T; W^{s,p}_{{\\text {loc}}}(E)\\big ) \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M114\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mtext>loc</mml:mtext></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo>;</mml:mo><mml:msubsup><mml:mi>L</mml:mi><mml:mtext>loc</mml:mtext><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>E</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msubsup><mml:mi>L</mml:mi><mml:mtext>loc</mml:mtext><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo>;</mml:mo><mml:msubsup><mml:mi>W</mml:mi><mml:mtext>loc</mml:mtext><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>E</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq45\"><alternatives><tex-math id=\"M115\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathcal {K}\\subset E$$\\end{document}</tex-math><mml:math id=\"M116\"><mml:mrow><mml:mi mathvariant=\"script\">K</mml:mi><mml:mo>⊂</mml:mo><mml:mi>E</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq46\"><alternatives><tex-math id=\"M117\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$[t_1,t_2]\\subset (0,T]$$\\end{document}</tex-math><mml:math id=\"M118\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">[</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ6\"><label>1.6</label><alternatives><tex-math id=\"M119\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,sup}}\\limits _{t_1<t<t_2}\\int _{\\mathbb {R}^N}\\frac{\|u(x,t)\|^{p-1}}{1+\|x\|^{N+sp}}\\,\\textrm{d}x<\\infty \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M120\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mn>1</mml:mn><mml:mo>+</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo><</mml:mo><mml:mi>∞</mml:mi></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ7\"><label>1.7</label><alternatives><tex-math id=\"M121\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned} \\int _{\\mathcal {K}}&u\\varphi \\,\\textrm{d}x\\bigg \|_{t_1}^{t_2} -\\int _{t_1}^{t_2}\\int _{\\mathcal {K}} u\\partial _t\\varphi \\, \\textrm{d}x\\textrm{d}t+\\int _{t_1}^{t_2} \\mathscr {E}\\big (u(\\cdot , t), \\varphi (\\cdot , t)\\big )\\,\\textrm{d}t\\le (\\ge )0 \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M122\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msub><mml:mo>∫</mml:mo><mml:mi mathvariant=\"script\">K</mml:mi></mml:msub></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mi>u</mml:mi><mml:mi>φ</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:msubsup><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:msubsup><mml:mo>-</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:mi mathvariant=\"script\">K</mml:mi></mml:msub><mml:mi>u</mml:mi><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mi>φ</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:msubsup><mml:mi mathvariant=\"script\">E</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>≥</mml:mo><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>0</mml:mn></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ62\"><alternatives><tex-math id=\"M123\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathscr {E}:=\\int _{\\mathbb {R}^N}\\int _{\\mathbb {R}^N}K(x,y,t)\\big \|u(x,t) - u(y,t)\\big \|^{p-2} \\big (u(x,t) - u(y,t)\\big )\\big (\\varphi (x,t) - \\varphi (y,t)\\big )\\,\\textrm{d}y\\textrm{d}x\\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M124\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi mathvariant=\"script\">E</mml:mi><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ8\"><label>1.8</label><alternatives><tex-math id=\"M125\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varphi \\in W^{1,2}_{{\\text {loc}}}\\big (0,T;L^2(\\mathcal {K})\\big )\\cap L^p_{{\\text {loc}}}\\big (0,T;W_o^{s,p}(\\mathcal {K}) \\big ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M126\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>φ</mml:mi><mml:mo>∈</mml:mo><mml:msubsup><mml:mi>W</mml:mi><mml:mtext>loc</mml:mtext><mml:mrow><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo>;</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi mathvariant=\"script\">K</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msubsup><mml:mi>L</mml:mi><mml:mtext>loc</mml:mtext><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo>;</mml:mo><mml:msubsup><mml:mi>W</mml:mi><mml:mi>o</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi mathvariant=\"script\">K</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq47\"><alternatives><tex-math id=\"M127\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$W_o^{s,p}(\\mathcal {K})$$\\end{document}</tex-math><mml:math id=\"M128\"><mml:mrow><mml:msubsup><mml:mi>W</mml:mi><mml:mi>o</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi mathvariant=\"script\">K</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq48\"><alternatives><tex-math id=\"M129\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varphi (\\cdot , t)\\in W^{s,p}(\\mathbb {R}^N)$$\\end{document}</tex-math><mml:math id=\"M130\"><mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>∈</mml:mo><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq49\"><alternatives><tex-math id=\"M131\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathcal {K}$$\\end{document}</tex-math><mml:math id=\"M132\"><mml:mi mathvariant=\"script\">K</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq50\"><alternatives><tex-math id=\"M133\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$L^\\infty $$\\end{document}</tex-math><mml:math id=\"M134\"><mml:msup><mml:mi>L</mml:mi><mml:mi>∞</mml:mi></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq51\"><alternatives><tex-math id=\"M135\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$L^1$$\\end{document}</tex-math><mml:math id=\"M136\"><mml:msup><mml:mi>L</mml:mi><mml:mn>1</mml:mn></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq52\"><alternatives><tex-math id=\"M137\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_\\varrho (x_o)$$\\end{document}</tex-math><mml:math id=\"M138\"><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq53\"><alternatives><tex-math id=\"M139\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho $$\\end{document}</tex-math><mml:math id=\"M140\"><mml:mi>ϱ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq54\"><alternatives><tex-math id=\"M141\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$x_o$$\\end{document}</tex-math><mml:math id=\"M142\"><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq55\"><alternatives><tex-math id=\"M143\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathbb {R}^N$$\\end{document}</tex-math><mml:math id=\"M144\"><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ63\"><alternatives><tex-math id=\"M145\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left\\{ \\begin{aligned} (x_o,t_o)+Q_\\varrho (\\theta )&:=K_{\\varrho }(x_o)\\times (t_o-\\theta \\varrho ^{sp},t_o),\\\\ (x_o,t_o)+Q(R,S)&:=K_R(x_o)\\times (t_o-S,t_o), \\end{aligned}\\right. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M146\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mfenced open=\"{\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow/><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq56\"><alternatives><tex-math id=\"M147\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)$$\\end{document}</tex-math><mml:math id=\"M148\"><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq57\"><alternatives><tex-math id=\"M149\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta =1$$\\end{document}</tex-math><mml:math id=\"M150\"><mml:mrow><mml:mi>θ</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ9\"><label>1.9</label><alternatives><tex-math id=\"M151\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\textrm{Tail}\\big (u; Q(R,S)\\big ):= \\mathop {\\mathrm{ess\\,sup}}\\limits _{t_o-S<t<t_o}\\left( R^{sp}\\int _{\\mathbb {R}^N\\setminus K_R(x_o)}\\frac{\|u(x,t)\|^{p-1}}{\|x-x_o\|^{N+sp}}\\,\\textrm{d}x\\right) ^{\\frac{1}{p-1}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M152\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>;</mml:mo><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:mrow></mml:munder><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo></mml:mrow><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq58\"><alternatives><tex-math id=\"M153\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q(R,S)\\subset E_T$$\\end{document}</tex-math><mml:math id=\"M154\"><mml:mrow><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq59\"><alternatives><tex-math id=\"M155\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$k\\in \\mathbb {R}$$\\end{document}</tex-math><mml:math id=\"M156\"><mml:mrow><mml:mi>k</mml:mi><mml:mo>∈</mml:mo><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ64\"><alternatives><tex-math id=\"M157\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} (u-k)_+=\\max \\{u-k,0\\}, \\qquad (u-k)_-=\\max \\{-(u-k),0\\}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M158\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:mo>=</mml:mo><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"2em\"/><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>=</mml:mo><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mo>-</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq60\"><alternatives><tex-math id=\"M159\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$``\\pm \"$$\\end{document}</tex-math><mml:math id=\"M160\"><mml:mrow><mml:mo>`</mml:mo><mml:mo>`</mml:mo><mml:mo>±</mml:mo><mml:mo>\"</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq61\"><alternatives><tex-math id=\"M161\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$``\\mp \"$$\\end{document}</tex-math><mml:math id=\"M162\"><mml:mrow><mml:mo>`</mml:mo><mml:mo>`</mml:mo><mml:mo>∓</mml:mo><mml:mo>\"</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq62\"><alternatives><tex-math id=\"M163\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M164\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq63\"><alternatives><tex-math id=\"M165\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma } (C_o,C_1,p)>0$$\\end{document}</tex-math><mml:math id=\"M166\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>></mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq64\"><alternatives><tex-math id=\"M167\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q(R,S) \\subset E_T$$\\end{document}</tex-math><mml:math id=\"M168\"><mml:mrow><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq65\"><alternatives><tex-math id=\"M169\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$k\\in \\mathbb {R}$$\\end{document}</tex-math><mml:math id=\"M170\"><mml:mrow><mml:mi>k</mml:mi><mml:mo>∈</mml:mo><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq66\"><alternatives><tex-math id=\"M171\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta (\\cdot ,t)$$\\end{document}</tex-math><mml:math id=\"M172\"><mml:mrow><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq67\"><alternatives><tex-math id=\"M173\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$ K_{R} $$\\end{document}</tex-math><mml:math id=\"M174\"><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq68\"><alternatives><tex-math id=\"M175\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t\\in (t_o-S,t_o)$$\\end{document}</tex-math><mml:math id=\"M176\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ65\"><alternatives><tex-math id=\"M177\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned}&\\int _{t_o-S}^{t_o}\\int _{K_R}\\int _{K_R}\\min \\big \\{\\zeta ^p(x,t),\\zeta ^p(y,t)\\big \\} \\frac{\|w_\\pm (x,t) - w_\\pm (y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\qquad +\\iint _{Q(R,S)} \\zeta ^p w_{\\pm }(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\int _{ K_R} \\frac{w^{p-1}_\\mp (y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) +\\int _{K_R}\\zeta ^p w^2_{\\pm }(x,t)\\,\\textrm{d}x\\bigg \|_{t_o-S}^{t_o}\\\\&\\quad \\le \\varvec{\\gamma }\\int _{t_o-S}^{t_o}\\int _{K_R}\\int _{K_R}\\max \\big \\{w^p_{\\pm }(x,t), w^p_{\\pm }(y,t)\\big \\} \\frac{\|\\zeta (x,t) - \\zeta (y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\qquad +\\varvec{\\gamma }\\iint _{Q(R,S)} \\zeta ^pw_{\\pm }(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in {\\text {supp}}\\zeta (\\cdot , t)\\\\ t\\in (t_o-S,t_o) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_R}\\frac{ w_{\\pm }^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\qquad + \\iint _{Q(R,S)} \|\\partial _t\\zeta ^p\|w_{\\pm }^2(x,t)\\,\\textrm{d}x\\textrm{d}t. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M178\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">min</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:msup><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"2em\"/><mml:mo>+</mml:mo><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>∓</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced><mml:mo>+</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msubsup><mml:mi>w</mml:mi><mml:mo>±</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:msubsup><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>±</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mo>±</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"2em\"/><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:mtext>supp</mml:mtext><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>±</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"2em\"/><mml:mo>+</mml:mo><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>±</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq69\"><alternatives><tex-math id=\"M179\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$w=u-k$$\\end{document}</tex-math><mml:math id=\"M180\"><mml:mrow><mml:mi>w</mml:mi><mml:mo>=</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq70\"><alternatives><tex-math id=\"M181\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varphi =w_+\\zeta ^p$$\\end{document}</tex-math><mml:math id=\"M182\"><mml:mrow><mml:mi>φ</mml:mi><mml:mo>=</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq71\"><alternatives><tex-math id=\"M183\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta $$\\end{document}</tex-math><mml:math id=\"M184\"><mml:mi>ζ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ66\"><alternatives><tex-math id=\"M185\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned}&\\int _{t_o-S}^{t_o}\\int _{\\mathbb {R}^N}\\int _{\\mathbb {R}^N} \\big \|u(x,t) - u(y,t)\\big \|^{p-2}\\big (u(x,t) - u(y,t)\\big )\\big (\\varphi (x,t) - \\varphi (y,t)\\big )\\,\\textrm{d}\\mu \\\\&\\quad =\\int _{t_o-S}^{t_o}\\int _{K_R}\\int _{K_R} \\big \|u(x,t) - u(y,t)\\big \|^{p-2}\\big (u(x,t) - u(y,t)\\big )\\big (\\varphi (x,t) - \\varphi (y,t)\\big )\\,\\textrm{d}\\mu \\\\&\\qquad +2\\int _{t_o-S}^{t_o}\\int _{K_{R}}\\int _{\\mathbb {R}^N\\setminus K_R} \\big \|u(x,t) - u(y,t)\\big \|^{p-2}\\big (u(x,t) - u(y,t)\\big ) \\varphi (x,t) \\,\\textrm{d}\\mu \\\\&\\quad =:I_1+I_2, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M186\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>=</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"2em\"/><mml:mo>+</mml:mo><mml:mn>2</mml:mn><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>=</mml:mo><mml:mo>:</mml:mo><mml:msub><mml:mi>I</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq72\"><alternatives><tex-math id=\"M187\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\textrm{d}\\mu =K(x,y,t)\\textrm{d}y\\textrm{d}x\\textrm{d}t$$\\end{document}</tex-math><mml:math id=\"M188\"><mml:mrow><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi><mml:mo>=</mml:mo><mml:mi>K</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq73\"><alternatives><tex-math id=\"M189\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$A_k=\\big \\{u(\\cdot , t)>k\\big \\}\\cap K_R$$\\end{document}</tex-math><mml:math id=\"M190\"><mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>k</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq74\"><alternatives><tex-math id=\"M191\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t\\in (t_o-S,t_o)$$\\end{document}</tex-math><mml:math id=\"M192\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq75\"><alternatives><tex-math id=\"M193\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$x\\in A_k$$\\end{document}</tex-math><mml:math id=\"M194\"><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq76\"><alternatives><tex-math id=\"M195\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$y\\in K_R{\\setminus } A_k$$\\end{document}</tex-math><mml:math id=\"M196\"><mml:mrow><mml:mi>y</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ10\"><label>2.1</label><alternatives><tex-math id=\"M197\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned} \\big \|u(x,t)&- u(y,t)\\big \|^{p-2}\\big (u(x,t) - u(y,t)\\big )\\big (\\varphi (x,t) - \\varphi (y,t)\\big )\\\\&=\\big (w_+(x,t)+w_-(y,t)\\big )^{p-1} w_+(x,t)\\zeta ^p(x,t)\\\\&\\ge c(p) w_+^p(x,t) \\zeta ^p(x,t)+c(p) w^{p-1} _-(y,t)w_+(x,t)\\zeta ^p(x,t), \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M198\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≥</mml:mo><mml:mi>c</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mi>c</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq77\"><alternatives><tex-math id=\"M199\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$c=c(p)$$\\end{document}</tex-math><mml:math id=\"M200\"><mml:mrow><mml:mi>c</mml:mi><mml:mo>=</mml:mo><mml:mi>c</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq78\"><alternatives><tex-math id=\"M201\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$x,y\\in A_k$$\\end{document}</tex-math><mml:math id=\"M202\"><mml:mrow><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>y</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ11\"><label>2.2</label><alternatives><tex-math id=\"M203\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned} \\big \|u(x,t)&- u(y,t)\\big \|^{p-2}\\big (u(x,t) - u(y,t)\\big )\\big (\\varphi (x,t) - \\varphi (y,t)\\big )\\\\&\\ge \\tfrac{1}{2}\\big \|w_+(x,t)-w_+(y,t)\\big \|^{p} \\max \\big \\{\\zeta ^p(x,t), \\zeta ^p(y,t)\\big \\}\\\\&\\quad - \\varvec{\\gamma }(p)\\max \\big \\{w_+^p(x,t), w_+^p(y,t)\\big \\}\\big \|\\zeta (x,t)-\\zeta (y,t)\\big \|^p. \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M204\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>-</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq79\"><alternatives><tex-math id=\"M205\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$u(x,t)\\ge u(y,t)$$\\end{document}</tex-math><mml:math id=\"M206\"><mml:mrow><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>≥</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ12\"><label>2.3</label><alternatives><tex-math id=\"M207\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned} \\big \|u(x,t)&- u(y,t)\\big \|^{p-2}\\big (u(x,t) - u(y,t)\\big )\\big (\\varphi (x,t) - \\varphi (y,t)\\big )\\\\&=\\big (w_+(x,t)-w_+(y,t)\\big )^{p-1} \\big (w_+(x,t)\\zeta ^p(x,t) - w_+(y,t)\\zeta ^p(y,t)\\big ). \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M208\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq80\"><alternatives><tex-math id=\"M209\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta (x,t)\\ge \\zeta (y,t)$$\\end{document}</tex-math><mml:math id=\"M210\"><mml:mrow><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>≥</mml:mo><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ67\"><alternatives><tex-math id=\"M211\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big (w_+(x,t)-w_+(y,t)\\big )^{p} \\zeta ^p(x,t), \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M212\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq81\"><alternatives><tex-math id=\"M213\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta (x,t)<\\zeta (y,t)$$\\end{document}</tex-math><mml:math id=\"M214\"><mml:mrow><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo><</mml:mo><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ68\"><alternatives><tex-math id=\"M215\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big (w_+(x,t)-w_+(y,t)\\big )^{p} \\zeta ^p(y,t)-\\big (w_+(x,t)-w_+(y,t)\\big )^{p-1} w_+(x,t) \\big (\\zeta ^p(y,t) - \\zeta ^p(x,t)\\big ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M216\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ13\"><label>2.4</label><alternatives><tex-math id=\"M217\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} a^p-b^p\\le \\varepsilon a^p + \\frac{p^p}{\\varepsilon ^{p-1}}(a-b)^p\\quad \\text {for}\\> a\\ge b\\ge 0,\\>\\varepsilon >0. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M218\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>a</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mo>-</mml:mo><mml:msup><mml:mi>b</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mo>≤</mml:mo><mml:mi>ε</mml:mi><mml:msup><mml:mi>a</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mo>+</mml:mo><mml:mfrac><mml:msup><mml:mi>p</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ε</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:mo>-</mml:mo><mml:mi>b</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"1em\"/><mml:mtext>for</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:mi>a</mml:mi><mml:mo>≥</mml:mo><mml:mi>b</mml:mi><mml:mo>≥</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mspace width=\"0.222222em\"/><mml:mi>ε</mml:mi><mml:mo>></mml:mo><mml:mn>0</mml:mn><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ69\"><alternatives><tex-math id=\"M219\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} a^p-b^p\\le p a^{p-1}(a-b)\\le \\varepsilon a^p + \\frac{p^p}{\\varepsilon ^{p-1}}(a-b)^p. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M220\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>a</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mo>-</mml:mo><mml:msup><mml:mi>b</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mo>≤</mml:mo><mml:mi>p</mml:mi><mml:msup><mml:mi>a</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:mo>-</mml:mo><mml:mi>b</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ε</mml:mi><mml:msup><mml:mi>a</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mo>+</mml:mo><mml:mfrac><mml:msup><mml:mi>p</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ε</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:mo>-</mml:mo><mml:mi>b</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq82\"><alternatives><tex-math id=\"M221\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$a=\\zeta (y,t)$$\\end{document}</tex-math><mml:math id=\"M222\"><mml:mrow><mml:mi>a</mml:mi><mml:mo>=</mml:mo><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq83\"><alternatives><tex-math id=\"M223\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$b=\\zeta (x,t)$$\\end{document}</tex-math><mml:math id=\"M224\"><mml:mrow><mml:mi>b</mml:mi><mml:mo>=</mml:mo><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ70\"><alternatives><tex-math id=\"M225\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varepsilon =\\big (w_+(x,t)-w_+(y,t)\\big )/2w_+(x,t) \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M226\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>ε</mml:mi><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">/</mml:mo><mml:mn>2</mml:mn><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ71\"><alternatives><tex-math id=\"M227\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big (w_+(x,t)&-w_+(y,t)\\big )^{p-1} w_+(x,t) \\big (\\zeta ^p(y,t) - \\zeta ^p(x,t)\\big )\\\\&\\le \\tfrac{1}{2}\\big (w_+(x,t)-w_+(y,t)\\big )^{p} \\zeta ^p(y,t)+\\varvec{\\gamma }(p)w_+^p(x,t) \\big (\\zeta (y,t) - \\zeta (x,t)\\big )^p. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M228\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq84\"><alternatives><tex-math id=\"M229\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta (x,t)<\\zeta (y,t)$$\\end{document}</tex-math><mml:math id=\"M230\"><mml:mrow><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo><</mml:mo><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq85\"><alternatives><tex-math id=\"M231\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_1$$\\end{document}</tex-math><mml:math id=\"M232\"><mml:msub><mml:mi>I</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ72\"><alternatives><tex-math id=\"M233\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} I_1&\\ge c\\int _{t_o-S}^{t_o}\\int _{A_k}\\int _{A_k} \\big \|w_+(x,t)-w_+(y,t)\\big \|^{p} \\max \\big \\{\\zeta ^p(x,t), \\zeta ^p(y,t)\\big \\}\\,\\textrm{d}\\mu \\\\&\\quad +2c\\int _{t_o-S}^{t_o}\\int _{A_{k}}\\int _{K_R\\setminus A_k} \\big \|w_+(x,t)-w_+(y,t)\\big \|^{p} \\zeta ^p(x,t) \\,\\textrm{d}\\mu \\\\&\\quad +2c\\int _{t_o-S}^{t_o}\\int _{A_{k}}\\int _{K_R\\setminus A_k} w_-^{p-1}(y,t) w_+(x,t)\\zeta ^p(x,t) \\,\\textrm{d}\\mu \\\\&\\quad - \\varvec{\\gamma }(p)\\int _{t_o-S}^{t_o}\\int _{K_R}\\int _{K_R}\\max \\big \\{w_+^p(x,t), w_+^p(y,t)\\big \\}\\big \|\\zeta (x,t)-\\zeta (y,t)\\big \|^p\\,\\textrm{d}\\mu \\\\&\\ge c\\int _{t_o-S}^{t_o}\\int _{K_R}\\int _{K_R} \\big \|w_+(x,t)-w_+(y,t)\\big \|^{p} \\min \\big \\{\\zeta ^p(x,t), \\zeta ^p(y,t)\\big \\}\\,\\textrm{d}\\mu \\\\&\\quad +c\\int _{t_o-S}^{t_o}\\int _{K_R}\\int _{K_R} w_-^{p-1}(y,t) w_+(x,t)\\zeta ^p(x,t) \\,\\textrm{d}\\mu \\\\&\\quad - \\varvec{\\gamma }(p)\\int _{t_o-S}^{t_o}\\int _{K_R}\\int _{K_R}\\max \\big \\{w_+^p(x,t), w_+^p(y,t)\\big \\}\\big \|\\zeta (x,t)-\\zeta (y,t)\\big \|^p\\,\\textrm{d}\\mu . \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M234\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msub><mml:mi>I</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≥</mml:mo><mml:mi>c</mml:mi><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mn>2</mml:mn><mml:mi>c</mml:mi><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mn>2</mml:mn><mml:mi>c</mml:mi><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>k</mml:mi></mml:msub></mml:mrow></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>-</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≥</mml:mo><mml:mi>c</mml:mi><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo movablelimits=\"true\">min</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mi>c</mml:mi><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>-</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq86\"><alternatives><tex-math id=\"M235\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_2$$\\end{document}</tex-math><mml:math id=\"M236\"><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ73\"><alternatives><tex-math id=\"M237\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} -\\big \|u(x,t)&- u(y,t)\\big \|^{p-2}\\big (u(x,t) - u(y,t)\\big ) \\big (u(x,t)-k\\big )_+\\\\&\\le \\big (u(y,t)-u(x,t)\\big )^{p-1}_+\\big (u(x,t)-k\\big )_+\\\\&\\le \\big (u(y,t)-k\\big )^{p-1}_+\\big (u(x,t)-k\\big )_+. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M238\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>-</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ74\"><alternatives><tex-math id=\"M239\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} -I_2&\\le 2\\int _{t_o-S}^{t_o}\\int _{K_{R}}\\int _{\\mathbb {R}^N\\setminus K_R} w_+^{p-1}(y,t) w_+(x,t)\\zeta ^p(x,t)\\,\\textrm{d}\\mu \\\\&\\le \\varvec{\\gamma } \\iint _{Q(R,S)} \\zeta ^pw_{+}(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in {\\text {supp}}\\zeta (\\cdot , t)\\\\ t\\in (t_o-S,t_o) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_R}\\frac{ w_{+}^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) . \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M240\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mn>2</mml:mn><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>μ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>+</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:mtext>supp</mml:mtext><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>+</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq87\"><alternatives><tex-math id=\"M241\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\square $$\\end{document}</tex-math><mml:math id=\"M242\"><mml:mo>□</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq88\"><alternatives><tex-math id=\"M243\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_R\\times (t_o- S, t)$$\\end{document}</tex-math><mml:math id=\"M244\"><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq89\"><alternatives><tex-math id=\"M245\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t\\in (t_o- S, t_o)$$\\end{document}</tex-math><mml:math id=\"M246\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq90\"><alternatives><tex-math id=\"M247\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$L^\\infty $$\\end{document}</tex-math><mml:math id=\"M248\"><mml:msup><mml:mi>L</mml:mi><mml:mi>∞</mml:mi></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq91\"><alternatives><tex-math id=\"M249\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta $$\\end{document}</tex-math><mml:math id=\"M250\"><mml:mi>ζ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq92\"><alternatives><tex-math id=\"M251\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M252\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq93\"><alternatives><tex-math id=\"M253\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma } (C_o,C_1,p)>0$$\\end{document}</tex-math><mml:math id=\"M254\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>></mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq94\"><alternatives><tex-math id=\"M255\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q(r,\\tau )\\subset Q(R,S) \\subset E_T$$\\end{document}</tex-math><mml:math id=\"M256\"><mml:mrow><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>r</mml:mi><mml:mo>,</mml:mo><mml:mi>τ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq95\"><alternatives><tex-math id=\"M257\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$k\\in \\mathbb {R}$$\\end{document}</tex-math><mml:math id=\"M258\"><mml:mrow><mml:mi>k</mml:mi><mml:mo>∈</mml:mo><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ75\"><alternatives><tex-math id=\"M259\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,sup}}\\limits _{t_o-\\tau<t<t_o}\\int _{K_r}&w^2_{\\pm }(x,t)\\,\\textrm{d}x+ \\int _{t_o-\\tau }^{t_o}\\int _{K_r}\\int _{K_r} \\frac{\|w_\\pm (x,t) - w_\\pm (y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le \\frac{\\varvec{\\gamma } R^{(1-s)p}}{(R-r)^p}\\int _{t_o-S}^{t_o}\\int _{K_R} w^p_{\\pm }(x,t) \\,\\textrm{d}x\\textrm{d}t\\\\&\\quad +\\frac{\\varvec{\\gamma } R^{N}}{(R-r)^{N+sp}}\\iint _{Q(R,S)} w_{\\pm }(x,t)\\,\\textrm{d}x\\textrm{d}t\\big [\\textrm{Tail}\\big (w_\\pm ; Q(R,S)\\big )\\big ]^{p-1}\\\\&\\quad + \\frac{\\varvec{\\gamma }}{S-\\tau }\\iint _{Q(R,S)} w_{\\pm }^2(x,t)\\,\\textrm{d}x\\textrm{d}t\\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M260\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>τ</mml:mi><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>r</mml:mi></mml:msub></mml:msub></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>±</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>τ</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>r</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>r</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:msup><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>-</mml:mo><mml:mi>r</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mfrac><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>±</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>R</mml:mi><mml:mi>N</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>-</mml:mo><mml:mi>r</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi>S</mml:mi><mml:mo>-</mml:mo><mml:mi>τ</mml:mi></mml:mrow></mml:mfrac><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>±</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ76\"><alternatives><tex-math id=\"M261\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,sup}}\\limits _{t_o-S<t<t_o}\\int _{K_r}&w^2_{\\pm }(x,t)\\,\\textrm{d}x+ \\int _{t_o-S}^{t_o}\\int _{K_r}\\int _{K_r} \\frac{\|w_\\pm (x,t) - w_\\pm (y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\quad +\\frac{1}{r^{N+sp}}\\int _{t_o-S}^{t_o}\\int _{K_r}\\int _{K_r} w_{\\pm }(x,t) w^{p-1}_\\mp (y,t)\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\\\&\\le \\int _{K_R} w^2_\\pm (x,t_o-S)\\,\\textrm{d}x+\\frac{\\varvec{\\gamma } R^{(1-s)p}}{(R-r)^p}\\int _{t_o-S}^{t_o}\\int _{K_R} w^p_{\\pm }(x,t) \\,\\textrm{d}x\\textrm{d}t\\\\&\\quad +\\frac{\\varvec{\\gamma } R^{N}}{(R-r)^{N+sp}}\\iint _{Q(R,S)} w_{\\pm }(x,t)\\,\\textrm{d}x\\textrm{d}t\\big [\\textrm{Tail}\\big (w_\\pm ; Q(R,S)\\big )\\big ]^{p-1}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M262\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>r</mml:mi></mml:msub></mml:msub></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>±</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>r</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>r</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:msup><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:msup><mml:mi>r</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>r</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>r</mml:mi></mml:msub></mml:msub><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>∓</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>±</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>-</mml:mo><mml:mi>r</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mfrac><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>±</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>R</mml:mi><mml:mi>N</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>-</mml:mo><mml:mi>r</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq96\"><alternatives><tex-math id=\"M263\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$w=u-k$$\\end{document}</tex-math><mml:math id=\"M264\"><mml:mrow><mml:mi>w</mml:mi><mml:mo>=</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq97\"><alternatives><tex-math id=\"M265\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p>1$$\\end{document}</tex-math><mml:math id=\"M266\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq98\"><alternatives><tex-math id=\"M267\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathcal {Q}:=K_R(x_o)\\times (T_1,T_2]$$\\end{document}</tex-math><mml:math id=\"M268\"><mml:mrow><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>T</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>T</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq99\"><alternatives><tex-math id=\"M269\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M270\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq100\"><alternatives><tex-math id=\"M271\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^{\\pm }$$\\end{document}</tex-math><mml:math id=\"M272\"><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq101\"><alternatives><tex-math id=\"M273\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M274\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ77\"><alternatives><tex-math id=\"M275\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\mu }^+\\ge \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\mathcal {Q}}u, \\quad \\varvec{\\mu }^-\\le \\mathop {\\mathrm{ess\\,inf}}\\limits _{\\mathcal {Q}} u, \\quad \\varvec{\\omega }\\ge \\varvec{\\mu }^+-\\varvec{\\mu }^-. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M276\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>≥</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mi mathvariant=\"script\">Q</mml:mi></mml:munder><mml:mi>u</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>≤</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">inf</mml:mi></mml:mrow><mml:mi mathvariant=\"script\">Q</mml:mi></mml:munder><mml:mi>u</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>≥</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq102\"><alternatives><tex-math id=\"M277\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)$$\\end{document}</tex-math><mml:math id=\"M278\"><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq103\"><alternatives><tex-math id=\"M279\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_\\varrho (\\theta )$$\\end{document}</tex-math><mml:math id=\"M280\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq104\"><alternatives><tex-math id=\"M281\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M282\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq105\"><alternatives><tex-math id=\"M283\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$ \\delta ,\\,\\xi \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M284\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mi>ξ</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq106\"><alternatives><tex-math id=\"M285\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta =\\delta (\\xi \\varvec{\\omega })^{2-p}$$\\end{document}</tex-math><mml:math id=\"M286\"><mml:mrow><mml:mi>θ</mml:mi><mml:mo>=</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq107\"><alternatives><tex-math id=\"M287\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$ Q_\\varrho (\\theta ) \\subset \\mathcal {Q}$$\\end{document}</tex-math><mml:math id=\"M288\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq108\"><alternatives><tex-math id=\"M289\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M290\"><mml:mrow><mml:mi>ν</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq109\"><alternatives><tex-math id=\"M291\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M292\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq110\"><alternatives><tex-math id=\"M293\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M294\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ78\"><alternatives><tex-math id=\"M295\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\pm \\big (\\varvec{\\mu }^{\\pm }-u\\big )\\le \\xi \\varvec{\\omega }\\Big \\}\\cap Q_{\\varrho }(\\theta )\\Big \| \\le \\nu \|Q_{\\varrho }(\\theta )\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M296\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ν</mml:mi><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ79\"><alternatives><tex-math id=\"M297\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}\\big ( \\big (u - \\varvec{\\mu }^{\\pm }\\big )_{\\pm }; \\mathcal {Q}\\big )>\\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M298\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ80\"><alternatives><tex-math id=\"M299\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\pm \\big (\\varvec{\\mu }^{\\pm }-u\\big )\\ge \\tfrac{1}{2}\\xi \\varvec{\\omega } \\quad \\text{ a.e. } \\text{ in } Q_{\\frac{1}{2}\\varrho }(\\theta ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M300\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>a.e.</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>in</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq111\"><alternatives><tex-math id=\"M301\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu \\approx \\delta ^q$$\\end{document}</tex-math><mml:math id=\"M302\"><mml:mrow><mml:mi>ν</mml:mi><mml:mo>≈</mml:mo><mml:msup><mml:mi>δ</mml:mi><mml:mi>q</mml:mi></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq112\"><alternatives><tex-math id=\"M303\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$ q>1$$\\end{document}</tex-math><mml:math id=\"M304\"><mml:mrow><mml:mi>q</mml:mi><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq113\"><alternatives><tex-math id=\"M305\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^-=0$$\\end{document}</tex-math><mml:math id=\"M306\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq114\"><alternatives><tex-math id=\"M307\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu $$\\end{document}</tex-math><mml:math id=\"M308\"><mml:mi>ν</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ81\"><alternatives><tex-math id=\"M309\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}(u_{-}; \\mathcal {Q}) \\le \\xi \\varvec{\\omega } \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M310\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ82\"><alternatives><tex-math id=\"M311\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ u\\le \\xi \\varvec{\\omega }\\Big \\}\\cap Q_{\\varrho }(\\theta )\\Big \| \\le \\nu \|Q_{\\varrho }(\\theta )\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M312\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ν</mml:mi><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ83\"><alternatives><tex-math id=\"M313\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u \\ge \\tfrac{1}{2}\\xi \\varvec{\\omega } \\quad \\text{ a.e. } \\text{ in } Q_{\\frac{1}{2}\\varrho }(\\theta ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M314\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>a.e.</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>in</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq115\"><alternatives><tex-math id=\"M315\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu $$\\end{document}</tex-math><mml:math id=\"M316\"><mml:mi>ν</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq116\"><alternatives><tex-math id=\"M317\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M318\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq117\"><alternatives><tex-math id=\"M319\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M320\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq118\"><alternatives><tex-math id=\"M321\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi $$\\end{document}</tex-math><mml:math id=\"M322\"><mml:mi>ξ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq119\"><alternatives><tex-math id=\"M323\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)=(0,0)$$\\end{document}</tex-math><mml:math id=\"M324\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq120\"><alternatives><tex-math id=\"M325\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$n\\in \\mathbb {N}\\cup \\{0\\}$$\\end{document}</tex-math><mml:math id=\"M326\"><mml:mrow><mml:mi>n</mml:mi><mml:mo>∈</mml:mo><mml:mi mathvariant=\"double-struck\">N</mml:mi><mml:mo>∪</mml:mo><mml:mo stretchy=\"false\">{</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ84\"><alternatives><tex-math id=\"M327\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left\\{ \\begin{array}{c} \\displaystyle k_n= \\frac{\\xi \\varvec{\\omega }}{2} +\\frac{\\xi \\varvec{\\omega } }{2^{n+1}}, \\\\ \\displaystyle \\varrho _n=\\frac{\\varrho }{2}+\\frac{\\varrho }{2^{n+1}},\\quad \\tilde{\\varrho }_n=\\frac{\\varrho _n+\\varrho _{n+1}}{2},\\\\ \\displaystyle \\hat{\\varrho }_n=\\frac{3\\varrho _n+ \\varrho _{n+1}}{4},\\quad \\bar{\\varrho }_n=\\frac{\\varrho _n+ 3\\varrho _{n+1}}{4},\\\\ \\displaystyle K_n=K_{\\varrho _n}, \\quad \\widetilde{K}_n=K_{\\tilde{\\varrho }_n},\\quad \\widehat{K}_n=K_{{\\hat{\\varrho }}_n},\\quad \\overline{K}_n=K_{\\bar{\\varrho }_n},\\\\ \\displaystyle Q_n=K_n\\times \\big (-\\theta \\varrho _n^{sp},0\\big ),\\quad \\widetilde{Q}_n=\\widetilde{K}_n\\times \\big (-\\theta \\tilde{\\varrho }_n^{sp},0\\big ),\\\\ \\widehat{Q}_n=\\widehat{K}_n\\times \\big (-\\theta \\hat{\\varrho }_n^{sp},0\\big ),\\quad \\overline{Q}_n=\\overline{K}_n\\times \\big (-\\theta \\bar{\\varrho }_n^{sp},0\\big ). \\end{array} \\right. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M328\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mfenced open=\"{\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:msub><mml:mi>k</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow><mml:mn>2</mml:mn></mml:mfrac><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mfrac><mml:mo>,</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:mrow/><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mn>2</mml:mn></mml:mfrac><mml:mo>+</mml:mo><mml:mfrac><mml:mi>ϱ</mml:mi><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mfrac><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mn>2</mml:mn></mml:mfrac><mml:mo>,</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:mrow/><mml:msub><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mn>3</mml:mn><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mn>4</mml:mn></mml:mfrac><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mover accent=\"true\"><mml:mrow><mml:mi>ϱ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:mn>3</mml:mn><mml:msub><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mn>4</mml:mn></mml:mfrac><mml:mo>,</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:mrow/><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:msub><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:msub><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mover><mml:mi>K</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:msub><mml:mover accent=\"true\"><mml:mrow><mml:mi>ϱ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:mrow/><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">^</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mover><mml:mi>Q</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mover><mml:mi>K</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mrow><mml:mi>ϱ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ85\"><alternatives><tex-math id=\"M329\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} Q_{n+1}\\subset \\overline{Q}_n\\subset \\widetilde{Q}_n\\subset \\widehat{Q}_n\\subset Q_n. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M330\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>⊂</mml:mo><mml:msub><mml:mover><mml:mi>Q</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>⊂</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>⊂</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>⊂</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq121\"><alternatives><tex-math id=\"M331\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta $$\\end{document}</tex-math><mml:math id=\"M332\"><mml:mi>ζ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq122\"><alternatives><tex-math id=\"M333\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_n$$\\end{document}</tex-math><mml:math id=\"M334\"><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq123\"><alternatives><tex-math id=\"M335\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widehat{Q}_{n}$$\\end{document}</tex-math><mml:math id=\"M336\"><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq124\"><alternatives><tex-math id=\"M337\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widetilde{Q}_{n}$$\\end{document}</tex-math><mml:math id=\"M338\"><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ86\"><alternatives><tex-math id=\"M339\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \|D\\zeta \|\\le \\frac{2^n}{\\varrho }\\quad \\text { and }\\quad \|\\partial _t \\zeta \|\\le \\frac{2^{psn}}{\\theta \\varrho ^{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M340\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>D</mml:mi><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:msup><mml:mn>2</mml:mn><mml:mi>n</mml:mi></mml:msup><mml:mi>ϱ</mml:mi></mml:mfrac><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>and</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"1em\"/><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi mathvariant=\"italic\">psn</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ87\"><alternatives><tex-math id=\"M341\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,sup}}\\limits _{-\\theta {\\tilde{\\varrho }}_n^{sp}<t<0}&\\int _{\\widetilde{K}_n} w^2_{-}(x,t)\\,\\textrm{d}x+ \\int _{-\\theta {\\tilde{\\varrho }}_n^{sp}}^{0}\\int _{\\widetilde{K}_n}\\int _{\\widetilde{K}_n} \\frac{\|w_-(x,t) - w_-(y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\quad \\le \\varvec{\\gamma }\\int _{-\\theta \\varrho _n^{sp}}^{0}\\int _{K_n}\\int _{K_n}\\max \\big \\{w^p_{-}(x,t), w^p_{-}(y,t)\\big \\} \\frac{\|\\zeta (x,t) - \\zeta (y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\qquad +\\varvec{\\gamma }\\iint _{Q_n} \\zeta ^p w_{-}(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in \\widehat{K}_n\\\\ t\\in (-\\theta \\varrho _n^{sp},0) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_n}\\frac{ w_{-}^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\qquad + \\iint _{Q_n} \|\\partial _t\\zeta ^p\|w_{-}^2(x,t)\\,\\textrm{d}x\\textrm{d}t. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M342\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:munder></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:msup><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"2em\"/><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mo>∬</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"2em\"/><mml:mo>+</mml:mo><mml:msub><mml:mo>∬</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq125\"><alternatives><tex-math id=\"M343\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$w_-=(u-k_n)_-$$\\end{document}</tex-math><mml:math id=\"M344\"><mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msub><mml:mi>k</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ88\"><alternatives><tex-math id=\"M345\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _{-\\theta \\varrho _n^{sp}}^{0}&\\int _{K_n}\\int _{K_n}\\max \\big \\{w_{-}(x,t), w_{-}(y,t)\\big \\}^p \\frac{\|\\zeta (x,t) - \\zeta (y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le 2^{pn+1} \\frac{(\\xi \\varvec{\\omega })^p}{\\varrho ^{sp}}\\int _{-\\theta \\varrho _n^{sp}}^{0}\\int _{K_n}\\int _{K_n} \\frac{ \\chi _{\\{u(x,t)<k_n\\}} }{\|x-y\|^{N+(s-1)p}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le \\varvec{\\gamma } 2^{pn} \\frac{(\\xi \\varvec{\\omega })^p}{\\varrho ^{sp}} \|A_n\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M346\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi>p</mml:mi><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:msub><mml:mi>χ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo><</mml:mo><mml:msub><mml:mi>k</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>s</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi mathvariant=\"italic\">pn</mml:mi></mml:mrow></mml:msup><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq126\"><alternatives><tex-math id=\"M347\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$A_n:=\\{u<k_n\\}\\cap Q_n$$\\end{document}</tex-math><mml:math id=\"M348\"><mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>u</mml:mi><mml:mo><</mml:mo><mml:msub><mml:mi>k</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq127\"><alternatives><tex-math id=\"M349\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|y\|\\ge \\varrho _n$$\\end{document}</tex-math><mml:math id=\"M350\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq128\"><alternatives><tex-math id=\"M351\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|x\|\\le {\\hat{\\varrho }}_n$$\\end{document}</tex-math><mml:math id=\"M352\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ89\"><alternatives><tex-math id=\"M353\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\frac{\|y-x\|}{\|y\|}\\ge 1-\\frac{{\\hat{\\varrho }}_n}{ \\varrho _n}=\\frac{1}{4}\\left( \\frac{\\varrho _n-\\varrho _{n+1}}{\\varrho _n}\\right) \\ge \\frac{1}{2^{n+4}}; \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M354\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo>-</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mfrac><mml:mo>≥</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mfrac><mml:msub><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:mfrac><mml:mo>=</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mrow><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:msub><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:mfrac></mml:mfenced><mml:mo>≥</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>4</mml:mn></mml:mrow></mml:msup></mml:mfrac><mml:mo>;</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq129\"><alternatives><tex-math id=\"M355\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$u\\ge \\varvec{\\mu }^-=0$$\\end{document}</tex-math><mml:math id=\"M356\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq130\"><alternatives><tex-math id=\"M357\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathcal {Q}$$\\end{document}</tex-math><mml:math id=\"M358\"><mml:mi mathvariant=\"script\">Q</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ90\"><alternatives><tex-math id=\"M359\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\iint _{Q_n}&\\zeta ^pw_{-}(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in \\widehat{K}_n\\\\ t\\in (-\\theta \\varrho _n^{sp},0) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_n}\\frac{ w_{-}^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\le \\varvec{\\gamma } 2^{(N+sp)n} \\xi \\varvec{\\omega } \|A_n\| \\left( \\varvec{\\gamma } \\frac{(\\xi \\varvec{\\omega })^{p-1}}{\\varrho ^{sp}}+\\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} t\\in (-\\theta \\varrho _n^{sp},0) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_R}\\frac{ u_{-}^{p-1}(y,t)}{\|y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&= \\varvec{\\gamma } 2^{(N+sp)n} \\frac{\\xi \\varvec{\\omega }}{\\varrho ^{sp}} \|A_n\| \\left( \\varvec{\\gamma } (\\xi \\varvec{\\omega })^{p-1} + \\left( \\frac{\\varrho }{R}\\right) ^{sp} [\\textrm{Tail}(u_-; \\mathcal {Q})]^{p-1} \\right) \\\\&\\le \\varvec{\\gamma } 2^{(N+sp)n} \\frac{(\\xi \\varvec{\\omega })^p}{\\varrho ^{sp}} \|A_n\|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M360\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msub><mml:mo>∬</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:msup><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>+</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:msup><mml:mfrac><mml:mrow><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">[</mml:mo><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:msup><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ91\"><alternatives><tex-math id=\"M361\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}(u_{-}; \\mathcal {Q}) \\le \\xi \\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M362\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ92\"><alternatives><tex-math id=\"M363\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\iint _{Q_n} \|\\partial _t\\zeta ^p \|(u-k_n)_{-}^2\\,\\textrm{d}x\\textrm{d}t\\le \\frac{2^{spn}}{\\theta \\varrho ^{sp}} (\\xi \\varvec{\\omega })^2 \|A_n\|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M364\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mo>∬</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msub><mml:mi>k</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>≤</mml:mo><mml:mfrac><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi mathvariant=\"italic\">spn</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ93\"><alternatives><tex-math id=\"M365\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,sup}}\\limits _{-\\theta \\tilde{\\varrho }^{sp}_n<t<0}&\\int _{\\widetilde{K}_n} w_-^2\\,\\textrm{d}x+ \\int _{-\\theta \\tilde{\\varrho }^{sp}_n}^{0}\\int _{\\widetilde{K}_n}\\int _{\\widetilde{K}_n} \\frac{\|w_-(x,t) - w_-(y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le \\varvec{\\gamma } 2^{(N+2p)n}\\frac{(\\xi \\varvec{\\omega })^p}{\\delta \\varrho ^{sp}}\|A_n\|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M366\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:munder></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:msup><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mn>2</mml:mn><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:msup><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq131\"><alternatives><tex-math id=\"M367\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0\\le \\phi \\le 1$$\\end{document}</tex-math><mml:math id=\"M368\"><mml:mrow><mml:mn>0</mml:mn><mml:mo>≤</mml:mo><mml:mi>ϕ</mml:mi><mml:mo>≤</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq132\"><alternatives><tex-math id=\"M369\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widetilde{Q}_n$$\\end{document}</tex-math><mml:math id=\"M370\"><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq133\"><alternatives><tex-math id=\"M371\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{Q}_n$$\\end{document}</tex-math><mml:math id=\"M372\"><mml:msub><mml:mover><mml:mi>Q</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq134\"><alternatives><tex-math id=\"M373\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_{n+1}$$\\end{document}</tex-math><mml:math id=\"M374\"><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq135\"><alternatives><tex-math id=\"M375\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|D\\phi \|\\le 2^n/\\varrho $$\\end{document}</tex-math><mml:math id=\"M376\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>D</mml:mi><mml:mi>ϕ</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mi>n</mml:mi></mml:msup><mml:mo stretchy=\"false\">/</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq136\"><alternatives><tex-math id=\"M377\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$d=2^{-n-4}$$\\end{document}</tex-math><mml:math id=\"M378\"><mml:mrow><mml:mi>d</mml:mi><mml:mo>=</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo>-</mml:mo><mml:mi>n</mml:mi><mml:mo>-</mml:mo><mml:mn>4</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ210\"></disp-formula>", "<inline-formula id=\"IEq137\"><alternatives><tex-math id=\"M379\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\varvec{b}}={\\varvec{b}}(p,N)>1$$\\end{document}</tex-math><mml:math id=\"M380\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">b</mml:mi></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">b</mml:mi></mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ94\"><alternatives><tex-math id=\"M381\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big \|w_-\\phi (x,t)&- w_-\\phi (y,t)\\big \|^p \\\\&\\le c \\big \|w_-(x,t) - w_-(y,t) \\big \|^p \\phi ^p(x,t) + c w^p_-(y,t) \\big \|\\phi (x,t) - \\phi (y,t)\\big \|^p, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M382\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mi>c</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϕ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mi>c</mml:mi><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq138\"><alternatives><tex-math id=\"M383\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$c=c(p)$$\\end{document}</tex-math><mml:math id=\"M384\"><mml:mrow><mml:mi>c</mml:mi><mml:mo>=</mml:mo><mml:mi>c</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ95\"><alternatives><tex-math id=\"M385\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varrho ^{sp}&\\int _{-\\theta \\tilde{\\varrho }^{sp}_n}^{0}\\int _{\\widetilde{K}_n}\\int _{\\widetilde{K}_n} \\frac{\\big \|w_-\\phi (x,t) - w_-\\phi (y,t)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le c \\varrho ^{sp}\\int _{-\\theta \\tilde{\\varrho }^{sp}_n}^{0}\\int _{\\widetilde{K}_n}\\int _{\\widetilde{K}_n} \\frac{\\big \|w_-(x,t) - w_-(y,t)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\quad + c \\varrho ^{sp}\\int _{-\\theta \\tilde{\\varrho }^{sp}_n}^{0}\\int _{\\widetilde{K}_n}\\int _{\\widetilde{K}_n} \\frac{w^p_-(y,t)\\big \|\\phi (x,t) - \\phi (y,t)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le c \\varrho ^{sp}\\int _{-\\theta \\tilde{\\varrho }^{sp}_n}^{0}\\int _{\\widetilde{K}_n}\\int _{\\widetilde{K}_n} \\frac{\\big \|w_-(x,t) - w_-(y,t)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\quad + \\varvec{\\gamma } 2^{pn} \\iint _{\\widetilde{Q}_n} w^p_-(y,t) \\,\\textrm{d}y\\textrm{d}t. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M386\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mi>c</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mi>c</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ϕ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mi>c</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msubsup><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi mathvariant=\"italic\">pn</mml:mi></mml:mrow></mml:msup><mml:msub><mml:mo>∬</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ96\"><alternatives><tex-math id=\"M387\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\kappa :=1+\\frac{2(\\kappa _* -1)}{p\\kappa _}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M388\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>κ</mml:mi><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mn>2</mml:mn><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub></mml:mrow></mml:mfrac><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq139\"><alternatives><tex-math id=\"M389\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$ {\\varvec{Y}}_n=\|A_n\|/\|Q_n\|$$\\end{document}</tex-math><mml:math id=\"M390\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mi>n</mml:mi></mml:msub><mml:mrow><mml:mo>=</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo stretchy=\"false\">/</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ97\"><alternatives><tex-math id=\"M391\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned} {\\varvec{Y}}_{n+1} \\le&\\varvec{\\gamma } \\delta ^{-\\left( \\frac{1}{\\kappa }+\\frac{\\kappa _}{\\kappa _\\kappa p}\\right) }(2{\\varvec{b}})^n {\\varvec{Y}}_n^{1+\\frac{\\kappa _ -1}{\\kappa _\\kappa p}}, \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M392\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>≤</mml:mo></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>δ</mml:mi><mml:mrow><mml:mo>-</mml:mo><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>κ</mml:mi></mml:mfrac><mml:mo>+</mml:mo><mml:mfrac><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mi>κ</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac></mml:mfenced></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>2</mml:mn><mml:mrow><mml:mi mathvariant=\"bold-italic\">b</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>n</mml:mi></mml:msup><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mi>n</mml:mi><mml:mrow><mml:mn>1</mml:mn><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mi>κ</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac></mml:mrow></mml:msubsup><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq140\"><alternatives><tex-math id=\"M393\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma }$$\\end{document}</tex-math><mml:math id=\"M394\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq141\"><alternatives><tex-math id=\"M395\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu $$\\end{document}</tex-math><mml:math id=\"M396\"><mml:mi>ν</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq142\"><alternatives><tex-math id=\"M397\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\varvec{Y}}_n\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M398\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq143\"><alternatives><tex-math id=\"M399\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\varvec{Y}}_o\\le \\nu $$\\end{document}</tex-math><mml:math id=\"M400\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mi>o</mml:mi></mml:msub><mml:mo>≤</mml:mo><mml:mi>ν</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq144\"><alternatives><tex-math id=\"M401\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\square $$\\end{document}</tex-math><mml:math id=\"M402\"><mml:mo>□</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq145\"><alternatives><tex-math id=\"M403\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M404\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq146\"><alternatives><tex-math id=\"M405\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M406\"><mml:mrow><mml:mi>ξ</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq147\"><alternatives><tex-math id=\"M407\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu _o$$\\end{document}</tex-math><mml:math id=\"M408\"><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq148\"><alternatives><tex-math id=\"M409\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M410\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq149\"><alternatives><tex-math id=\"M411\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi $$\\end{document}</tex-math><mml:math id=\"M412\"><mml:mi>ξ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ98\"><alternatives><tex-math id=\"M413\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\pm \\big (\\varvec{\\mu }^{\\pm }-u(\\cdot , t_o)\\big )\\ge \\xi \\varvec{\\omega } \\quad \\text { a.e. in } K_{\\varrho }(x_o), \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M414\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>a.e. in</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ99\"><alternatives><tex-math id=\"M415\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}\\big (\\big (u - \\varvec{\\mu }^{\\pm }\\big )_{\\pm }; \\mathcal {Q}\\big ) >\\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M416\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ100\"><alternatives><tex-math id=\"M417\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\pm \\big (\\varvec{\\mu }^{\\pm }-u\\big )\\ge \\tfrac{1}{2}\\xi \\varvec{\\omega }\\quad \\text { a.e. in }K_{\\frac{1}{2}\\varrho }(x_o)\\times \\big (t_o, t_o+\\nu _o(\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}\\big ], \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M418\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>a.e. in</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq150\"><alternatives><tex-math id=\"M419\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathcal {Q}$$\\end{document}</tex-math><mml:math id=\"M420\"><mml:mi mathvariant=\"script\">Q</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq151\"><alternatives><tex-math id=\"M421\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)=(0,0)$$\\end{document}</tex-math><mml:math id=\"M422\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq152\"><alternatives><tex-math id=\"M423\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^-=0$$\\end{document}</tex-math><mml:math id=\"M424\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq153\"><alternatives><tex-math id=\"M425\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q(R,S)\\equiv K_{\\varrho }\\times (0,\\theta \\varrho ^{sp})$$\\end{document}</tex-math><mml:math id=\"M426\"><mml:mrow><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≡</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq154\"><alternatives><tex-math id=\"M427\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta $$\\end{document}</tex-math><mml:math id=\"M428\"><mml:mi>θ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq155\"><alternatives><tex-math id=\"M429\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t_o-S$$\\end{document}</tex-math><mml:math id=\"M430\"><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq156\"><alternatives><tex-math id=\"M431\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t=0$$\\end{document}</tex-math><mml:math id=\"M432\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq157\"><alternatives><tex-math id=\"M433\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta (x)$$\\end{document}</tex-math><mml:math id=\"M434\"><mml:mrow><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq158\"><alternatives><tex-math id=\"M435\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_\\varrho $$\\end{document}</tex-math><mml:math id=\"M436\"><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq159\"><alternatives><tex-math id=\"M437\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\partial K_\\varrho $$\\end{document}</tex-math><mml:math id=\"M438\"><mml:mrow><mml:mi>∂</mml:mi><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq160\"><alternatives><tex-math id=\"M439\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$k\\le \\xi \\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M440\"><mml:mrow><mml:mi>k</mml:mi><mml:mo>≤</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq161\"><alternatives><tex-math id=\"M441\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t=0$$\\end{document}</tex-math><mml:math id=\"M442\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq162\"><alternatives><tex-math id=\"M443\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t_o-S$$\\end{document}</tex-math><mml:math id=\"M444\"><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq163\"><alternatives><tex-math id=\"M445\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$u(\\cdot , 0)\\ge \\xi \\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M446\"><mml:mrow><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>≥</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq164\"><alternatives><tex-math id=\"M447\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{\\varrho }$$\\end{document}</tex-math><mml:math id=\"M448\"><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq165\"><alternatives><tex-math id=\"M449\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\partial _t\\zeta $$\\end{document}</tex-math><mml:math id=\"M450\"><mml:mrow><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mi>ζ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq166\"><alternatives><tex-math id=\"M451\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta $$\\end{document}</tex-math><mml:math id=\"M452\"><mml:mi>ζ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ101\"><alternatives><tex-math id=\"M453\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,sup}}\\limits _{0<t<\\theta \\varrho ^{sp}}&\\int _{K_\\varrho }\\zeta ^p w_-^2\\,\\textrm{d}x+ \\int _{0}^{\\theta \\varrho ^{sp}}\\int _{K_\\varrho }\\int _{K_\\varrho } \\min \\big \\{\\zeta ^p(x),\\zeta ^p(y)\\big \\} \\frac{\|w_-(x,t) - w_-(y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\quad \\le \\varvec{\\gamma }\\int _{0}^{\\theta \\varrho ^{sp}}\\int _{K_\\varrho }\\int _{K_\\varrho }\\max \\big \\{w^p_{-}(x,t), w^p_{-}(y,t)\\big \\} \\frac{\|\\zeta (x) - \\zeta (y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\qquad +\\varvec{\\gamma }\\int _{0}^{\\theta \\varrho ^{sp}}\\int _{K_\\varrho } \\zeta ^pw_{-}(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in {\\text {supp}}\\zeta \\\\ t\\in (0,\\theta \\varrho ^{sp}) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_\\varrho }\\frac{ w_{-}^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) . \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M454\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:munder></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mn>0</mml:mn></mml:mrow><mml:mrow><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">min</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:msup><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mn>0</mml:mn></mml:mrow><mml:mrow><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"2em\"/><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mn>0</mml:mn></mml:mrow><mml:mrow><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:mtext>supp</mml:mtext><mml:mi>ζ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq167\"><alternatives><tex-math id=\"M455\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$k_n$$\\end{document}</tex-math><mml:math id=\"M456\"><mml:msub><mml:mi>k</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq168\"><alternatives><tex-math id=\"M457\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho _n$$\\end{document}</tex-math><mml:math id=\"M458\"><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq169\"><alternatives><tex-math id=\"M459\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\tilde{\\varrho }_n$$\\end{document}</tex-math><mml:math id=\"M460\"><mml:msub><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq170\"><alternatives><tex-math id=\"M461\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\hat{\\varrho }_n$$\\end{document}</tex-math><mml:math id=\"M462\"><mml:msub><mml:mover accent=\"true\"><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq171\"><alternatives><tex-math id=\"M463\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{\\varrho }_n$$\\end{document}</tex-math><mml:math id=\"M464\"><mml:msub><mml:mover accent=\"true\"><mml:mrow><mml:mi>ϱ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq172\"><alternatives><tex-math id=\"M465\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_n$$\\end{document}</tex-math><mml:math id=\"M466\"><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq173\"><alternatives><tex-math id=\"M467\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widetilde{K}_n$$\\end{document}</tex-math><mml:math id=\"M468\"><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq174\"><alternatives><tex-math id=\"M469\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widehat{K}_n$$\\end{document}</tex-math><mml:math id=\"M470\"><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq175\"><alternatives><tex-math id=\"M471\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{K}_n$$\\end{document}</tex-math><mml:math id=\"M472\"><mml:msub><mml:mover><mml:mi>K</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq176\"><alternatives><tex-math id=\"M473\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_n$$\\end{document}</tex-math><mml:math id=\"M474\"><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq177\"><alternatives><tex-math id=\"M475\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widetilde{Q}_n$$\\end{document}</tex-math><mml:math id=\"M476\"><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq178\"><alternatives><tex-math id=\"M477\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widehat{Q}_n$$\\end{document}</tex-math><mml:math id=\"M478\"><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq179\"><alternatives><tex-math id=\"M479\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{Q}_n$$\\end{document}</tex-math><mml:math id=\"M480\"><mml:msub><mml:mover><mml:mi>Q</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq180\"><alternatives><tex-math id=\"M481\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_n=K_n\\times (0,\\theta \\varrho ^{sp})$$\\end{document}</tex-math><mml:math id=\"M482\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq181\"><alternatives><tex-math id=\"M483\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widetilde{Q}_n=\\widetilde{K}_n\\times (0,\\theta \\varrho ^{sp})$$\\end{document}</tex-math><mml:math id=\"M484\"><mml:mrow><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq182\"><alternatives><tex-math id=\"M485\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widehat{Q}_n=\\widehat{K}_n\\times (0,\\theta \\varrho ^{sp})$$\\end{document}</tex-math><mml:math id=\"M486\"><mml:mrow><mml:msub><mml:mover accent=\"true\"><mml:mi>Q</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq183\"><alternatives><tex-math id=\"M487\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{Q}_n=\\overline{K}_n\\times (0,\\theta \\varrho ^{sp})$$\\end{document}</tex-math><mml:math id=\"M488\"><mml:mrow><mml:msub><mml:mover><mml:mi>Q</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mover><mml:mi>K</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq184\"><alternatives><tex-math id=\"M489\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_n$$\\end{document}</tex-math><mml:math id=\"M490\"><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq185\"><alternatives><tex-math id=\"M491\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widehat{K}_n$$\\end{document}</tex-math><mml:math id=\"M492\"><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq186\"><alternatives><tex-math id=\"M493\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widetilde{K}_n$$\\end{document}</tex-math><mml:math id=\"M494\"><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq187\"><alternatives><tex-math id=\"M495\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\overline{K}_n$$\\end{document}</tex-math><mml:math id=\"M496\"><mml:msub><mml:mover><mml:mi>K</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq188\"><alternatives><tex-math id=\"M497\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho _n$$\\end{document}</tex-math><mml:math id=\"M498\"><mml:msub><mml:mi>ϱ</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq189\"><alternatives><tex-math id=\"M499\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta (x)$$\\end{document}</tex-math><mml:math id=\"M500\"><mml:mrow><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq190\"><alternatives><tex-math id=\"M501\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_n$$\\end{document}</tex-math><mml:math id=\"M502\"><mml:msub><mml:mi>K</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq191\"><alternatives><tex-math id=\"M503\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widehat{K}_n$$\\end{document}</tex-math><mml:math id=\"M504\"><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">^</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq192\"><alternatives><tex-math id=\"M505\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\widetilde{K}_n$$\\end{document}</tex-math><mml:math id=\"M506\"><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq193\"><alternatives><tex-math id=\"M507\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|D\\zeta \|\\le 2^n/\\varrho $$\\end{document}</tex-math><mml:math id=\"M508\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>D</mml:mi><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mi>n</mml:mi></mml:msup><mml:mo stretchy=\"false\">/</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ102\"><alternatives><tex-math id=\"M509\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}(u_{-}; \\mathcal {Q}) \\le \\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M510\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ103\"><alternatives><tex-math id=\"M511\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,sup}}\\limits _{0<t<\\theta \\varrho ^{sp} }&\\int _{\\widetilde{K}_n} w_-^2\\,\\textrm{d}x+ \\int ^{\\theta \\varrho ^{sp}}_{0}\\int _{\\widetilde{K}_n}\\int _{\\widetilde{K}_n} \\frac{\|w_-(x,t) - w_-(y,t)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le \\varvec{\\gamma } 2^{(N+2p)n}\\frac{(\\xi \\varvec{\\omega })^p}{\\varrho ^{sp}}\|A_n\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M512\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mn>0</mml:mn><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:munder></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mover accent=\"true\"><mml:mi>K</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mi>n</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:msup><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mn>2</mml:mn><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:msup><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq194\"><alternatives><tex-math id=\"M513\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$A_n:=\\{u<k_n\\}\\cap Q_n$$\\end{document}</tex-math><mml:math id=\"M514\"><mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>u</mml:mi><mml:mo><</mml:mo><mml:msub><mml:mi>k</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ104\"><alternatives><tex-math id=\"M515\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned} {\\varvec{Y}}_{n+1} \\le&\\varvec{\\gamma }{\\varvec{b}}^n \\bigg [\\frac{\\theta }{(\\xi \\varvec{\\omega })^{2-p}}\\bigg ]^{\\frac{\\kappa _ -1}{\\kappa _\\kappa p}}{\\varvec{Y}}_n^{1+\\frac{\\kappa _ -1}{\\kappa _\\kappa p}}, \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M516\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mrow><mml:mi>n</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>≤</mml:mo></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">b</mml:mi></mml:mrow></mml:mrow><mml:mi>n</mml:mi></mml:msup><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mfrac><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:msup><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mi>κ</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mi>n</mml:mi><mml:mrow><mml:mn>1</mml:mn><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mi>κ</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac></mml:mrow></mml:msubsup><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq195\"><alternatives><tex-math id=\"M517\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$ {\\varvec{Y}}_n=\|A_n\|/\|Q_n\|$$\\end{document}</tex-math><mml:math id=\"M518\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mi>n</mml:mi></mml:msub><mml:mrow><mml:mo>=</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo stretchy=\"false\">/</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>n</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq196\"><alternatives><tex-math id=\"M519\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma },\\,{\\varvec{b}}$$\\end{document}</tex-math><mml:math id=\"M520\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mrow><mml:mi mathvariant=\"bold-italic\">b</mml:mi></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq197\"><alternatives><tex-math id=\"M521\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu _o$$\\end{document}</tex-math><mml:math id=\"M522\"><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ105\"><alternatives><tex-math id=\"M523\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} {\\varvec{Y}}_o\\le \\frac{\\nu _o(\\xi \\varvec{\\omega })^{2-p}}{\\theta }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M524\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mi>o</mml:mi></mml:msub><mml:mo>≤</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow><mml:mi>θ</mml:mi></mml:mfrac><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq198\"><alternatives><tex-math id=\"M525\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\varvec{Y}}_n\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M526\"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">Y</mml:mi></mml:mrow><mml:mi>n</mml:mi></mml:msub><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq199\"><alternatives><tex-math id=\"M527\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta =\\nu _o(\\xi \\varvec{\\omega })^{2-p}$$\\end{document}</tex-math><mml:math id=\"M528\"><mml:mrow><mml:mi>θ</mml:mi><mml:mo>=</mml:mo><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq200\"><alternatives><tex-math id=\"M529\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\square $$\\end{document}</tex-math><mml:math id=\"M530\"><mml:mo>□</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq201\"><alternatives><tex-math id=\"M531\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M532\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq202\"><alternatives><tex-math id=\"M533\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi $$\\end{document}</tex-math><mml:math id=\"M534\"><mml:mi>ξ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq203\"><alternatives><tex-math id=\"M535\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha $$\\end{document}</tex-math><mml:math id=\"M536\"><mml:mi>α</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq204\"><alternatives><tex-math id=\"M537\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M538\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq205\"><alternatives><tex-math id=\"M539\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varepsilon $$\\end{document}</tex-math><mml:math id=\"M540\"><mml:mi>ε</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq206\"><alternatives><tex-math id=\"M541\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M542\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq207\"><alternatives><tex-math id=\"M543\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha $$\\end{document}</tex-math><mml:math id=\"M544\"><mml:mi>α</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ106\"><alternatives><tex-math id=\"M545\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\pm \\big (\\varvec{\\mu }^{\\pm }-u(\\cdot , t_o)\\big )\\ge \\xi \\varvec{\\omega } \\Big \\}\\cap K_{\\varrho }(x_o)\\Big \| \\ge \\alpha \\big \|K_{\\varrho }\\big \|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M546\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>α</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ107\"><alternatives><tex-math id=\"M547\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}\\big (\\big (u - \\varvec{\\mu }^{\\pm }\\big )_{\\pm }; \\mathcal {Q}\\big ) >\\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M548\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ108\"><alternatives><tex-math id=\"M549\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\pm \\big (\\varvec{\\mu }^{\\pm }-u(\\cdot , t)\\big )\\ge \\varepsilon \\xi \\varvec{\\omega }\\Big \\} \\cap K_{\\varrho }(x_o)\\Big \| \\ge \\frac{\\alpha }{2} \|K_\\varrho \| \\quad \\text{ for } \\text{ all } t\\in \\big (t_o,t_o+\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}\\big ], \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M550\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mfrac><mml:mi>α</mml:mi><mml:mn>2</mml:mn></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>for</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>all</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq208\"><alternatives><tex-math id=\"M551\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathcal {Q}$$\\end{document}</tex-math><mml:math id=\"M552\"><mml:mi mathvariant=\"script\">Q</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq209\"><alternatives><tex-math id=\"M553\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varepsilon \\approx \\alpha $$\\end{document}</tex-math><mml:math id=\"M554\"><mml:mrow><mml:mi>ε</mml:mi><mml:mo>≈</mml:mo><mml:mi>α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq210\"><alternatives><tex-math id=\"M555\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta \\approx \\alpha ^{p+N+1}$$\\end{document}</tex-math><mml:math id=\"M556\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>≈</mml:mo><mml:msup><mml:mi>α</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>+</mml:mo><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq211\"><alternatives><tex-math id=\"M557\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^-=0$$\\end{document}</tex-math><mml:math id=\"M558\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq212\"><alternatives><tex-math id=\"M559\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)=(0,0)$$\\end{document}</tex-math><mml:math id=\"M560\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq213\"><alternatives><tex-math id=\"M561\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q=K_{\\varrho }\\times (0,\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}]$$\\end{document}</tex-math><mml:math id=\"M562\"><mml:mrow><mml:mi>Q</mml:mi><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ109\"><alternatives><tex-math id=\"M563\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} w_- =(u-k)_- \\quad \\text {and}\\quad k= \\xi \\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M564\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mspace width=\"1em\"/><mml:mtext>and</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>k</mml:mi><mml:mo>=</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq214\"><alternatives><tex-math id=\"M565\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta (x,t)\\equiv \\zeta (x)$$\\end{document}</tex-math><mml:math id=\"M566\"><mml:mrow><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>≡</mml:mo><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq215\"><alternatives><tex-math id=\"M567\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{(1-\\sigma )\\varrho }$$\\end{document}</tex-math><mml:math id=\"M568\"><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq216\"><alternatives><tex-math id=\"M569\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M570\"><mml:mrow><mml:mi>σ</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq217\"><alternatives><tex-math id=\"M571\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{(1-\\frac{1}{2}\\sigma )\\varrho }$$\\end{document}</tex-math><mml:math id=\"M572\"><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq218\"><alternatives><tex-math id=\"M573\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|D\\zeta \|\\le 4(\\sigma \\varrho )^{-1}$$\\end{document}</tex-math><mml:math id=\"M574\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>D</mml:mi><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mn>4</mml:mn><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq219\"><alternatives><tex-math id=\"M575\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0<t<\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}$$\\end{document}</tex-math><mml:math id=\"M576\"><mml:mrow><mml:mn>0</mml:mn><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ110\"><alternatives><tex-math id=\"M577\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned}&\\int _{K_{(1-\\sigma )\\varrho }\\times \\{t\\}} w^2_{-}\\,\\textrm{d}x-\\int _{K_{\\varrho }\\times \\{0\\}} w^2_{-}\\,\\textrm{d}x\\\\&\\quad \\le \\varvec{\\gamma }\\int _0^{\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}}\\int _{K_\\varrho }\\int _{K_\\varrho }\\max \\big \\{w^p_{-}(x,t), w^p_{-}(y,t)\\big \\} \\frac{\|\\zeta (x) -\\zeta (y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\qquad +\\varvec{\\gamma }\\iint _{Q} \\zeta ^p w_{-}(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in {\\text {supp}}\\zeta \\\\ t\\in (0, \\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_\\varrho }\\frac{ w_{-}^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) . \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M578\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"2em\"/><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mo>∬</mml:mo><mml:mi>Q</mml:mi></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:mtext>supp</mml:mtext><mml:mi>ζ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ111\"><alternatives><tex-math id=\"M579\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _0^{\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}}&\\int _{K_\\varrho }\\int _{K_\\varrho }\\max \\big \\{w^p_{-}(x,t), w^p_{-}(y,t)\\big \\} \\frac{\|\\zeta (x) - \\zeta (y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le \\varvec{\\gamma } [\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp} ](\\xi \\varvec{\\omega })^p\\int _{K_\\varrho }\\int _{K_\\varrho } \\frac{\|\\zeta (x) - \\zeta (y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\\\&\\le \\varvec{\\gamma } [\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp} ]\\frac{(\\xi \\varvec{\\omega })^p}{(\\sigma \\varrho )^p}\\int _{K_\\varrho }\\int _{K_\\varrho } \\frac{1}{\|x-y\|^{N+(s-1)p}}\\,\\textrm{d}x\\textrm{d}y\\\\&\\le \\varvec{\\gamma }\\frac{ \\delta (\\xi \\varvec{\\omega })^{2}}{\\sigma ^p}\|K_\\varrho \|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M580\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:msubsup></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">[</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">[</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mfrac><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:msub><mml:mfrac><mml:mn>1</mml:mn><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>s</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup></mml:mrow><mml:msup><mml:mi>σ</mml:mi><mml:mi>p</mml:mi></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq220\"><alternatives><tex-math id=\"M581\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$x\\in {\\text {supp}}\\zeta \\subset K_{(1-\\frac{1}{2}\\sigma )\\varrho }$$\\end{document}</tex-math><mml:math id=\"M582\"><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:mtext>supp</mml:mtext><mml:mi>ζ</mml:mi><mml:mo>⊂</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq221\"><alternatives><tex-math id=\"M583\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$y\\in \\mathbb {R}^N{\\setminus } K_{\\varrho }$$\\end{document}</tex-math><mml:math id=\"M584\"><mml:mrow><mml:mi>y</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ112\"><alternatives><tex-math id=\"M585\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\frac{\|x-y\|}{\|y\|}\\ge 1-\\frac{\|x\|}{\|y\|}\\ge \\tfrac{1}{2}\\sigma ; \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M586\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mfrac><mml:mo>≥</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mfrac><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>σ</mml:mi><mml:mo>;</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ113\"><alternatives><tex-math id=\"M587\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\iint _{Q}&\\zeta ^p w_{-}(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in {\\text {supp}}\\zeta \\\\ t\\in (0, \\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_\\varrho }\\frac{ w_{-}^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\le \\varvec{\\gamma } \\frac{\\xi \\varvec{\\omega } \|Q\|}{\\sigma ^{N+sp}} \\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} t\\in (0, \\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_\\varrho }\\frac{ w_{-}^{p-1}(y,t)}{\|y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&= \\varvec{\\gamma } \\frac{\\xi \\varvec{\\omega } \|Q\|}{\\sigma ^{N+sp}} \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} t\\in (0, \\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}) \\end{array}} \\left( \\int _{K_R\\setminus K_\\varrho }\\frac{ w_{-}^{p-1}(y,t)}{\|y\|^{N+sp}}\\,\\textrm{d}y+ \\int _{\\mathbb {R}^N\\setminus K_R}\\frac{ w_{-}^{p-1}(y,t)}{\|y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\le \\varvec{\\gamma } \\frac{\\xi \\varvec{\\omega } \|Q\|}{\\sigma ^{N+sp}} \\left( \\varvec{\\gamma } \\frac{(\\xi \\varvec{\\omega })^{p-1}}{\\varrho ^{sp}}+\\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} t\\in (0, \\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_R}\\frac{ u_{-}^{p-1}(y,t)}{\|y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&= \\varvec{\\gamma } \\frac{\\xi \\varvec{\\omega } \|Q\|}{\\sigma ^{N+sp}\\varrho ^{sp}} \\left( \\varvec{\\gamma } (\\xi \\varvec{\\omega })^{p-1} + \\left( \\frac{\\varrho }{R}\\right) ^{sp} [\\textrm{Tail}(u_-; \\mathcal {Q})]^{p-1} \\right) \\\\&\\le \\varvec{\\gamma } \\frac{(\\xi \\varvec{\\omega })^p}{\\sigma ^{N+sp} \\varrho ^{sp}} \|Q\|=\\varvec{\\gamma }\\frac{\\delta (\\xi \\varvec{\\omega })^{2}}{\\sigma ^{N+sp}}\|K_\\varrho \|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M588\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msub><mml:mo>∬</mml:mo><mml:mi>Q</mml:mi></mml:msub></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:mtext>supp</mml:mtext><mml:mi>ζ</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mrow><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mrow><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mo>+</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mrow><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>+</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mrow><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">[</mml:mo><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup></mml:mrow><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ114\"><alternatives><tex-math id=\"M589\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}(u_{-}; \\mathcal {Q}) \\le \\xi \\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M590\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq222\"><alternatives><tex-math id=\"M591\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0<t<\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}$$\\end{document}</tex-math><mml:math id=\"M592\"><mml:mrow><mml:mn>0</mml:mn><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ115\"><alternatives><tex-math id=\"M593\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _{K_{(1-\\sigma )\\varrho }\\times \\{t\\}} (u-\\xi \\varvec{\\omega })^2_- \\,\\textrm{d}x&\\le \\int _{K_\\varrho \\times \\{0\\}} (u-\\xi \\varvec{\\omega })^2_-\\, \\textrm{d}x+ \\varvec{\\gamma }\\frac{\\delta (\\xi \\varvec{\\omega })^{2}}{\\sigma ^{p+N}}\|K_\\varrho \|\\nonumber \\\\&\\le (\\xi \\varvec{\\omega })^{2}\\Big [(1-\\alpha ) +\\varvec{\\gamma }\\frac{ \\delta }{\\sigma ^{p+N}}\\Big ]\|K_\\varrho \|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M594\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup></mml:mrow><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>+</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>α</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mi>δ</mml:mi><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>+</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ116\"><alternatives><tex-math id=\"M595\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _{K_{(1-\\sigma )\\varrho }\\times \\{t\\}} (u-\\xi \\varvec{\\omega })^2_- \\,\\textrm{d}x&\\ge \\int _{K_{(1-\\sigma )\\varrho }\\times \\{t\\}} (u-\\xi \\varvec{\\omega })^2_- \\chi _{\\{u< \\varepsilon \\xi \\varvec{\\omega }\\}} \\,\\textrm{d}x\\\\&\\ge (1-\\varepsilon )^2 (\\xi \\varvec{\\omega })^{2}\|A_{\\varepsilon ,(1-\\sigma )\\varrho }(t)\| \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M596\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≥</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:msub><mml:mi>χ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>u</mml:mi><mml:mo><</mml:mo><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≥</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>ε</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ117\"><alternatives><tex-math id=\"M597\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} A_{\\varepsilon ,(1-\\sigma )\\varrho }(t):=\\Big \\{u(\\cdot ,t)<\\varepsilon \\xi \\varvec{\\omega }\\Big \\}\\cap K_{(1-\\sigma )\\varrho }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M598\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo><</mml:mo><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ118\"><alternatives><tex-math id=\"M599\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \|A_{\\varepsilon ,\\varrho }(t)\|&=\|A_{\\varepsilon ,(1-\\sigma )\\varrho }(t)\\cup (A_{\\varepsilon ,\\varrho }(t)-A_{\\varepsilon ,(1-\\sigma )\\varrho }(t))\|\\\\&\\le \|A_{\\varepsilon ,(1-\\sigma )\\varrho }(t)\|+\|K_\\varrho - K_{(1-\\sigma )\\varrho }\|\\\\&\\le \|A_{\\varepsilon ,(1-\\sigma )\\varrho }(t)\|+N\\sigma \|K_\\varrho \|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M600\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo>=</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>∪</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo>≤</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>+</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo>≤</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>+</mml:mo><mml:mi>N</mml:mi><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>.</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq223\"><alternatives><tex-math id=\"M601\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0<t<\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}$$\\end{document}</tex-math><mml:math id=\"M602\"><mml:mrow><mml:mn>0</mml:mn><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ119\"><alternatives><tex-math id=\"M603\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \|A_{\\varepsilon ,\\varrho }(t)\|\\le \\frac{1}{(1-\\varepsilon )^2}\\Big [(1-\\alpha ) +\\varvec{\\gamma }\\frac{ \\delta }{\\sigma ^{p+N}} \\Big ]\|K_\\varrho \|+ N\\sigma \|K_\\varrho \|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M604\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>≤</mml:mo></mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>ε</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup></mml:mfrac><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>α</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mi>δ</mml:mi><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>+</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>+</mml:mo><mml:mi>N</mml:mi><mml:mi>σ</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>.</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq224\"><alternatives><tex-math id=\"M605\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma $$\\end{document}</tex-math><mml:math id=\"M606\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq225\"><alternatives><tex-math id=\"M607\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M608\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq226\"><alternatives><tex-math id=\"M609\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varepsilon $$\\end{document}</tex-math><mml:math id=\"M610\"><mml:mi>ε</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ120\"><alternatives><tex-math id=\"M611\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} N\\sigma =\\tfrac{1}{4}\\alpha ,\\quad \\varvec{\\gamma }\\frac{ \\delta }{\\sigma ^{p+N}} =\\tfrac{1}{8}\\alpha , \\quad \\frac{1-\\frac{7}{8}\\alpha }{(1-\\varepsilon )^2}\\le 1-\\tfrac{1}{4}\\alpha . \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M612\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>N</mml:mi><mml:mi>σ</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mi>α</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mi>δ</mml:mi><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>+</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>8</mml:mn></mml:mfrac></mml:mstyle><mml:mi>α</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mfrac><mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mfrac><mml:mn>7</mml:mn><mml:mn>8</mml:mn></mml:mfrac><mml:mi>α</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>ε</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup></mml:mfrac><mml:mo>≤</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mi>α</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ121\"><alternatives><tex-math id=\"M613\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \|A_{\\varepsilon ,\\varrho }(t)\|\\le (1-\\tfrac{1}{2}\\alpha ) \|K_\\varrho \| \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M614\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>A</mml:mi><mml:mrow><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>≤</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>α</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq227\"><alternatives><tex-math id=\"M615\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0<t<\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}$$\\end{document}</tex-math><mml:math id=\"M616\"><mml:mrow><mml:mn>0</mml:mn><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq228\"><alternatives><tex-math id=\"M617\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\square $$\\end{document}</tex-math><mml:math id=\"M618\"><mml:mo>□</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq229\"><alternatives><tex-math id=\"M619\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)$$\\end{document}</tex-math><mml:math id=\"M620\"><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq230\"><alternatives><tex-math id=\"M621\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_\\varrho (\\theta )$$\\end{document}</tex-math><mml:math id=\"M622\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq231\"><alternatives><tex-math id=\"M623\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M624\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq232\"><alternatives><tex-math id=\"M625\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M626\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq233\"><alternatives><tex-math id=\"M627\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma $$\\end{document}</tex-math><mml:math id=\"M628\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq234\"><alternatives><tex-math id=\"M629\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi $$\\end{document}</tex-math><mml:math id=\"M630\"><mml:mi>ξ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq235\"><alternatives><tex-math id=\"M631\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(0,\\tfrac{1}{2})$$\\end{document}</tex-math><mml:math id=\"M632\"><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ122\"><alternatives><tex-math id=\"M633\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\pm \\big (\\varvec{\\mu }^{\\pm }-u(\\cdot , t)\\big )\\ge \\xi \\varvec{\\omega } \\Big \\}\\cap K_{\\varrho }(x_o)\\Big \| \\ge \\alpha \\big \|K_{\\varrho }\\big \|\\quad \\text{ for } \\text{ all } t\\in \\big (t_o-\\delta (\\sigma \\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}, t_o\\big ]. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M634\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>α</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>for</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>all</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq236\"><alternatives><tex-math id=\"M635\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta =\\delta (\\sigma \\xi \\varvec{\\omega })^{2-p}$$\\end{document}</tex-math><mml:math id=\"M636\"><mml:mrow><mml:mi>θ</mml:mi><mml:mo>=</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq237\"><alternatives><tex-math id=\"M637\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma }>0$$\\end{document}</tex-math><mml:math id=\"M638\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mo>></mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq238\"><alternatives><tex-math id=\"M639\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M640\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq239\"><alternatives><tex-math id=\"M641\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{\\alpha , \\delta , \\sigma ,\\xi \\}$$\\end{document}</tex-math><mml:math id=\"M642\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>α</mml:mi><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:mo>,</mml:mo><mml:mi>σ</mml:mi><mml:mo>,</mml:mo><mml:mi>ξ</mml:mi><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ123\"><alternatives><tex-math id=\"M643\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}\\big (\\big (u - \\varvec{\\mu }^{\\pm }\\big )_{\\pm }; \\mathcal {Q}\\big ) >\\sigma \\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M644\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ124\"><alternatives><tex-math id=\"M645\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\pm \\big (\\varvec{\\mu }^{\\pm }-u\\big )\\le \\sigma \\xi \\varvec{\\omega } \\Big \\}\\cap Q_{\\varrho }(\\theta )\\Big \| \\le \\varvec{\\gamma } \\frac{\\sigma ^{p-1}}{\\delta \\alpha } \|Q_{\\varrho }(\\theta )\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M646\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mi>δ</mml:mi><mml:mi>α</mml:mi></mml:mrow></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq240\"><alternatives><tex-math id=\"M647\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_{2\\varrho }(\\theta )$$\\end{document}</tex-math><mml:math id=\"M648\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq241\"><alternatives><tex-math id=\"M649\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathcal {Q}$$\\end{document}</tex-math><mml:math id=\"M650\"><mml:mi mathvariant=\"script\">Q</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq242\"><alternatives><tex-math id=\"M651\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^-=0$$\\end{document}</tex-math><mml:math id=\"M652\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq243\"><alternatives><tex-math id=\"M653\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)=(0,0)$$\\end{document}</tex-math><mml:math id=\"M654\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq244\"><alternatives><tex-math id=\"M655\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{2\\varrho }\\times (-\\theta \\varrho ^{sp}, 0]$$\\end{document}</tex-math><mml:math id=\"M656\"><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ125\"><alternatives><tex-math id=\"M657\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} w_- =(u-k)_- \\quad \\text {and}\\quad k= \\sigma \\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M658\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mspace width=\"1em\"/><mml:mtext>and</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>k</mml:mi><mml:mo>=</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq245\"><alternatives><tex-math id=\"M659\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta $$\\end{document}</tex-math><mml:math id=\"M660\"><mml:mi>ζ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq246\"><alternatives><tex-math id=\"M661\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{ 2\\varrho }$$\\end{document}</tex-math><mml:math id=\"M662\"><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq247\"><alternatives><tex-math id=\"M663\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{\\varrho }$$\\end{document}</tex-math><mml:math id=\"M664\"><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq248\"><alternatives><tex-math id=\"M665\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{\\frac{3}{2}\\varrho }$$\\end{document}</tex-math><mml:math id=\"M666\"><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mfrac><mml:mn>3</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq249\"><alternatives><tex-math id=\"M667\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|D\\zeta \|\\le 4/\\varrho $$\\end{document}</tex-math><mml:math id=\"M668\"><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>D</mml:mi><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>≤</mml:mo><mml:mn>4</mml:mn><mml:mo stretchy=\"false\">/</mml:mo><mml:mi>ϱ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ126\"><alternatives><tex-math id=\"M669\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\iint _{Q_\\varrho (\\theta )}&w_{-}(y,t) \\,\\textrm{d}y\\textrm{d}t\\left( \\int _{ K_{2\\varrho }} \\frac{w^{p-1}_+(x,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\right) \\\\&\\le \\varvec{\\gamma }\\int _{-\\theta \\varrho ^{sp}}^{0}\\int _{K_{2\\varrho }}\\int _{K_{2\\varrho }}\\max \\big \\{w_{-}^p(x,t), w_{-}^p(y,t)\\big \\} \\frac{\|\\zeta (x) - \\zeta (y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\quad +\\varvec{\\gamma }\\iint _{Q_{2\\varrho }(\\theta )} \\zeta ^p w_{-}(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in K_{\\frac{3}{2}\\varrho }\\\\ t\\in (-\\theta \\varrho ^{sp},0) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_{2\\varrho }}\\frac{ w_{-}^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\quad + \\int _{K_{2\\varrho } } w_-^2(x,-\\theta \\varrho ^{sp}) \\,\\textrm{d}x. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M670\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:msub></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mfrac><mml:mn>3</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ127\"><alternatives><tex-math id=\"M671\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _{-\\theta \\varrho ^{sp}}^{0}&\\int _{K_{2\\varrho }}\\int _{K_{2\\varrho }}\\max \\big \\{w_{-}^p(x,t), w_{-}^p(y,t)\\big \\} \\frac{\|\\zeta (x) - \\zeta (y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t\\\\&\\le \\theta \\varrho ^{sp} (\\sigma \\xi \\varvec{\\omega })^p\\int _{K_{2\\varrho }}\\int _{K_{2\\varrho }} \\frac{\|\\zeta (x) - \\zeta (y)\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\\\&\\le \\varvec{\\gamma }\\theta \\varrho ^{sp} \\frac{(\\sigma \\xi \\varvec{\\omega })^p}{\\varrho ^p}\\int _{K_{2\\varrho }}\\int _{K_{2\\varrho }} \\frac{1}{\|x-y\|^{N+(s-1)p}}\\,\\textrm{d}x\\textrm{d}y\\\\&\\le \\varvec{\\gamma }\\theta \\varrho ^{sp} \\frac{(\\sigma \\xi \\varvec{\\omega })^p}{\\varrho ^p}\\frac{\|K_{2\\varrho }\|}{\\varrho ^{(s-1)p}}\\\\&\\le \\varvec{\\gamma } \\frac{(\\sigma \\xi \\varvec{\\omega })^p}{\\varrho ^{sp}}\|Q_{\\varrho }(\\theta )\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M672\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow><mml:mn>0</mml:mn></mml:msubsup></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mo movablelimits=\"true\">max</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mi>p</mml:mi></mml:msup></mml:mfrac><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:mn>1</mml:mn><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>s</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mi>p</mml:mi></mml:msup></mml:mfrac><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>s</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq250\"><alternatives><tex-math id=\"M673\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|K_{2\\varrho }\|=2^N \|K_\\varrho \|$$\\end{document}</tex-math><mml:math id=\"M674\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>=</mml:mo></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mi>N</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq251\"><alternatives><tex-math id=\"M675\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|x\|\\le \\frac{3}{2}\\varrho $$\\end{document}</tex-math><mml:math id=\"M676\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:mn>3</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ϱ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq252\"><alternatives><tex-math id=\"M677\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|y\|\\ge 2\\varrho $$\\end{document}</tex-math><mml:math id=\"M678\"><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>≥</mml:mo><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ128\"><alternatives><tex-math id=\"M679\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\frac{\|x-y\|}{\|y\|}\\ge 1-\\frac{\|x\|}{\|y\|}\\ge \\frac{1}{4}; \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M680\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mfrac><mml:mo>≥</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mfrac><mml:mo>≥</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mo>;</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ129\"><alternatives><tex-math id=\"M681\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\iint _{Q_{2\\varrho }(\\theta )}&\\zeta ^p w_{-}(x,t)\\,\\textrm{d}x\\textrm{d}t\\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} x\\in K_{\\frac{3}{2}\\varrho }\\\\ t\\in (-\\theta \\varrho ^{sp},0) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_{2\\varrho }}\\frac{ w_{-}^{p-1}(y,t)}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\le \\varvec{\\gamma }(\\sigma \\xi \\varvec{\\omega }) \|Q_{2\\varrho }(\\theta )\| \\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} t\\in (-\\theta \\varrho ^{sp},0) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_{2\\varrho }}\\frac{ w_{-}^{p-1}(y,t)}{\|y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\le \\varvec{\\gamma }(\\sigma \\xi \\varvec{\\omega }) \|Q_{2\\varrho }(\\theta )\| \\left( \\varvec{\\gamma }\\frac{(\\sigma \\xi \\varvec{\\omega })^{p-1}}{\\varrho ^{sp}}+\\mathop {\\mathrm{ess\\,sup}}\\limits _{\\begin{array}{c} t\\in (-\\theta \\varrho ^{sp},0) \\end{array}} \\int _{\\mathbb {R}^N\\setminus K_{R}}\\frac{ u_{-}^{p-1}(y,t)}{\|y\|^{N+sp}}\\,\\textrm{d}y\\right) \\\\&\\le \\varvec{\\gamma }\\frac{\\sigma \\xi \\varvec{\\omega }}{\\varrho ^{sp}} \|Q_{2\\varrho }(\\theta )\| \\left( \\varvec{\\gamma } (\\sigma \\xi \\varvec{\\omega })^{p-1}+\\left( \\frac{\\varrho }{R}\\right) ^{sp} [\\textrm{Tail}(u_{-}; \\mathcal {Q})]^{p-1} \\right) \\\\&\\le \\varvec{\\gamma } \\frac{(\\sigma \\xi \\varvec{\\omega })^p}{\\varrho ^{sp}}\|Q_{\\varrho }(\\theta )\|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M682\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:msub></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mfrac><mml:mn>3</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>+</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:mrow><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">[</mml:mo><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ130\"><alternatives><tex-math id=\"M683\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}(u_{-}; \\mathcal {Q}) \\le \\sigma \\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M684\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq253\"><alternatives><tex-math id=\"M685\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|Q_{2\\varrho }(\\theta )\|=2^{N+p}\|Q_{\\varrho }(\\theta )\|$$\\end{document}</tex-math><mml:math id=\"M686\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>=</mml:mo></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ131\"><alternatives><tex-math id=\"M687\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _{K_{2\\varrho } } w_-^2(x,-\\theta \\varrho ^{sp}) \\,\\textrm{d}x\\le (\\sigma \\xi \\varvec{\\omega })^2\|K_{2\\varrho }\|\\le \\varvec{\\gamma } \\frac{(\\sigma \\xi \\varvec{\\omega })^p}{\\delta \\varrho ^{sp}}\|Q_{\\varrho }(\\theta )\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M688\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msubsup><mml:mi>w</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq254\"><alternatives><tex-math id=\"M689\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta =\\delta (\\sigma \\xi \\varvec{\\omega })^{2-p}$$\\end{document}</tex-math><mml:math id=\"M690\"><mml:mrow><mml:mi>θ</mml:mi><mml:mo>=</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq255\"><alternatives><tex-math id=\"M691\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|K_{2\\varrho }\|=2^N \|K_\\varrho \|$$\\end{document}</tex-math><mml:math id=\"M692\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>=</mml:mo></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mi>N</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ132\"><alternatives><tex-math id=\"M693\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\gamma } \\frac{(\\sigma \\xi \\varvec{\\omega })^p}{\\delta \\varrho ^{sp}}\|Q_{\\varrho }(\\theta )\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M694\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq256\"><alternatives><tex-math id=\"M695\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma }$$\\end{document}</tex-math><mml:math id=\"M696\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq257\"><alternatives><tex-math id=\"M697\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M698\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq258\"><alternatives><tex-math id=\"M699\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{\\alpha , \\delta , \\sigma ,\\xi \\}$$\\end{document}</tex-math><mml:math id=\"M700\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>α</mml:mi><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:mo>,</mml:mo><mml:mi>σ</mml:mi><mml:mo>,</mml:mo><mml:mi>ξ</mml:mi><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ133\"><alternatives><tex-math id=\"M701\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\iint _{Q_\\varrho (\\theta ) }&w_{-}(y,t) \\chi _{\\{u(y,t)\\le \\frac{1}{2}\\sigma \\xi \\varvec{\\omega }\\}} \\,\\textrm{d}y\\textrm{d}t\\left( \\int _{ K_{2\\varrho }} \\frac{w^{p-1}_+(x,t)\\chi _{\\{u(x,t)\\ge \\xi \\varvec{\\omega }\\} }}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\right) \\\\&\\ge \\tfrac{1}{2}\\sigma \\xi \\varvec{\\omega }\\Big \|\\Big \\{u\\le \\tfrac{1}{2}\\sigma \\xi \\varvec{\\omega }\\Big \\}\\cap Q_\\varrho (\\theta )\\Big \| \\left( \\frac{ (\\tfrac{1}{2}\\xi \\varvec{\\omega })^{p-1}\\alpha \|K_\\varrho \|}{(4\\varrho )^{N+sp}} \\right) \\\\&=2^{-(2N+p+2sp)}\\frac{(\\xi \\varvec{\\omega })^p\\alpha \\sigma }{\\varrho ^{sp}} \\Big \|\\Big \\{u\\le \\tfrac{1}{2}\\sigma \\xi \\varvec{\\omega }\\Big \\}\\cap Q_\\varrho (\\theta )\\Big \|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M702\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:msub></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mi>w</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mi>χ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:msubsup><mml:mi>w</mml:mi><mml:mo>+</mml:mo><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mi>χ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>≥</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mi>α</mml:mi><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo>-</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>2</mml:mn><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>p</mml:mi><mml:mo>+</mml:mo><mml:mn>2</mml:mn><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msup><mml:mfrac><mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mi>α</mml:mi><mml:mi>σ</mml:mi></mml:mrow><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>σ</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq259\"><alternatives><tex-math id=\"M703\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\square $$\\end{document}</tex-math><mml:math id=\"M704\"><mml:mo>□</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq260\"><alternatives><tex-math id=\"M705\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$1<p\\le 2$$\\end{document}</tex-math><mml:math id=\"M706\"><mml:mrow><mml:mn>1</mml:mn><mml:mo><</mml:mo><mml:mi>p</mml:mi><mml:mo>≤</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq261\"><alternatives><tex-math id=\"M707\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathcal {Q}$$\\end{document}</tex-math><mml:math id=\"M708\"><mml:mi mathvariant=\"script\">Q</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq262\"><alternatives><tex-math id=\"M709\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^{\\pm }$$\\end{document}</tex-math><mml:math id=\"M710\"><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq263\"><alternatives><tex-math id=\"M711\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M712\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq264\"><alternatives><tex-math id=\"M713\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$1<p\\le 2$$\\end{document}</tex-math><mml:math id=\"M714\"><mml:mrow><mml:mn>1</mml:mn><mml:mo><</mml:mo><mml:mi>p</mml:mi><mml:mo>≤</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq265\"><alternatives><tex-math id=\"M715\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M716\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq266\"><alternatives><tex-math id=\"M717\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$1<p\\le 2$$\\end{document}</tex-math><mml:math id=\"M718\"><mml:mrow><mml:mn>1</mml:mn><mml:mo><</mml:mo><mml:mi>p</mml:mi><mml:mo>≤</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq267\"><alternatives><tex-math id=\"M719\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha ,\\xi \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M720\"><mml:mrow><mml:mi>α</mml:mi><mml:mo>,</mml:mo><mml:mi>ξ</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ134\"><alternatives><tex-math id=\"M721\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{\\pm \\big (\\varvec{\\mu }^{\\pm }-u(\\cdot , t_o)\\big )\\ge \\xi \\varvec{\\omega } \\Big \\}\\cap K_{\\varrho }(x_o) \\Big \| \\ge \\alpha \\big \|K_\\varrho \\big \|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M722\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>α</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq268\"><alternatives><tex-math id=\"M723\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta ,\\,\\eta \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M724\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mi>η</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq269\"><alternatives><tex-math id=\"M725\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M726\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq270\"><alternatives><tex-math id=\"M727\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha $$\\end{document}</tex-math><mml:math id=\"M728\"><mml:mi>α</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ135\"><alternatives><tex-math id=\"M729\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}\\big (\\big (u - \\varvec{\\mu }^{\\pm }\\big )_{\\pm }; \\mathcal {Q}\\big ) >\\eta \\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M730\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>η</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ136\"><alternatives><tex-math id=\"M731\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\pm \\big (\\varvec{\\mu }^{\\pm }-u\\big )\\ge \\eta \\xi \\varvec{\\omega } \\quad \\text{ a.e. } \\text{ in } K_{2\\varrho }(x_o) \\times \\big ( t_o+\\tfrac{1}{2} \\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}, t_o+\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}\\big ], \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M732\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>±</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>±</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>η</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>a.e.</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>in</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ137\"><alternatives><tex-math id=\"M733\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} K_{4\\varrho }(x_o)\\times \\big (t_o, t_o+\\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}\\big ]\\subset \\mathcal {Q}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M734\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>+</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq271\"><alternatives><tex-math id=\"M735\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta \\approx \\alpha ^{p+N+1}$$\\end{document}</tex-math><mml:math id=\"M736\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>≈</mml:mo><mml:msup><mml:mi>α</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>+</mml:mo><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq272\"><alternatives><tex-math id=\"M737\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\eta \\approx \\alpha ^q$$\\end{document}</tex-math><mml:math id=\"M738\"><mml:mrow><mml:mi>η</mml:mi><mml:mo>≈</mml:mo><mml:msup><mml:mi>α</mml:mi><mml:mi>q</mml:mi></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq273\"><alternatives><tex-math id=\"M739\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$q>1$$\\end{document}</tex-math><mml:math id=\"M740\"><mml:mrow><mml:mi>q</mml:mi><mml:mo>></mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq274\"><alternatives><tex-math id=\"M741\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M742\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq275\"><alternatives><tex-math id=\"M743\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)=(0,0)$$\\end{document}</tex-math><mml:math id=\"M744\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq276\"><alternatives><tex-math id=\"M745\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^{-}=0$$\\end{document}</tex-math><mml:math id=\"M746\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq277\"><alternatives><tex-math id=\"M747\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M748\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq278\"><alternatives><tex-math id=\"M749\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\eta $$\\end{document}</tex-math><mml:math id=\"M750\"><mml:mi>η</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ138\"><alternatives><tex-math id=\"M751\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{u(\\cdot , 0) \\ge \\xi \\varvec{\\omega } \\Big \\}\\cap K_{\\varrho } \\Big \| \\ge \\alpha \\big \|K_\\varrho \\big \| \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M752\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>α</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>ϱ</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ139\"><alternatives><tex-math id=\"M753\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}\\big (u_{-}; \\mathcal {Q}\\big ) \\le \\eta \\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M754\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>η</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ140\"><alternatives><tex-math id=\"M755\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u\\ge \\eta \\xi \\varvec{\\omega } \\quad \\text{ a.e. } \\text{ in } K_{2\\varrho } \\times \\big ( \\tfrac{1}{2} \\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}, \\delta (\\xi \\varvec{\\omega })^{2-p}\\varrho ^{sp}\\big ]. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M756\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:mi>η</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>a.e.</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>in</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>ϱ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq279\"><alternatives><tex-math id=\"M757\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M758\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq280\"><alternatives><tex-math id=\"M759\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\eta $$\\end{document}</tex-math><mml:math id=\"M760\"><mml:mi>η</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq281\"><alternatives><tex-math id=\"M761\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M762\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq282\"><alternatives><tex-math id=\"M763\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha $$\\end{document}</tex-math><mml:math id=\"M764\"><mml:mi>α</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq283\"><alternatives><tex-math id=\"M765\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi $$\\end{document}</tex-math><mml:math id=\"M766\"><mml:mi>ξ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq284\"><alternatives><tex-math id=\"M767\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t_o=0$$\\end{document}</tex-math><mml:math id=\"M768\"><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq285\"><alternatives><tex-math id=\"M769\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{4\\varrho }$$\\end{document}</tex-math><mml:math id=\"M770\"><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq286\"><alternatives><tex-math id=\"M771\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha $$\\end{document}</tex-math><mml:math id=\"M772\"><mml:mi>α</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq287\"><alternatives><tex-math id=\"M773\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$4^{-N}\\alpha $$\\end{document}</tex-math><mml:math id=\"M774\"><mml:mrow><mml:msup><mml:mn>4</mml:mn><mml:mrow><mml:mo>-</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:msup><mml:mi>α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ141\"><alternatives><tex-math id=\"M775\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}(u_{-}; \\mathcal {Q}) \\le \\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M776\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq288\"><alternatives><tex-math id=\"M777\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta , \\varepsilon \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M778\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>,</mml:mo><mml:mi>ε</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq289\"><alternatives><tex-math id=\"M779\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\{s, p, N, C_o, C_1\\}$$\\end{document}</tex-math><mml:math id=\"M780\"><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq290\"><alternatives><tex-math id=\"M781\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha $$\\end{document}</tex-math><mml:math id=\"M782\"><mml:mi>α</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ142\"><alternatives><tex-math id=\"M783\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ u(\\cdot , t) \\ge \\varepsilon \\xi \\varvec{\\omega }\\Big \\} \\cap K_{4\\varrho } \\Big \| \\ge \\frac{\\alpha }{2} 4^{-N} \|K_{4\\varrho }\| \\quad \\text{ for } \\text{ all } t\\in \\big (0, \\delta (\\xi \\varvec{\\omega })^{2-p}(4\\varrho )^{sp}\\big ]. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M784\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mfrac><mml:mi>α</mml:mi><mml:mn>2</mml:mn></mml:mfrac><mml:msup><mml:mn>4</mml:mn><mml:mrow><mml:mo>-</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>for</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>all</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq291\"><alternatives><tex-math id=\"M785\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(0,\\bar{t})+Q_{4\\varrho }(\\delta (\\sigma \\varepsilon \\xi \\varvec{\\omega })^{2-p})$$\\end{document}</tex-math><mml:math id=\"M786\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq292\"><alternatives><tex-math id=\"M787\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{t}\\in \\big (\\delta (\\sigma \\varepsilon \\xi \\varvec{\\omega })^{2-p}(4\\varrho )^{sp}, \\delta (\\xi \\varvec{\\omega })^{2-p}(4\\varrho )^{sp}\\big ]$$\\end{document}</tex-math><mml:math id=\"M788\"><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq293\"><alternatives><tex-math id=\"M789\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi $$\\end{document}</tex-math><mml:math id=\"M790\"><mml:mi>ξ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq294\"><alternatives><tex-math id=\"M791\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha $$\\end{document}</tex-math><mml:math id=\"M792\"><mml:mi>α</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq295\"><alternatives><tex-math id=\"M793\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varepsilon \\xi $$\\end{document}</tex-math><mml:math id=\"M794\"><mml:mrow><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq296\"><alternatives><tex-math id=\"M795\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\tfrac{1}{2} 4^{-N}\\alpha $$\\end{document}</tex-math><mml:math id=\"M796\"><mml:mrow><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msup><mml:mn>4</mml:mn><mml:mrow><mml:mo>-</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:msup><mml:mi>α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq297\"><alternatives><tex-math id=\"M797\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M798\"><mml:mrow><mml:mi>σ</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq298\"><alternatives><tex-math id=\"M799\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta (\\sigma \\varepsilon \\xi \\varvec{\\omega })^{2-p}\\le \\delta (\\xi \\varvec{\\omega })^{2-p}$$\\end{document}</tex-math><mml:math id=\"M800\"><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo>≤</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ143\"><alternatives><tex-math id=\"M801\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} (0,\\bar{t})+Q_{4\\varrho }(\\delta (\\sigma \\varepsilon \\xi \\varvec{\\omega })^{2-p})\\subset K_{4\\varrho }\\times \\big (0, \\delta (\\xi \\varvec{\\omega })^{2-p}(4\\varrho )^{sp}\\big ] \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M802\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq299\"><alternatives><tex-math id=\"M803\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{t}$$\\end{document}</tex-math><mml:math id=\"M804\"><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq300\"><alternatives><tex-math id=\"M805\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p\\le 2$$\\end{document}</tex-math><mml:math id=\"M806\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>≤</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq301\"><alternatives><tex-math id=\"M807\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu $$\\end{document}</tex-math><mml:math id=\"M808\"><mml:mi>ν</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq302\"><alternatives><tex-math id=\"M809\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M810\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq303\"><alternatives><tex-math id=\"M811\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma $$\\end{document}</tex-math><mml:math id=\"M812\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ144\"><alternatives><tex-math id=\"M813\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\gamma } \\frac{\\sigma ^{p-1}}{\\delta \\alpha } <\\nu , \\quad \\text {i.e.}\\quad \\sigma \\le \\left( \\frac{\\nu \\delta \\alpha }{\\varvec{\\gamma }}\\right) ^{\\frac{1}{p-1}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M814\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mi>δ</mml:mi><mml:mi>α</mml:mi></mml:mrow></mml:mfrac><mml:mo><</mml:mo><mml:mi>ν</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>σ</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mrow><mml:mi>ν</mml:mi><mml:mi>δ</mml:mi><mml:mi>α</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac></mml:mfenced><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq304\"><alternatives><tex-math id=\"M815\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma }$$\\end{document}</tex-math><mml:math id=\"M816\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq305\"><alternatives><tex-math id=\"M817\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma $$\\end{document}</tex-math><mml:math id=\"M818\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ145\"><alternatives><tex-math id=\"M819\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\frac{\\varrho }{R}\\right) ^{\\frac{sp}{p-1}} \\textrm{Tail}\\big ( u_{-}; \\mathcal {Q}\\big ) \\le \\sigma \\varepsilon \\xi \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M820\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>ϱ</mml:mi><mml:mi>R</mml:mi></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>u</mml:mi><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:mi mathvariant=\"script\">Q</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq306\"><alternatives><tex-math id=\"M821\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma $$\\end{document}</tex-math><mml:math id=\"M822\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq307\"><alternatives><tex-math id=\"M823\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(0,\\bar{t})+Q_{4\\varrho }(\\delta (\\sigma \\varepsilon \\xi \\varvec{\\omega })^{2-p})$$\\end{document}</tex-math><mml:math id=\"M824\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq308\"><alternatives><tex-math id=\"M825\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{t}\\in \\big (\\delta (\\sigma \\varepsilon \\xi \\varvec{\\omega })^{2-p}(4\\varrho )^{sp}, \\delta (\\xi \\varvec{\\omega })^{2-p}(4\\varrho )^{sp}\\big ]$$\\end{document}</tex-math><mml:math id=\"M826\"><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq309\"><alternatives><tex-math id=\"M827\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi $$\\end{document}</tex-math><mml:math id=\"M828\"><mml:mi>ξ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq310\"><alternatives><tex-math id=\"M829\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma \\varepsilon \\xi $$\\end{document}</tex-math><mml:math id=\"M830\"><mml:mrow><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq311\"><alternatives><tex-math id=\"M831\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{t}$$\\end{document}</tex-math><mml:math id=\"M832\"><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ146\"><alternatives><tex-math id=\"M833\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u\\ge \\tfrac{1}{2}\\sigma \\varepsilon \\xi \\varvec{\\omega }\\quad \\text {a.e. in}\\>K_{2\\varrho } \\times \\big ( \\delta (\\sigma \\varepsilon \\xi \\varvec{\\omega })^{2-p}(4\\varrho )^{sp}, \\delta (\\xi \\varvec{\\omega })^{2-p}(4\\varrho )^{sp}\\big ]. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M834\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mtext>a.e. in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>ϱ</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>ξ</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>4</mml:mn><mml:mi>ϱ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq312\"><alternatives><tex-math id=\"M835\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\eta =\\sigma \\varepsilon $$\\end{document}</tex-math><mml:math id=\"M836\"><mml:mrow><mml:mi>η</mml:mi><mml:mo>=</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq313\"><alternatives><tex-math id=\"M837\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha $$\\end{document}</tex-math><mml:math id=\"M838\"><mml:mi>α</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq314\"><alternatives><tex-math id=\"M839\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\square $$\\end{document}</tex-math><mml:math id=\"M840\"><mml:mo>□</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq315\"><alternatives><tex-math id=\"M841\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$1<p\\le 2$$\\end{document}</tex-math><mml:math id=\"M842\"><mml:mrow><mml:mn>1</mml:mn><mml:mo><</mml:mo><mml:mi>p</mml:mi><mml:mo>≤</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq316\"><alternatives><tex-math id=\"M843\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p\\rightarrow 2$$\\end{document}</tex-math><mml:math id=\"M844\"><mml:mrow><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq317\"><alternatives><tex-math id=\"M845\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_{\\widetilde{R}}\\subset E_T$$\\end{document}</tex-math><mml:math id=\"M846\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub><mml:mo>⊂</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ147\"><alternatives><tex-math id=\"M847\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\omega }=2\\mathop {\\mathrm{ess\\,sup}}\\limits _{Q_{\\widetilde{R}}} \|u\| +\\textrm{Tail}(u; Q_{\\widetilde{R}}) \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M848\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>=</mml:mo><mml:mn>2</mml:mn><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:munder><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq318\"><alternatives><tex-math id=\"M849\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_o=Q_R(\\varvec{\\omega }^{2-p})$$\\end{document}</tex-math><mml:math id=\"M850\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq319\"><alternatives><tex-math id=\"M851\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_o\\subset Q_{\\widetilde{R}}$$\\end{document}</tex-math><mml:math id=\"M852\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>⊂</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ148\"><alternatives><tex-math id=\"M853\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\mu }^+=\\mathop {\\mathrm{ess\\,sup}}\\limits _{Q_o}u, \\qquad \\varvec{\\mu }^-=\\mathop {\\mathrm{ess\\,inf}}\\limits _{Q_o}u. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M854\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"2em\"/><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">inf</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq320\"><alternatives><tex-math id=\"M855\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)=(0,0)$$\\end{document}</tex-math><mml:math id=\"M856\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ14\"><label>4.1</label><alternatives><tex-math id=\"M857\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_R(\\varvec{\\omega }^{2-p})}u\\le \\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M858\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq321\"><alternatives><tex-math id=\"M859\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_{\\widetilde{R}}$$\\end{document}</tex-math><mml:math id=\"M860\"><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq322\"><alternatives><tex-math id=\"M861\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M862\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq323\"><alternatives><tex-math id=\"M863\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha =\\tfrac{1}{2}$$\\end{document}</tex-math><mml:math id=\"M864\"><mml:mrow><mml:mi>α</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq324\"><alternatives><tex-math id=\"M865\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$c\\in (0,\\tfrac{1}{4})$$\\end{document}</tex-math><mml:math id=\"M866\"><mml:mrow><mml:mi>c</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ149\"><alternatives><tex-math id=\"M867\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\tau :=\\delta (\\tfrac{1}{4} \\varvec{\\omega })^{2-p}( c R)^{sp} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M868\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>τ</mml:mi><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ150\"><alternatives><tex-math id=\"M869\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left\\{ \\begin{array}{ll} \\Big \|\\Big \\{u\\big (\\cdot ,-\\tau \\big )-\\varvec{\\mu }^->\\tfrac{1}{4} \\varvec{\\omega }\\Big \\} \\cap K_{c R}\\Big \| \\ge \\tfrac{1}{2} \|K_{c R}\|,\\\\ \\Big \|\\Big \\{\\varvec{\\mu }^+ - u\\big (\\cdot ,-\\tau \\big )>\\tfrac{1}{4} \\varvec{\\omega }\\Big \\} \\cap K_{c R}\\Big \| \\ge \\tfrac{1}{2} \|K_{c R}\|. \\end{array}\\right. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M870\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mfenced open=\"{\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mo>-</mml:mo><mml:mi>τ</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>></mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow/><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mo>-</mml:mo><mml:mi>τ</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq325\"><alternatives><tex-math id=\"M871\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^+ - \\varvec{\\mu }^-\\ge \\tfrac{1}{2}\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M872\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq326\"><alternatives><tex-math id=\"M873\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^+ - \\varvec{\\mu }^-<\\tfrac{1}{2}\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M874\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo><</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq327\"><alternatives><tex-math id=\"M875\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha =\\tfrac{1}{2}$$\\end{document}</tex-math><mml:math id=\"M876\"><mml:mrow><mml:mi>α</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq328\"><alternatives><tex-math id=\"M877\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi =\\tfrac{1}{4}$$\\end{document}</tex-math><mml:math id=\"M878\"><mml:mrow><mml:mi>ξ</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq329\"><alternatives><tex-math id=\"M879\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho =cR$$\\end{document}</tex-math><mml:math id=\"M880\"><mml:mrow><mml:mi>ϱ</mml:mi><mml:mo>=</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq330\"><alternatives><tex-math id=\"M881\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\eta \\in (0,\\tfrac{1}{2})$$\\end{document}</tex-math><mml:math id=\"M882\"><mml:mrow><mml:mi>η</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ15\"><label>4.2</label><alternatives><tex-math id=\"M883\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c^{\\frac{sp}{p-1}} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }^{-}\\big )_{-}; Q_o\\big ) > \\eta \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M884\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>η</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ151\"><alternatives><tex-math id=\"M885\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u-\\varvec{\\mu }^{-} \\ge \\eta \\varvec{\\omega } \\quad \\text {a.e. in}\\> Q_{cR}(\\tfrac{1}{2}\\delta (\\tfrac{1}{4} \\varvec{\\omega })^{2-p}), \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M886\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>≥</mml:mo><mml:mi>η</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mtext>a.e. in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ16\"><label>4.3</label><alternatives><tex-math id=\"M887\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{cR}(\\frac{1}{2}\\delta (\\frac{1}{4} \\varvec{\\omega })^{2-p})} u\\le \\big (1-\\eta )\\varvec{\\omega }=:\\varvec{\\omega }_1. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M888\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mrow><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>=</mml:mo><mml:mo>:</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mn>1</mml:mn></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ17\"><label>4.4</label><alternatives><tex-math id=\"M889\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }^{-}\\big )_{-}; Q_o\\big ) \\le \\varvec{\\gamma }\\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M890\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq331\"><alternatives><tex-math id=\"M891\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M892\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ152\"><alternatives><tex-math id=\"M893\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big [\\textrm{Tail}&\\big ( \\big (u-\\varvec{\\mu }^{-}\\big )_{-}; Q_o\\big )\\big ]^{p-1} =R^{sp} \\mathop {\\mathrm{ess\\,sup}}\\limits _{-\\varvec{\\omega }^{2-p}R^{sp}<t<0}\\int _{\\mathbb {R}^N\\setminus K_{R}}\\frac{\\big (u-\\varvec{\\mu }^{-}\\big )_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x\\\\&\\le \\varvec{\\gamma } \\varvec{\\omega }^{p-1}+\\varvec{\\gamma } R^{sp} \\mathop {\\mathrm{ess\\,sup}}\\limits _{-\\varvec{\\omega }^{2-p}R^{sp}<t<0} \\int _{\\mathbb {R}^N\\setminus K_R} \\frac{u_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x\\\\&=\\varvec{\\gamma } \\varvec{\\omega }^{p-1}+\\varvec{\\gamma } R^{sp} \\mathop {\\mathrm{ess\\,sup}}\\limits _{-\\varvec{\\omega }^{2-p}R^{sp}<t<0} \\bigg [ \\int _{\\mathbb {R}^N\\setminus K_{\\widetilde{R}}} \\frac{u_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x+ \\int _{K_{\\widetilde{R}}\\setminus K_{R}} \\frac{u_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x\\bigg ]\\\\&\\le \\varvec{\\gamma }\\varvec{\\omega }^{p-1}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M894\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mtext>Tail</mml:mtext></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>=</mml:mo><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:munder><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">]</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ18\"><label>4.5</label><alternatives><tex-math id=\"M895\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c^{\\frac{sp}{p-1}}\\varvec{\\gamma }\\varvec{\\omega }\\le \\eta \\varvec{\\omega },\\quad \\text {i.e.}\\quad c\\le \\left( \\frac{\\eta }{\\varvec{\\gamma }}\\right) ^{\\frac{p-1}{sp}}, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M896\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>≤</mml:mo><mml:mi>η</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>c</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mi>η</mml:mi><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq332\"><alternatives><tex-math id=\"M897\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$R_1=\\lambda R$$\\end{document}</tex-math><mml:math id=\"M898\"><mml:mrow><mml:msub><mml:mi>R</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>=</mml:mo><mml:mi>λ</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq333\"><alternatives><tex-math id=\"M899\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda \\le c$$\\end{document}</tex-math><mml:math id=\"M900\"><mml:mrow><mml:mi>λ</mml:mi><mml:mo>≤</mml:mo><mml:mi>c</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ19\"><label>4.6</label><alternatives><tex-math id=\"M901\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} Q_{R_1}(\\varvec{\\omega }_1^{2-p}) \\subset Q_{cR}(\\tfrac{1}{2}\\delta (\\tfrac{1}{4} \\varvec{\\omega })^{2-p}),\\quad \\text {i.e.}\\quad \\lambda \\le 2^{\\frac{2p-5}{p}}\\delta ^{\\frac{1}{p}}c. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M902\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mn>1</mml:mn><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>λ</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mfrac><mml:mrow><mml:mn>2</mml:mn><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>5</mml:mn></mml:mrow><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:msup><mml:mi>δ</mml:mi><mml:mfrac><mml:mn>1</mml:mn><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:mi>c</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ153\"><alternatives><tex-math id=\"M903\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{R_1}(\\varvec{\\omega }_1^{2-p})}u\\le \\varvec{\\omega }_1, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M904\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mn>1</mml:mn><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq334\"><alternatives><tex-math id=\"M905\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i=1,\\cdots , j$$\\end{document}</tex-math><mml:math id=\"M906\"><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mo>⋯</mml:mo><mml:mo>,</mml:mo><mml:mi>j</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ154\"><alternatives><tex-math id=\"M907\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left\\{ \\begin{array}{c} \\displaystyle R_o=R,\\quad R_i=\\lambda R_{i-1}, \\quad \\varvec{\\omega }_i=(1-\\eta )\\varvec{\\omega }_{i-1}, \\quad Q_i=Q_{R_i}(\\varvec{\\omega }_i^{2-p}),\\\\ \\displaystyle \\varvec{\\mu }_i^+=\\mathop {\\mathrm{ess\\,sup}}\\limits _{Q_i}u, \\quad \\varvec{\\mu }_i^-=\\mathop {\\mathrm{ess\\,inf}}\\limits _{Q_i}u, \\quad \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_i}u\\le \\varvec{\\omega }_i. \\end{array} \\right. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M908\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mfenced open=\"{\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:msub><mml:mi>R</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mi>λ</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mi>Q</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:mrow/><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>i</mml:mi><mml:mo>+</mml:mo></mml:msubsup><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">inf</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq335\"><alternatives><tex-math id=\"M909\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(j+1)$$\\end{document}</tex-math><mml:math id=\"M910\"><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq336\"><alternatives><tex-math id=\"M911\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M912\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq337\"><alternatives><tex-math id=\"M913\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$c\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M914\"><mml:mrow><mml:mi>c</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq338\"><alternatives><tex-math id=\"M915\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^{\\pm }_j$$\\end{document}</tex-math><mml:math id=\"M916\"><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>±</mml:mo></mml:msubsup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq339\"><alternatives><tex-math id=\"M917\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }_j$$\\end{document}</tex-math><mml:math id=\"M918\"><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq340\"><alternatives><tex-math id=\"M919\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$R_j$$\\end{document}</tex-math><mml:math id=\"M920\"><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq341\"><alternatives><tex-math id=\"M921\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_j$$\\end{document}</tex-math><mml:math id=\"M922\"><mml:msub><mml:mi>Q</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ155\"><alternatives><tex-math id=\"M923\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\tau :=\\delta (\\tfrac{1}{4} \\varvec{\\omega }_j)^{2-p}( c R_j)^{sp} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M924\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>τ</mml:mi><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ156\"><alternatives><tex-math id=\"M925\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left\\{ \\begin{array}{ll} \\Big \|\\Big \\{u\\big (\\cdot ,-\\tau \\big )-\\varvec{\\mu }^-_j>\\tfrac{1}{4} \\varvec{\\omega }_j\\Big \\} \\cap K_{c R_j}\\Big \| \\ge \\tfrac{1}{2} \|K_{c R_j}\|,\\\\ \\Big \|\\Big \\{\\varvec{\\mu }^+_j - u\\big (\\cdot ,-\\tau \\big )>\\tfrac{1}{4} \\varvec{\\omega }_j\\Big \\} \\cap K_{c R_j}\\Big \| \\ge \\tfrac{1}{2} \|K_{c R_j}\|. \\end{array}\\right. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M926\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mfenced open=\"{\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mo>-</mml:mo><mml:mi>τ</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:mo>></mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow/><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo></mml:msubsup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mo>-</mml:mo><mml:mi>τ</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq342\"><alternatives><tex-math id=\"M927\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^+_j - \\varvec{\\mu }^-_j\\ge \\tfrac{1}{2}\\varvec{\\omega }_j$$\\end{document}</tex-math><mml:math id=\"M928\"><mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo></mml:msubsup><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq343\"><alternatives><tex-math id=\"M929\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^+_j - \\varvec{\\mu }^-_j<\\tfrac{1}{2}\\varvec{\\omega }_j$$\\end{document}</tex-math><mml:math id=\"M930\"><mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo></mml:msubsup><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:mo><</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq344\"><alternatives><tex-math id=\"M931\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_j$$\\end{document}</tex-math><mml:math id=\"M932\"><mml:msub><mml:mi>Q</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq345\"><alternatives><tex-math id=\"M933\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha =\\tfrac{1}{2}$$\\end{document}</tex-math><mml:math id=\"M934\"><mml:mrow><mml:mi>α</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq346\"><alternatives><tex-math id=\"M935\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi =\\tfrac{1}{4}$$\\end{document}</tex-math><mml:math id=\"M936\"><mml:mrow><mml:mi>ξ</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq347\"><alternatives><tex-math id=\"M937\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho =cR_j$$\\end{document}</tex-math><mml:math id=\"M938\"><mml:mrow><mml:mi>ϱ</mml:mi><mml:mo>=</mml:mo><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq348\"><alternatives><tex-math id=\"M939\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\eta $$\\end{document}</tex-math><mml:math id=\"M940\"><mml:mi>η</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ20\"><label>4.7</label><alternatives><tex-math id=\"M941\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c^{\\frac{sp}{p-1}} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}; Q_j\\big ) > \\eta \\varvec{\\omega }_j, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M942\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>j</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>η</mml:mi><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ157\"><alternatives><tex-math id=\"M943\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u-\\varvec{\\mu }_j^{-} \\ge \\eta \\varvec{\\omega }_j \\quad \\text {a.e. in}\\> Q_{cR_j}(\\tfrac{1}{2}\\delta (\\tfrac{1}{4} \\varvec{\\omega }_j)^{2-p}), \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M944\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:mo>≥</mml:mo><mml:mi>η</mml:mi><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mspace width=\"1em\"/><mml:mtext>a.e. in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ21\"><label>4.8</label><alternatives><tex-math id=\"M945\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{cR_j}(\\frac{1}{2}\\delta (\\frac{1}{4} \\varvec{\\omega }_j)^{2-p})} u\\le \\big (1-\\eta \\big )\\varvec{\\omega }_j=:\\varvec{\\omega }_{j+1}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M946\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mo>:</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ22\"><label>4.9</label><alternatives><tex-math id=\"M947\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}; Q_j\\big ) \\le \\varvec{\\gamma }\\varvec{\\omega }_j. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M948\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>j</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ158\"><alternatives><tex-math id=\"M949\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big [\\textrm{Tail}&\\big ( \\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}; Q_j\\big )\\big ]^{p-1}=R_j^{sp}\\mathop {\\mathrm{ess\\,sup}}\\limits _{-\\varvec{\\omega }_j^{2-p}R_j^{sp}<t<0}\\int _{\\mathbb {R}^N\\setminus K_j} \\frac{\\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x\\\\&=R_j^{sp}\\mathop {\\mathrm{ess\\,sup}}\\limits _{-\\varvec{\\omega }_j^{2-p}R_j^{sp}<t<0} \\bigg [ \\int _{\\mathbb {R}^N\\setminus K_R} \\frac{\\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x+ \\sum _{i=1}^{j}\\int _{K_{i-1}\\setminus K_{i}} \\frac{\\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x\\bigg ]. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M950\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mtext>Tail</mml:mtext></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>j</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>=</mml:mo><mml:msubsup><mml:mi>R</mml:mi><mml:mi>j</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:msubsup><mml:mi>R</mml:mi><mml:mi>j</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:msubsup><mml:mi>R</mml:mi><mml:mi>j</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:msubsup><mml:mi>R</mml:mi><mml:mi>j</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:munder><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:munderover><mml:mo>∑</mml:mo><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mi>j</mml:mi></mml:munderover><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq349\"><alternatives><tex-math id=\"M951\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_i=K_{R_i}$$\\end{document}</tex-math><mml:math id=\"M952\"><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq350\"><alternatives><tex-math id=\"M953\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M954\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq351\"><alternatives><tex-math id=\"M955\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t\\in (-\\varvec{\\omega }_j^{2-p}R_j^{sp},0)$$\\end{document}</tex-math><mml:math id=\"M956\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:msubsup><mml:mi>R</mml:mi><mml:mi>j</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ159\"><alternatives><tex-math id=\"M957\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _{\\mathbb {R}^N\\setminus K_R} \\frac{\\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x&\\le \\varvec{\\gamma }\\int _{\\mathbb {R}^N\\setminus K_R} \\frac{\|\\varvec{\\mu }_j^{-}\|^{p-1}+u_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x\\\\&\\le \\varvec{\\gamma }\\frac{\\varvec{\\omega }^{p-1}}{R^{sp}}+\\varvec{\\gamma }\\int _{K_{\\widetilde{R}}\\setminus K_R} \\frac{u_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x+\\varvec{\\gamma }\\int _{\\mathbb {R}^N\\setminus K_{\\widetilde{R}}} \\frac{u_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x\\\\&\\le \\varvec{\\gamma }\\frac{\\varvec{\\omega }^{p-1}}{R^{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M958\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:msubsup><mml:mi>u</mml:mi><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq352\"><alternatives><tex-math id=\"M959\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i=1,2,\\cdots ,j$$\\end{document}</tex-math><mml:math id=\"M960\"><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mn>2</mml:mn><mml:mo>,</mml:mo><mml:mo>⋯</mml:mo><mml:mo>,</mml:mo><mml:mi>j</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ160\"><alternatives><tex-math id=\"M961\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}\\le \\varvec{\\mu }_j^{-} - \\varvec{\\mu }_{i-1}^{-}\\le \\varvec{\\mu }_j^{+} - \\varvec{\\mu }_{i-1}^{-}\\le \\varvec{\\mu }_{i-1}^{+} - \\varvec{\\mu }_{i-1}^{-} \\le \\varvec{\\omega }_{i-1}\\quad \\text {a.e. in}\\>Q_{i-1}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M962\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>≤</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mo>-</mml:mo></mml:msubsup><mml:mo>≤</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo></mml:msubsup><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mo>-</mml:mo></mml:msubsup><mml:mo>≤</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mo>+</mml:mo></mml:msubsup><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mo>-</mml:mo></mml:msubsup><mml:mo>≤</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mspace width=\"1em\"/><mml:mtext>a.e. in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq353\"><alternatives><tex-math id=\"M963\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t\\in (-\\varvec{\\omega }_j^{2-p}R_j^{sp},0)$$\\end{document}</tex-math><mml:math id=\"M964\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:msubsup><mml:mi>R</mml:mi><mml:mi>j</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ161\"><alternatives><tex-math id=\"M965\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _{K_{i-1}\\setminus K_{i}} \\frac{\\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}^{p-1}}{\|x\|^{N+sp}}\\,\\textrm{d}x\\le \\varvec{\\gamma } \\frac{\\varvec{\\omega }_{i-1}^{p-1}}{R_i^{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M966\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:msubsup><mml:mi>R</mml:mi><mml:mi>i</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mfrac><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ162\"><alternatives><tex-math id=\"M967\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned} \\big [\\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }_j^{-}\\big )_{-}; Q_j\\big )\\big ]^{p-1}&\\le \\varvec{\\gamma } R_j^{sp} \\frac{\\varvec{\\omega }^{p-1}}{R^{sp}}+\\varvec{\\gamma } R_j^{sp} \\sum _{i=1}^{j} \\frac{\\varvec{\\omega }_{i-1}^{p-1}}{R_i^{sp}}\\\\&\\le \\varvec{\\gamma } \\varvec{\\omega }_{j}^{p-1} \\sum _{i=1}^{j} (1 - \\eta )^{(j-i+1)(1-p)}\\lambda ^{(j-i)sp}. \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M968\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>j</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mi>R</mml:mi><mml:mi>j</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:mfrac><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>+</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mi>R</mml:mi><mml:mi>j</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup><mml:munderover><mml:mo>∑</mml:mo><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mi>j</mml:mi></mml:munderover><mml:mfrac><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:msubsup><mml:mi>R</mml:mi><mml:mi>i</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msubsup></mml:mfrac></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msubsup><mml:munderover><mml:mo>∑</mml:mo><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mi>j</mml:mi></mml:munderover><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>j</mml:mi><mml:mo>-</mml:mo><mml:mi>i</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msup><mml:msup><mml:mi>λ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>j</mml:mi><mml:mo>-</mml:mo><mml:mi>i</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq354\"><alternatives><tex-math id=\"M969\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(1-\\eta )^{1-p}$$\\end{document}</tex-math><mml:math id=\"M970\"><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq355\"><alternatives><tex-math id=\"M971\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda $$\\end{document}</tex-math><mml:math id=\"M972\"><mml:mi>λ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ163\"><alternatives><tex-math id=\"M973\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} (1-\\eta )^{1-p}\\lambda ^{sp}\\le \\tfrac{1}{2},\\quad \\text {i.e.}\\quad \\lambda \\le 2^{-\\frac{1}{sp}}(1-\\eta )^{\\frac{p-1}{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M974\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>λ</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>≤</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>λ</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo>-</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ23\"><label>4.10</label><alternatives><tex-math id=\"M975\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c^{sp}\\varvec{\\gamma } \\le \\eta ^{p-1},\\quad \\text {i.e.}\\quad c\\le \\frac{1}{\\varvec{\\gamma }}\\eta ^{\\frac{p-1}{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M976\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>c</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mo>≤</mml:mo><mml:msup><mml:mi>η</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>c</mml:mi><mml:mo>≤</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac><mml:msup><mml:mi>η</mml:mi><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq356\"><alternatives><tex-math id=\"M977\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$R_{j+1}=\\lambda R_j$$\\end{document}</tex-math><mml:math id=\"M978\"><mml:mrow><mml:msub><mml:mi>R</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mi>λ</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq357\"><alternatives><tex-math id=\"M979\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda \\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M980\"><mml:mrow><mml:mi>λ</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ24\"><label>4.11</label><alternatives><tex-math id=\"M981\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} Q_{R_{j+1}}\\big (\\varvec{\\omega }_{j+1}^{2-p}\\big ) \\subset Q_{cR_j}\\big (\\tfrac{1}{2}\\delta \\big (\\tfrac{1}{4} \\varvec{\\omega }_j\\big )^{2-p}\\big ),\\quad \\text {i.e.}\\quad \\lambda \\le 2^{\\frac{2p-5}{p}}\\delta ^{\\frac{1}{p}}c. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M982\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>δ</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>λ</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mfrac><mml:mrow><mml:mn>2</mml:mn><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>5</mml:mn></mml:mrow><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:msup><mml:mi>δ</mml:mi><mml:mfrac><mml:mn>1</mml:mn><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:mi>c</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq358\"><alternatives><tex-math id=\"M983\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda $$\\end{document}</tex-math><mml:math id=\"M984\"><mml:mi>λ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq359\"><alternatives><tex-math id=\"M985\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\lambda $$\\end{document}</tex-math><mml:math id=\"M986\"><mml:mi>λ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ164\"><alternatives><tex-math id=\"M987\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\lambda =\\min \\Big \\{ 2^{-\\frac{1}{sp}}(1-\\eta )^{\\frac{p-1}{sp}}, 2^{\\frac{2p-5}{p}}\\delta ^{\\frac{1}{p}}c\\Big \\}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M988\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>λ</mml:mi><mml:mo>=</mml:mo><mml:mo movablelimits=\"true\">min</mml:mo><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mrow><mml:mo>-</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mo>,</mml:mo><mml:msup><mml:mn>2</mml:mn><mml:mfrac><mml:mrow><mml:mn>2</mml:mn><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>5</mml:mn></mml:mrow><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:msup><mml:mi>δ</mml:mi><mml:mfrac><mml:mn>1</mml:mn><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:mi>c</mml:mi><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ165\"><alternatives><tex-math id=\"M989\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{R_{j+1}}(\\varvec{\\omega }_{j+1}^{2-p})}u\\le \\varvec{\\omega }_{j+1}, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M990\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msubsup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq360\"><alternatives><tex-math id=\"M991\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p> 2$$\\end{document}</tex-math><mml:math id=\"M992\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>></mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq361\"><alternatives><tex-math id=\"M993\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_{\\widetilde{R}}\\subset E_T$$\\end{document}</tex-math><mml:math id=\"M994\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub><mml:mo>⊂</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ166\"><alternatives><tex-math id=\"M995\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\omega }=2\\mathop {\\mathrm{ess\\,sup}}\\limits _{Q_{\\widetilde{R}}} \|u\| +\\textrm{Tail}(u; Q_{\\widetilde{R}}) \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M996\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>=</mml:mo><mml:mn>2</mml:mn><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:munder><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>u</mml:mi><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq362\"><alternatives><tex-math id=\"M997\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_o=Q_R(a\\theta )$$\\end{document}</tex-math><mml:math id=\"M998\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq363\"><alternatives><tex-math id=\"M999\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta =(\\frac{1}{4}\\varvec{\\omega })^{2-p}$$\\end{document}</tex-math><mml:math id=\"M1000\"><mml:mrow><mml:mi>θ</mml:mi><mml:mo>=</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq364\"><alternatives><tex-math id=\"M1001\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$a\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M1002\"><mml:mrow><mml:mi>a</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq365\"><alternatives><tex-math id=\"M1003\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_o\\subset Q_{\\widetilde{R}}$$\\end{document}</tex-math><mml:math id=\"M1004\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>⊂</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ167\"><alternatives><tex-math id=\"M1005\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\mu }^+=\\mathop {\\mathrm{ess\\,sup}}\\limits _{Q_o}u, \\qquad \\varvec{\\mu }^-=\\mathop {\\mathrm{ess\\,inf}}\\limits _{Q_o}u. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1006\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"2em\"/><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">inf</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq366\"><alternatives><tex-math id=\"M1007\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(x_o,t_o)=(0,0)$$\\end{document}</tex-math><mml:math id=\"M1008\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>x</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ25\"><label>5.1</label><alternatives><tex-math id=\"M1009\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{R}\\big (a\\big (\\frac{1}{4}\\varvec{\\omega }\\big )^{2-p}\\big )}u\\le \\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1010\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>a</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq367\"><alternatives><tex-math id=\"M1011\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_{\\widetilde{R}}$$\\end{document}</tex-math><mml:math id=\"M1012\"><mml:msub><mml:mi>Q</mml:mi><mml:mover accent=\"true\"><mml:mi>R</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq368\"><alternatives><tex-math id=\"M1013\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$1<p\\le 2$$\\end{document}</tex-math><mml:math id=\"M1014\"><mml:mrow><mml:mn>1</mml:mn><mml:mo><</mml:mo><mml:mi>p</mml:mi><mml:mo>≤</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq369\"><alternatives><tex-math id=\"M1015\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p>2$$\\end{document}</tex-math><mml:math id=\"M1016\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>></mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ26\"><label>5.2</label><alternatives><tex-math id=\"M1017\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\mu }^+ -\\varvec{\\mu }^- >\\tfrac{1}{2}\\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1018\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>></mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq370\"><alternatives><tex-math id=\"M1019\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^+ -\\varvec{\\mu }^- \\le \\frac{1}{2}\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M1020\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>≤</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq371\"><alternatives><tex-math id=\"M1021\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$a,\\, c\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M1022\"><mml:mrow><mml:mi>a</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mi>c</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq372\"><alternatives><tex-math id=\"M1023\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$a>2c^{sp}$$\\end{document}</tex-math><mml:math id=\"M1024\"><mml:mrow><mml:mi>a</mml:mi><mml:mo>></mml:mo><mml:mn>2</mml:mn><mml:msup><mml:mi>c</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq373\"><alternatives><tex-math id=\"M1025\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{t}\\in \\big (-a\\theta R^{sp}+\\theta (cR)^{sp},0\\big ]$$\\end{document}</tex-math><mml:math id=\"M1026\"><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>a</mml:mi><mml:mi>θ</mml:mi><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ27\"><label>5.3</label><alternatives><tex-math id=\"M1027\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{u\\le \\varvec{\\mu }^-+\\tfrac{1}{4} \\varvec{\\omega }\\Big \\} \\cap (0,\\bar{t})+Q_{cR}(\\theta )\\Big \|\\le \\nu \|Q_{cR}(\\theta )\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1028\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>+</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ν</mml:mi><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq374\"><alternatives><tex-math id=\"M1029\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu $$\\end{document}</tex-math><mml:math id=\"M1030\"><mml:mi>ν</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq375\"><alternatives><tex-math id=\"M1031\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta =1$$\\end{document}</tex-math><mml:math id=\"M1032\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq376\"><alternatives><tex-math id=\"M1033\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta =1$$\\end{document}</tex-math><mml:math id=\"M1034\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq377\"><alternatives><tex-math id=\"M1035\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi =\\frac{1}{4}$$\\end{document}</tex-math><mml:math id=\"M1036\"><mml:mrow><mml:mi>ξ</mml:mi><mml:mo>=</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq378\"><alternatives><tex-math id=\"M1037\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho =cR$$\\end{document}</tex-math><mml:math id=\"M1038\"><mml:mrow><mml:mi>ϱ</mml:mi><mml:mo>=</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ28\"><label>5.4</label><alternatives><tex-math id=\"M1039\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c^{\\frac{sp}{p-1}} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }^{-}\\big )_{-}; Q_o\\big ) > \\tfrac{1}{4} \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1040\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ29\"><label>5.5</label><alternatives><tex-math id=\"M1041\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u\\ge \\varvec{\\mu }^-+\\tfrac{1}{8}\\varvec{\\omega } \\quad \\text{ a.e. } \\text{ in } (0,\\bar{t})+Q_{\\frac{1}{2} cR}(\\theta ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1042\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>+</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>8</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>a.e.</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>in</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq379\"><alternatives><tex-math id=\"M1043\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M1044\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ168\"><alternatives><tex-math id=\"M1045\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }^{-}\\big )_{-}; Q_o\\big ) \\le \\varvec{\\gamma }\\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1046\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ30\"><label>5.6</label><alternatives><tex-math id=\"M1047\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c^{\\frac{sp}{p-1}} \\varvec{\\gamma }\\varvec{\\omega }\\le \\tfrac{1}{4}\\varvec{\\omega },\\quad \\text {i.e.}\\quad c\\le \\left( \\frac{1}{4\\varvec{\\gamma }}\\right) ^{\\frac{p-1}{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1048\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>≤</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>c</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mn>4</mml:mn><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mrow></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq380\"><alternatives><tex-math id=\"M1049\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t_=\\bar{t}- \\theta (\\tfrac{1}{2} cR)^{sp}$$\\end{document}</tex-math><mml:math id=\"M1050\"><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq381\"><alternatives><tex-math id=\"M1051\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho =\\tfrac{1}{2}cR$$\\end{document}</tex-math><mml:math id=\"M1052\"><mml:mrow><mml:mi>ϱ</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq382\"><alternatives><tex-math id=\"M1053\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi _o\\in (0,\\tfrac{1}{8})$$\\end{document}</tex-math><mml:math id=\"M1054\"><mml:mrow><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>∈</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>8</mml:mn></mml:mfrac></mml:mstyle><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ31\"><label>5.7</label><alternatives><tex-math id=\"M1055\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} (\\tfrac{1}{2}c)^{\\frac{sp}{p-1}} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }^{-}\\big )_{-}; Q_o\\big ) > \\xi _o \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1056\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ32\"><label>5.8</label><alternatives><tex-math id=\"M1057\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u\\ge \\varvec{\\mu }^-+\\tfrac{1}{2}\\xi _o \\varvec{\\omega } \\quad \\text{ a.e. } \\text{ in } K_{\\frac{1}{4}cR}\\times \\big (t_, t_+\\nu _o(\\xi _o\\varvec{\\omega })^{2-p}(\\tfrac{1}{2}cR)^{sp}\\big ]. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1058\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>-</mml:mo></mml:msup><mml:mo>+</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>a.e.</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>in</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq383\"><alternatives><tex-math id=\"M1059\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi _o$$\\end{document}</tex-math><mml:math id=\"M1060\"><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ33\"><label>5.9</label><alternatives><tex-math id=\"M1061\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\nu _o(\\xi _o\\varvec{\\omega })^{2-p}(\\tfrac{1}{2}cR)^{sp}\\ge a(\\tfrac{1}{4}\\varvec{\\omega })^{2-p}R^{sp},\\quad \\text {i.e.}\\quad \\xi _o= \\tfrac{1}{4}\\left( \\frac{\\nu _o c^{sp}}{2^p a}\\right) ^{\\frac{1}{p-2}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1062\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>≥</mml:mo><mml:mi>a</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mrow><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mi>c</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow><mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mi>p</mml:mi></mml:msup><mml:mi>a</mml:mi></mml:mrow></mml:mfrac></mml:mfenced><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq384\"><alternatives><tex-math id=\"M1063\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t=0$$\\end{document}</tex-math><mml:math id=\"M1064\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ34\"><label>5.10</label><alternatives><tex-math id=\"M1065\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{\\frac{1}{4}cR}(\\theta )} u\\le \\big (1-\\tfrac{1}{2}\\xi _o \\big )\\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1066\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq385\"><alternatives><tex-math id=\"M1067\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi _o$$\\end{document}</tex-math><mml:math id=\"M1068\"><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq386\"><alternatives><tex-math id=\"M1069\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma }\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M1070\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ169\"><alternatives><tex-math id=\"M1071\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\tfrac{1}{2}c\\right) ^{\\frac{sp}{p-1}}\\varvec{\\gamma }\\varvec{\\omega }\\le \\xi _o \\varvec{\\omega }\\equiv \\tfrac{1}{4}\\left( \\frac{\\nu _o c^{sp}}{2^p a}\\right) ^{\\frac{1}{p-2}} \\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1072\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi></mml:mfenced><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>≤</mml:mo><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>≡</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mrow><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:msup><mml:mi>c</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow><mml:mrow><mml:msup><mml:mn>2</mml:mn><mml:mi>p</mml:mi></mml:msup><mml:mi>a</mml:mi></mml:mrow></mml:mfrac></mml:mfenced><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq387\"><alternatives><tex-math id=\"M1073\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi _o$$\\end{document}</tex-math><mml:math id=\"M1074\"><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ35\"><label>5.11</label><alternatives><tex-math id=\"M1075\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} a=\\frac{\\nu _o}{\\varvec{\\gamma }}c^{\\frac{sp}{p-1}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1076\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>a</mml:mi><mml:mo>=</mml:mo><mml:mfrac><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq388\"><alternatives><tex-math id=\"M1077\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$a>2c^{sp}$$\\end{document}</tex-math><mml:math id=\"M1078\"><mml:mrow><mml:mi>a</mml:mi><mml:mo>></mml:mo><mml:mn>2</mml:mn><mml:msup><mml:mi>c</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ36\"><label>5.12</label><alternatives><tex-math id=\"M1079\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} a=\\frac{\\nu _o}{\\varvec{\\gamma }}c^{\\frac{sp}{p-1}}>2c^{sp},\\quad \\text {i.e.}\\quad c<\\left( \\frac{\\nu _o}{\\varvec{\\gamma }}\\right) ^{sp\\frac{p-1}{p-2}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1080\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>a</mml:mi><mml:mo>=</mml:mo><mml:mfrac><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mo>></mml:mo><mml:mn>2</mml:mn><mml:msup><mml:mi>c</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>c</mml:mi><mml:mo><</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac></mml:mfenced><mml:mrow><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:mfrac></mml:mrow></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq389\"><alternatives><tex-math id=\"M1081\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{t}\\in \\big (-a\\theta R^{sp}+\\theta (cR)^{sp},0\\big ]$$\\end{document}</tex-math><mml:math id=\"M1082\"><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>a</mml:mi><mml:mi>θ</mml:mi><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ170\"><alternatives><tex-math id=\"M1083\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{\\varvec{\\mu }^+-u\\ge \\tfrac{1}{4} \\varvec{\\omega }\\Big \\} \\cap (0,\\bar{t})+Q_{cR}(\\theta )\\Big \|> \\nu \|Q_{cR}(\\theta )\|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1084\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>ν</mml:mi><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq390\"><alternatives><tex-math id=\"M1085\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t_\\in \\big [\\bar{t}-\\theta (cR)^{sp}, \\bar{t}-\\tfrac{1}{2}\\nu \\theta (cR)^{sp}\\big ]$$\\end{document}</tex-math><mml:math id=\"M1086\"><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>-</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ν</mml:mi><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ171\"><alternatives><tex-math id=\"M1087\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{\\varvec{\\mu }^+-u(\\cdot , t_)\\ge \\tfrac{1}{4} \\varvec{\\omega }\\Big \\} \\cap K_{cR} \\Big \|> \\tfrac{1}{2}\\nu \|K_{cR}\|. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1088\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ν</mml:mi><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ172\"><alternatives><tex-math id=\"M1089\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{\\varvec{\\mu }^+-u\\ge \\tfrac{1}{4}\\varvec{\\omega }\\Big \\}\\cap (0,\\bar{t})+Q_{cR}(\\theta )\\Big \|&= \\int _{\\bar{t}-\\theta (cR)^p}^{\\bar{t} -\\frac{1}{2}\\nu \\theta (cR)^{sp}} \\Big \|\\Big \\{\\varvec{\\mu }^+-u(\\cdot , s)\\ge \\tfrac{1}{4}\\varvec{\\omega }\\Big \\}\\cap K_{cR}\\Big \|\\,\\textrm{d}s\\\\&+\\int ^{\\bar{t}}_{\\bar{t}-\\frac{1}{2}\\nu \\theta (cR)^{sp}} \\Big \|\\Big \\{\\varvec{\\mu }^+-u(\\cdot , s)\\ge \\tfrac{1}{4}\\varvec{\\omega }\\Big \\}\\cap K_{cR}\\Big \|\\,\\textrm{d}s\\\\&<\\tfrac{1}{2}\\nu \|K_{cR}\|\\theta (cR)^{sp}\\big (1-\\tfrac{1}{2}\\nu \\big ) +\\tfrac{1}{2}\\nu \\theta (cR)^{sp}\|K_{cR} \|\\\\&<\\nu \| Q_{cR}(\\theta )\|, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1090\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>-</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ν</mml:mi><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>s</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>s</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>-</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>ν</mml:mi><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>s</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>s</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo><</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mi>ν</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>θ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ν</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ν</mml:mi><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow><mml:mo><</mml:mo><mml:mi>ν</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>,</mml:mo></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq391\"><alternatives><tex-math id=\"M1091\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\alpha =\\tfrac{1}{2}\\nu $$\\end{document}</tex-math><mml:math id=\"M1092\"><mml:mrow><mml:mi>α</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>ν</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq392\"><alternatives><tex-math id=\"M1093\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho =cR$$\\end{document}</tex-math><mml:math id=\"M1094\"><mml:mrow><mml:mi>ϱ</mml:mi><mml:mo>=</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq393\"><alternatives><tex-math id=\"M1095\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta $$\\end{document}</tex-math><mml:math id=\"M1096\"><mml:mi>δ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq394\"><alternatives><tex-math id=\"M1097\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varepsilon $$\\end{document}</tex-math><mml:math id=\"M1098\"><mml:mi>ε</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq395\"><alternatives><tex-math id=\"M1099\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu $$\\end{document}</tex-math><mml:math id=\"M1100\"><mml:mi>ν</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq396\"><alternatives><tex-math id=\"M1101\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi _1\\in (0,\\frac{1}{4})$$\\end{document}</tex-math><mml:math id=\"M1102\"><mml:mrow><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>∈</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ37\"><label>5.13</label><alternatives><tex-math id=\"M1103\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c^{\\frac{sp}{p-1}} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }^{+}\\big )_{+}; Q_o\\big ) >\\xi _1\\varvec{\\omega }, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1104\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ38\"><label>5.14</label><alternatives><tex-math id=\"M1105\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\varvec{\\mu }^{+}-u(\\cdot , t) \\ge \\varepsilon \\xi _1\\varvec{\\omega }\\Big \\} \\cap K_{cR} \\Big \| \\ge \\frac{\\alpha }{2} \|K_{cR}\| \\> \\text{ for } \\text{ all } t\\in \\big (t_,t_+\\delta (\\xi _1\\varvec{\\omega })^{2-p}(cR)^{sp}\\big ]. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1106\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mfrac><mml:mi>α</mml:mi><mml:mn>2</mml:mn></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mspace width=\"0.222222em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>for</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>all</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq397\"><alternatives><tex-math id=\"M1107\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi _1$$\\end{document}</tex-math><mml:math id=\"M1108\"><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ173\"><alternatives><tex-math id=\"M1109\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\delta (\\xi _1\\varvec{\\omega })^{2-p}(cR)^{sp}\\ge \\theta (cR)^{sp},\\quad \\text {i.e.}\\quad \\xi _1=\\tfrac{1}{4}\\delta ^{\\frac{1}{p-2}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1110\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>δ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>≥</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msup><mml:mi>δ</mml:mi><mml:mfrac><mml:mn>1</mml:mn><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq398\"><alternatives><tex-math id=\"M1111\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{t}$$\\end{document}</tex-math><mml:math id=\"M1112\"><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq399\"><alternatives><tex-math id=\"M1113\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M1114\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ174\"><alternatives><tex-math id=\"M1115\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }^{+}\\big )_{+}; Q_o\\big ) \\le \\varvec{\\gamma }\\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1116\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ39\"><label>5.15</label><alternatives><tex-math id=\"M1117\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c\\le \\left( \\frac{\\xi _1}{\\varvec{\\gamma }}\\right) ^{\\frac{p-1}{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1118\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>c</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ40\"><label>5.16</label><alternatives><tex-math id=\"M1119\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\varvec{\\mu }^{+}-u(\\cdot , t) \\ge \\varepsilon \\xi _1\\varvec{\\omega }\\Big \\} \\cap K_{cR} \\Big \| \\ge \\frac{\\alpha }{2} \|K_{cR}\| \\> \\text{ for } \\text{ all } t\\in \\big (-a\\theta R^{sp}+\\theta (cR)^{sp},0\\big ], \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1120\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mfrac><mml:mi>α</mml:mi><mml:mn>2</mml:mn></mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mspace width=\"0.222222em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>for</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>all</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>a</mml:mi><mml:mi>θ</mml:mi><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq400\"><alternatives><tex-math id=\"M1121\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{t}$$\\end{document}</tex-math><mml:math id=\"M1122\"><mml:mover accent=\"true\"><mml:mrow><mml:mi>t</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq401\"><alternatives><tex-math id=\"M1123\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta =1$$\\end{document}</tex-math><mml:math id=\"M1124\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq402\"><alternatives><tex-math id=\"M1125\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\xi =\\varepsilon \\xi _1$$\\end{document}</tex-math><mml:math id=\"M1126\"><mml:mrow><mml:mi>ξ</mml:mi><mml:mo>=</mml:mo><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq403\"><alternatives><tex-math id=\"M1127\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varrho =cR$$\\end{document}</tex-math><mml:math id=\"M1128\"><mml:mrow><mml:mi>ϱ</mml:mi><mml:mo>=</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq404\"><alternatives><tex-math id=\"M1129\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\nu $$\\end{document}</tex-math><mml:math id=\"M1130\"><mml:mi>ν</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq405\"><alternatives><tex-math id=\"M1131\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta =1$$\\end{document}</tex-math><mml:math id=\"M1132\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq406\"><alternatives><tex-math id=\"M1133\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma \\in (0,\\tfrac{1}{2})$$\\end{document}</tex-math><mml:math id=\"M1134\"><mml:mrow><mml:mi>σ</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ175\"><alternatives><tex-math id=\"M1135\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\gamma } \\frac{\\sigma ^{p-1}}{\\alpha }\\le \\nu . \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1136\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mfrac><mml:msup><mml:mi>σ</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mi>α</mml:mi></mml:mfrac><mml:mo>≤</mml:mo><mml:mi>ν</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq407\"><alternatives><tex-math id=\"M1137\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\gamma }$$\\end{document}</tex-math><mml:math id=\"M1138\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq408\"><alternatives><tex-math id=\"M1139\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\sigma $$\\end{document}</tex-math><mml:math id=\"M1140\"><mml:mi>σ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ41\"><label>5.17</label><alternatives><tex-math id=\"M1141\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} a\\theta R^{sp}-\\theta (cR)^{sp}\\ge (\\sigma \\varepsilon \\xi _1\\varvec{\\omega })^{2-p}(cR)^{sp},\\quad \\text {i.e.}\\quad c\\le \\left( \\frac{\\nu _o}{\\varvec{\\gamma }}\\right) ^{\\frac{p-1}{sp(p-2)}}(\\sigma \\varepsilon \\xi _1)^{\\frac{p-1}{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1142\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>a</mml:mi><mml:mi>θ</mml:mi><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>-</mml:mo><mml:mi>θ</mml:mi><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>≥</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>c</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:msub><mml:mi>ν</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mfrac></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ176\"><alternatives><tex-math id=\"M1143\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\varvec{\\mu }^{+}-u(\\cdot , t)\\ge \\varepsilon \\xi _1\\varvec{\\omega } \\Big \\}\\cap K_{cR}\\Big \| \\ge \\alpha \\big \|K_{cR}\\big \|\\quad \\text{ for } \\text{ all } t\\in \\big ( -(\\sigma \\varepsilon \\xi _1\\varvec{\\omega })^{2-p}(cR)^p, 0\\big ], \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1144\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mo>·</mml:mo><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mi>α</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mspace width=\"1em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>for</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mspace width=\"0.333333em\"/><mml:mtext>all</mml:mtext><mml:mspace width=\"0.333333em\"/><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>c</mml:mi><mml:mi>R</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo>,</mml:mo><mml:mn>0</mml:mn><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ42\"><label>5.18</label><alternatives><tex-math id=\"M1145\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c^{\\frac{sp}{p-1}} \\textrm{Tail}\\big ( u-\\varvec{\\mu }^{+}\\big )_{+}; Q_o\\big ) >\\sigma \\varepsilon \\xi _1\\varvec{\\omega } \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1146\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mi>c</mml:mi><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ177\"><alternatives><tex-math id=\"M1147\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\Big \|\\Big \\{ \\varvec{\\mu }^{+}-u \\le \\sigma \\varepsilon \\xi _1\\varvec{\\omega } \\Big \\}\\cap Q_{cR}({\\widetilde{\\theta }})\\Big \| \\le \\nu \\big \|Q_{cR}({\\widetilde{\\theta }})\|,\\quad \\text {where}\\>{\\widetilde{\\theta }}=(\\sigma \\varepsilon \\xi _1\\varvec{\\omega })^{2-p}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1148\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mover accent=\"true\"><mml:mi>θ</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mi>ν</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">cR</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mover accent=\"true\"><mml:mi>θ</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>where</mml:mtext><mml:mspace width=\"0.222222em\"/></mml:mrow><mml:mover accent=\"true\"><mml:mi>θ</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mo>=</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq409\"><alternatives><tex-math id=\"M1149\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\delta =1$$\\end{document}</tex-math><mml:math id=\"M1150\"><mml:mrow><mml:mi>δ</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ178\"><alternatives><tex-math id=\"M1151\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varvec{\\mu }^{+}-u \\ge \\tfrac{1}{2}\\sigma \\varepsilon \\xi _1\\varvec{\\omega }\\quad \\text {a.e. in}\\>Q_{\\frac{1}{2}cR}({\\widetilde{\\theta }}), \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1152\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mspace width=\"1em\"/><mml:mtext>a.e. in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mover accent=\"true\"><mml:mi>θ</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ43\"><label>5.19</label><alternatives><tex-math id=\"M1153\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{\\frac{1}{2}cR}({\\widetilde{\\theta }})} u\\le \\big (1- \\tfrac{1}{2}\\sigma \\varepsilon \\xi _1\\big )\\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1154\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mover accent=\"true\"><mml:mi>θ</mml:mi><mml:mo stretchy=\"true\">~</mml:mo></mml:mover><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq410\"><alternatives><tex-math id=\"M1155\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }$$\\end{document}</tex-math><mml:math id=\"M1156\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ179\"><alternatives><tex-math id=\"M1157\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\textrm{Tail}\\big ( \\big (u-\\varvec{\\mu }^{+}\\big )_{+}; Q_o\\big ) \\le \\varvec{\\gamma }\\varvec{\\omega }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1158\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mo>+</mml:mo></mml:msup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ44\"><label>5.20</label><alternatives><tex-math id=\"M1159\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} c\\le \\left( \\frac{\\sigma \\varepsilon \\xi _1}{\\varvec{\\gamma }}\\right) ^{\\frac{p-1}{sp}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1160\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>c</mml:mi><mml:mo>≤</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mfrac><mml:mrow><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow></mml:mfrac></mml:mfenced><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ45\"><label>5.21</label><alternatives><tex-math id=\"M1161\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{\\frac{1}{4}cR}( \\theta )} u\\le \\big (1- \\eta \\big )\\varvec{\\omega }:=\\varvec{\\omega }_1, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1162\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ180\"><alternatives><tex-math id=\"M1163\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\eta =\\min \\big \\{\\tfrac{1}{2}\\xi _o, \\tfrac{1}{2}\\sigma \\varepsilon \\xi _1\\big \\}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1164\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>η</mml:mi><mml:mo>=</mml:mo><mml:mo movablelimits=\"true\">min</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">{</mml:mo></mml:mrow><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mi>ξ</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mi>σ</mml:mi><mml:mi>ε</mml:mi><mml:msub><mml:mi>ξ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">}</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq411\"><alternatives><tex-math id=\"M1165\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta _1=(\\tfrac{1}{4}\\varvec{\\omega }_1)^{2-p}$$\\end{document}</tex-math><mml:math id=\"M1166\"><mml:mrow><mml:msub><mml:mi>θ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>=</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq412\"><alternatives><tex-math id=\"M1167\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$R_1=\\tfrac{1}{4} c R$$\\end{document}</tex-math><mml:math id=\"M1168\"><mml:mrow><mml:msub><mml:mi>R</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ181\"><alternatives><tex-math id=\"M1169\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} Q_{R_1}(a\\theta _1)\\subset Q_{\\frac{1}{4}cR}( \\theta ),\\quad \\text {i.e.}\\quad a\\le \\big [\\tfrac{1}{4}(1-\\eta )\\big ]^{p-2}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1170\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:msub><mml:mi>θ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>θ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mtext>i.e.</mml:mtext><mml:mspace width=\"1em\"/><mml:mi>a</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ182\"><alternatives><tex-math id=\"M1171\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{R_1}( a\\theta _1)} u\\le \\varvec{\\omega }_1, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1172\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:msub><mml:mi>θ</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq413\"><alternatives><tex-math id=\"M1173\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$i=1,\\cdots , j$$\\end{document}</tex-math><mml:math id=\"M1174\"><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mo>⋯</mml:mo><mml:mo>,</mml:mo><mml:mi>j</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ183\"><alternatives><tex-math id=\"M1175\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left\\{ \\begin{array}{c} \\displaystyle R_o=R,\\quad R_i=\\tfrac{1}{4}c R_{i-1}, \\quad \\varvec{\\omega }_i=(1-\\eta )\\varvec{\\omega }_{i-1},\\\\ \\theta _i=\\left( \\tfrac{1}{4}\\varvec{\\omega }_i\\right) ^{2-p}, \\quad Q_i=Q_{R_i}(a\\theta _i),\\\\ \\displaystyle \\varvec{\\mu }_i^+=\\mathop {\\mathrm{ess\\,sup}}\\limits _{Q_i}u, \\quad \\varvec{\\mu }_i^-=\\mathop {\\mathrm{ess\\,inf}}\\limits _{Q_i}u, \\quad \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_i}u\\le \\varvec{\\omega }_i. \\end{array} \\right. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1176\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mfenced open=\"{\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:msub><mml:mi>R</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>,</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:msub><mml:mi>θ</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi></mml:msub></mml:mfenced><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mi>Q</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:msub><mml:mi>θ</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mstyle displaystyle=\"true\" scriptlevel=\"0\"><mml:mrow><mml:mrow/><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>i</mml:mi><mml:mo>+</mml:mo></mml:msubsup><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>i</mml:mi><mml:mo>-</mml:mo></mml:msubsup><mml:mo>=</mml:mo><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">inf</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>i</mml:mi></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mstyle></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq414\"><alternatives><tex-math id=\"M1177\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(j+1)$$\\end{document}</tex-math><mml:math id=\"M1178\"><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq415\"><alternatives><tex-math id=\"M1179\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$1<p\\le 2$$\\end{document}</tex-math><mml:math id=\"M1180\"><mml:mrow><mml:mn>1</mml:mn><mml:mo><</mml:mo><mml:mi>p</mml:mi><mml:mo>≤</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq416\"><alternatives><tex-math id=\"M1181\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\mu }^{\\pm }_j$$\\end{document}</tex-math><mml:math id=\"M1182\"><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>±</mml:mo></mml:msubsup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq417\"><alternatives><tex-math id=\"M1183\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varvec{\\omega }_j$$\\end{document}</tex-math><mml:math id=\"M1184\"><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq418\"><alternatives><tex-math id=\"M1185\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$R_j$$\\end{document}</tex-math><mml:math id=\"M1186\"><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq419\"><alternatives><tex-math id=\"M1187\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta _j$$\\end{document}</tex-math><mml:math id=\"M1188\"><mml:msub><mml:mi>θ</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq420\"><alternatives><tex-math id=\"M1189\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$Q_j$$\\end{document}</tex-math><mml:math id=\"M1190\"><mml:msub><mml:mi>Q</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ46\"><label>5.22</label><alternatives><tex-math id=\"M1191\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{\\frac{1}{4}cR_j}( \\theta _j)} u\\le \\big (1- \\eta \\big )\\varvec{\\omega }_j:=\\varvec{\\omega }_{j+1}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1192\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>θ</mml:mi><mml:mi>j</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>η</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq421\"><alternatives><tex-math id=\"M1193\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\theta _{j+1}=(\\tfrac{1}{4}\\varvec{\\omega }_{j+1})^{2-p}$$\\end{document}</tex-math><mml:math id=\"M1194\"><mml:mrow><mml:msub><mml:mi>θ</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mo>-</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq422\"><alternatives><tex-math id=\"M1195\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$R_{j+1}=\\tfrac{1}{4} c R_j$$\\end{document}</tex-math><mml:math id=\"M1196\"><mml:mrow><mml:msub><mml:mi>R</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac></mml:mstyle><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ184\"><alternatives><tex-math id=\"M1197\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} Q_{R_{j+1}}(a\\theta _{j+1})\\subset Q_{\\frac{1}{4}cR_j}( \\theta _j), \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1198\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:msub><mml:mi>θ</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mn>4</mml:mn></mml:mfrac><mml:mi>c</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mi>j</mml:mi></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>θ</mml:mi><mml:mi>j</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ185\"><alternatives><tex-math id=\"M1199\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathop {\\mathrm{ess\\,osc}}\\limits _{Q_{R_{j+1}}( a\\theta _{j+1})} u \\le \\varvec{\\omega }_{j+1}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1200\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">osc</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>Q</mml:mi><mml:msub><mml:mi>R</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>a</mml:mi><mml:msub><mml:mi>θ</mml:mi><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:munder><mml:mi>u</mml:mi><mml:mo>≤</mml:mo><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mrow><mml:mi>j</mml:mi><mml:mo>+</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ186\"><alternatives><tex-math id=\"M1201\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\textrm{Tail}\\big (\\big (u - \\varvec{\\mu }_j^{\\pm }\\big )_{\\pm }; Q_j\\big ) \\le \\varvec{\\gamma }\\varvec{\\omega }_j. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1202\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:msubsup><mml:mrow><mml:mi mathvariant=\"bold-italic\">μ</mml:mi></mml:mrow><mml:mi>j</mml:mi><mml:mo>±</mml:mo></mml:msubsup><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>±</mml:mo></mml:msub><mml:mo>;</mml:mo><mml:msub><mml:mi>Q</mml:mi><mml:mi>j</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"bold-italic\">ω</mml:mi></mml:mrow><mml:mi>j</mml:mi></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq423\"><alternatives><tex-math id=\"M1203\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$W^{s,p}$$\\end{document}</tex-math><mml:math id=\"M1204\"><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq424\"><alternatives><tex-math id=\"M1205\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p=1$$\\end{document}</tex-math><mml:math id=\"M1206\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq425\"><alternatives><tex-math id=\"M1207\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$s\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M1208\"><mml:mrow><mml:mi>s</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq426\"><alternatives><tex-math id=\"M1209\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p\\ge 1$$\\end{document}</tex-math><mml:math id=\"M1210\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>≥</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq427\"><alternatives><tex-math id=\"M1211\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$sp<N$$\\end{document}</tex-math><mml:math id=\"M1212\"><mml:mrow><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq428\"><alternatives><tex-math id=\"M1213\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$u:\\mathbb {R}^N\\rightarrow \\mathbb {R}$$\\end{document}</tex-math><mml:math id=\"M1214\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>:</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo stretchy=\"false\">→</mml:mo><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ187\"><alternatives><tex-math id=\"M1215\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\left( \\int _{\\mathbb {R}^N} \|u\|^{\\frac{Np}{N-sp}}\\,\\textrm{d}x\\right) ^{\\frac{N-sp}{N}}\\le C \\int _{\\mathbb {R}^N}\\int _{\\mathbb {R}^N}\\frac{\\big \|u(x) - u (y)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1216\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">Np</mml:mi></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced><mml:mfrac><mml:mrow><mml:mi>N</mml:mi><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:mfrac></mml:msup><mml:mo>≤</mml:mo><mml:mi>C</mml:mi><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq429\"><alternatives><tex-math id=\"M1217\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$C=C(s,p,N)$$\\end{document}</tex-math><mml:math id=\"M1218\"><mml:mrow><mml:mi>C</mml:mi><mml:mo>=</mml:mo><mml:mi>C</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq430\"><alternatives><tex-math id=\"M1219\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_R$$\\end{document}</tex-math><mml:math id=\"M1220\"><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq431\"><alternatives><tex-math id=\"M1221\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$s\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M1222\"><mml:mrow><mml:mi>s</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq432\"><alternatives><tex-math id=\"M1223\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p\\ge 1$$\\end{document}</tex-math><mml:math id=\"M1224\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>≥</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq433\"><alternatives><tex-math id=\"M1225\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$u\\in W^{s,p}(K_R)$$\\end{document}</tex-math><mml:math id=\"M1226\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq434\"><alternatives><tex-math id=\"M1227\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{(1-d)R}$$\\end{document}</tex-math><mml:math id=\"M1228\"><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>d</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq435\"><alternatives><tex-math id=\"M1229\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$d\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M1230\"><mml:mrow><mml:mi>d</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ211\"></disp-formula>", "<inline-formula id=\"IEq436\"><alternatives><tex-math id=\"M1231\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$C=C(\\kappa , s, p, N)$$\\end{document}</tex-math><mml:math id=\"M1232\"><mml:mrow><mml:mi>C</mml:mi><mml:mo>=</mml:mo><mml:mi>C</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>κ</mml:mi><mml:mo>,</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ188\"><alternatives><tex-math id=\"M1233\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\kappa \\in \\left\\{ \\begin{array}{cl} \\Big [1,\\frac{N}{N-sp}\\Big ],\\quad &{}sp<N,\\\\ {[}1,\\infty ),\\quad &{}sp\\ge N. \\end{array} \\right. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1234\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>κ</mml:mi><mml:mo>∈</mml:mo><mml:mfenced open=\"{\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mfrac><mml:mi>N</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow/><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mo stretchy=\"false\">[</mml:mo><mml:mn>1</mml:mn><mml:mo>,</mml:mo><mml:mi>∞</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow/><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo>≥</mml:mo><mml:mi>N</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq437\"><alternatives><tex-math id=\"M1235\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$R=1$$\\end{document}</tex-math><mml:math id=\"M1236\"><mml:mrow><mml:mi>R</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq438\"><alternatives><tex-math id=\"M1237\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_1$$\\end{document}</tex-math><mml:math id=\"M1238\"><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq439\"><alternatives><tex-math id=\"M1239\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$W^{s,p}(\\mathbb {R}^N)$$\\end{document}</tex-math><mml:math id=\"M1240\"><mml:mrow><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq440\"><alternatives><tex-math id=\"M1241\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$sp<N$$\\end{document}</tex-math><mml:math id=\"M1242\"><mml:mrow><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ47\"><label>A.1</label><alternatives><tex-math id=\"M1243\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned}&\\left( \\int _{\\mathbb {R}^N} \|u\|^{\\frac{Np}{N-sp}}\\,\\textrm{d}x\\right) ^{\\frac{N-sp}{N}} \\\\&\\quad \\le C \\int _{\\mathbb {R}^N}\\int _{\\mathbb {R}^N}\\frac{\\big \|u(x) - u (y)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\\\&\\quad = C \\int _{K_1}\\int _{K_1}\\frac{\\big \|u(x) - u (y)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y+ 2C\\int _{K_1}\\int _{\\mathbb {R}^N\\setminus K_1}\\frac{\|u(y) \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\\\&\\quad \\le C \\int _{K_1}\\int _{K_1}\\frac{\\big \|u(x) - u (y)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y+ \\frac{C}{d^{N+sp}}\\int _{K_1} \|u(y) \|^p \\,\\textrm{d}y. \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1244\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mi mathvariant=\"italic\">Np</mml:mi></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced><mml:mfrac><mml:mrow><mml:mi>N</mml:mi><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:mfrac></mml:msup></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>≤</mml:mo><mml:mi>C</mml:mi><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>=</mml:mo><mml:mi>C</mml:mi><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mo>+</mml:mo><mml:mn>2</mml:mn><mml:mi>C</mml:mi><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>≤</mml:mo><mml:mi>C</mml:mi><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mo>+</mml:mo><mml:mfrac><mml:mi>C</mml:mi><mml:msup><mml:mi>d</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq441\"><alternatives><tex-math id=\"M1245\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$y\\in K_{1-d}$$\\end{document}</tex-math><mml:math id=\"M1246\"><mml:mrow><mml:mi>y</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>d</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq442\"><alternatives><tex-math id=\"M1247\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${\\text {supp}}u$$\\end{document}</tex-math><mml:math id=\"M1248\"><mml:mrow><mml:mtext>supp</mml:mtext><mml:mi>u</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq443\"><alternatives><tex-math id=\"M1249\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$x\\in \\mathbb {R}^N\\setminus K_1$$\\end{document}</tex-math><mml:math id=\"M1250\"><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq444\"><alternatives><tex-math id=\"M1251\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\kappa $$\\end{document}</tex-math><mml:math id=\"M1252\"><mml:mi>κ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq445\"><alternatives><tex-math id=\"M1253\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\kappa $$\\end{document}</tex-math><mml:math id=\"M1254\"><mml:mi>κ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq446\"><alternatives><tex-math id=\"M1255\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$sp\\ge N$$\\end{document}</tex-math><mml:math id=\"M1256\"><mml:mrow><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo>≥</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq447\"><alternatives><tex-math id=\"M1257\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$W^{\\bar{s},p}(K_1)\\subset W^{s,p}(K_1)$$\\end{document}</tex-math><mml:math id=\"M1258\"><mml:mrow><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>⊂</mml:mo><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq448\"><alternatives><tex-math id=\"M1259\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$0<\\bar{s}\\le s<1$$\\end{document}</tex-math><mml:math id=\"M1260\"><mml:mrow><mml:mn>0</mml:mn><mml:mo><</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>≤</mml:mo><mml:mi>s</mml:mi><mml:mo><</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ189\"><alternatives><tex-math id=\"M1261\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned}&\\int _{K_1}\\int _{K_1}\\frac{\\big \|u(x) - u (y)\\big \|^p}{\|x-y\|^{N+\\bar{s}p}}\\,\\textrm{d}x\\textrm{d}y\\\\&\\quad = \\int _{K_1}\\int _{K_1\\cap \\{\|x-y\|<1\\}}\\frac{\\big \|u(x) - u (y)\\big \|^p}{\|x-y\|^{N+\\bar{s}p}}\\,\\textrm{d}x\\textrm{d}y+ \\int _{K_1}\\int _{K_1\\cap \\{\|x-y\|\\ge 1\\}}\\frac{\\big \|u(x) - u (y)\\big \|^p}{\|x-y\|^{N+\\bar{s}p}}\\,\\textrm{d}x\\textrm{d}y\\\\&\\quad \\le \\int _{K_1}\\int _{K_1}\\frac{\\big \|u(x) - u (y)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y+ C(\\bar{s},p,N)\\int _{K_1}\|u(x)\|^p\\,\\textrm{d}x. \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1262\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>=</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>∩</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi></mml:mrow><mml:mo>-</mml:mo><mml:mrow><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo><</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mo>+</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>∩</mml:mo><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo><mml:mo>≥</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>≤</mml:mo><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mo>+</mml:mo><mml:mi>C</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq449\"><alternatives><tex-math id=\"M1263\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{s}=\\frac{(\\kappa -1)}{\\kappa p}N$$\\end{document}</tex-math><mml:math id=\"M1264\"><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>κ</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>κ</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac><mml:mi>N</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq450\"><alternatives><tex-math id=\"M1265\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\bar{s}p<N$$\\end{document}</tex-math><mml:math id=\"M1266\"><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mi>N</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq451\"><alternatives><tex-math id=\"M1267\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$W^{\\bar{s},p}(K_1)$$\\end{document}</tex-math><mml:math id=\"M1268\"><mml:mrow><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mover accent=\"true\"><mml:mrow><mml:mi>s</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq452\"><alternatives><tex-math id=\"M1269\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\square $$\\end{document}</tex-math><mml:math id=\"M1270\"><mml:mo>□</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq453\"><alternatives><tex-math id=\"M1271\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$s\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M1272\"><mml:mrow><mml:mi>s</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq454\"><alternatives><tex-math id=\"M1273\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p\\ge 1$$\\end{document}</tex-math><mml:math id=\"M1274\"><mml:mrow><mml:mi>p</mml:mi><mml:mo>≥</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ190\"><alternatives><tex-math id=\"M1275\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\kappa _* := \\left\\{ \\begin{array}{cl} \\frac{N}{N-sp} ,\\quad &{} \\qquad sp<N,\\\\ 2,\\quad &{}\\qquad sp\\ge N. \\end{array} \\right. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1276\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mfenced open=\"{\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd><mml:mrow><mml:mfrac><mml:mi>N</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:mfrac><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow/><mml:mspace width=\"2em\"/><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mrow><mml:mrow/><mml:mn>2</mml:mn><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mrow/><mml:mspace width=\"2em\"/><mml:mi>s</mml:mi><mml:mi>p</mml:mi><mml:mo>≥</mml:mo><mml:mi>N</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mfenced></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ191\"><alternatives><tex-math id=\"M1277\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} u\\in L^{p}\\big (t_1,t_2; W^{s,p}(K_R)\\big )\\cap L^{\\infty }\\big (t_1,t_2; L^{2}(K_R)\\big ), \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1278\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo>;</mml:mo><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>∩</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mi>∞</mml:mi></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo>;</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mn>2</mml:mn></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq455\"><alternatives><tex-math id=\"M1279\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$K_{(1-d)R}$$\\end{document}</tex-math><mml:math id=\"M1280\"><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>d</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq456\"><alternatives><tex-math id=\"M1281\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$d\\in (0,1)$$\\end{document}</tex-math><mml:math id=\"M1282\"><mml:mrow><mml:mi>d</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq457\"><alternatives><tex-math id=\"M1283\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$t\\in (t_1,t_2)$$\\end{document}</tex-math><mml:math id=\"M1284\"><mml:mrow><mml:mi>t</mml:mi><mml:mo>∈</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ212\"></disp-formula>", "<inline-formula id=\"IEq458\"><alternatives><tex-math id=\"M1285\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$C=C(s,p,N)$$\\end{document}</tex-math><mml:math id=\"M1286\"><mml:mrow><mml:mi>C</mml:mi><mml:mo>=</mml:mo><mml:mi>C</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ192\"><alternatives><tex-math id=\"M1287\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\kappa :=1+\\frac{2(\\kappa _* -1)}{p\\kappa _}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1288\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>κ</mml:mi><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mn>1</mml:mn><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mn>2</mml:mn><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub></mml:mrow></mml:mfrac><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq459\"><alternatives><tex-math id=\"M1289\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$R=1$$\\end{document}</tex-math><mml:math id=\"M1290\"><mml:mrow><mml:mi>R</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq460\"><alternatives><tex-math id=\"M1291\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\kappa $$\\end{document}</tex-math><mml:math id=\"M1292\"><mml:mi>κ</mml:mi></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ193\"><alternatives><tex-math id=\"M1293\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _{t_1}^{t_2}&\\int _{K_1}\|u \|^{\\kappa p}\\,\\textrm{d}x\\textrm{d}t=\\int _{t_1}^{t_2}\\int _{K_1}\|u \|^{ p}\|u \|^{(\\kappa -1) p}\\,\\textrm{d}x\\textrm{d}t\\\\&\\le \\int _{t_1}^{t_2}\\left( \\int _{K_1}\|u \|^{\\kappa _ p}\\,\\textrm{d}x\\right) ^{\\frac{1}{\\kappa _}} \\left( \\int _{K_1}\|u \|^{p\\frac{\\kappa _ (\\kappa -1)}{\\kappa _-1}}\\,\\textrm{d}x\\right) ^{\\frac{1-\\kappa _}{\\kappa _}}\\textrm{d}t\\\\&\\le C \\left( \\int _{t_1}^{t_2}\\int _{K_1} \\int _{K_1}\\frac{\\big \|u(x,t) - u (y,t)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}x\\textrm{d}y\\textrm{d}t+ \\frac{1}{d^{N+sp}}\\int _{t_1}^{t_2}\\int _{K_1} \|u(x,t)\|^p\\,\\textrm{d}x\\textrm{d}t\\right) \\\\&\\quad \\times \\left( \\mathop {\\mathrm{ess\\,sup}}\\limits _{t_1<t<t_2}\\int _{K_1} \|u(x,t)\|^2\\,\\textrm{d}x\\right) ^{\\frac{\\kappa _ -1}{\\kappa _*}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1294\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:msubsup></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>κ</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>=</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>κ</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:msubsup><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced><mml:mfrac><mml:mn>1</mml:mn><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub></mml:mfrac></mml:msup><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mfrac><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>κ</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:mrow></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced><mml:mfrac><mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub></mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub></mml:mfrac></mml:msup><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mi>C</mml:mi><mml:mfenced close=\")\" open=\"(\"><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>+</mml:mo><mml:mfrac><mml:mn>1</mml:mn><mml:msup><mml:mi>d</mml:mi><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:msubsup><mml:mo>∫</mml:mo><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>×</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:munder><mml:mrow><mml:mi mathvariant=\"normal\">ess</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mi mathvariant=\"normal\">sup</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:mrow></mml:munder><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:msub><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi></mml:mfenced><mml:mfrac><mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:msub><mml:mi>κ</mml:mi><mml:mrow><mml:mrow/><mml:mo>∗</mml:mo></mml:mrow></mml:msub></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq461\"><alternatives><tex-math id=\"M1295\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\square $$\\end{document}</tex-math><mml:math id=\"M1296\"><mml:mo>□</mml:mo></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq462\"><alternatives><tex-math id=\"M1297\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$v\\in L^1(E_T)$$\\end{document}</tex-math><mml:math id=\"M1298\"><mml:mrow><mml:mi>v</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mn>1</mml:mn></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ194\"><alternatives><tex-math id=\"M1299\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\llbracket v \\rrbracket _h(x,t) := \\tfrac{1}{h} \\int _0^t \\mathrm e^{\\frac{\\tau -t}{h}} v(x,\\tau ) \\, \\textrm{d}\\tau ,\\quad \\llbracket v \\rrbracket _{\\bar{h}}(x,t) := \\tfrac{1}{h} \\int _t^T \\mathrm e^{\\frac{t-\\tau }{h}} v(x,\\tau ) \\, \\textrm{d}\\tau . \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1300\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>h</mml:mi></mml:mfrac></mml:mstyle><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>t</mml:mi></mml:msubsup><mml:msup><mml:mi mathvariant=\"normal\">e</mml:mi><mml:mfrac><mml:mrow><mml:mi>τ</mml:mi><mml:mo>-</mml:mo><mml:mi>t</mml:mi></mml:mrow><mml:mi>h</mml:mi></mml:mfrac></mml:msup><mml:mi>v</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>τ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>τ</mml:mi><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>h</mml:mi></mml:mfrac></mml:mstyle><mml:msubsup><mml:mo>∫</mml:mo><mml:mi>t</mml:mi><mml:mi>T</mml:mi></mml:msubsup><mml:msup><mml:mi mathvariant=\"normal\">e</mml:mi><mml:mfrac><mml:mrow><mml:mi>t</mml:mi><mml:mo>-</mml:mo><mml:mi>τ</mml:mi></mml:mrow><mml:mi>h</mml:mi></mml:mfrac></mml:msup><mml:mi>v</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>τ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>τ</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ48\"><label>B.1</label><alternatives><tex-math id=\"M1301\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\partial _t \\llbracket v \\rrbracket _h =\\tfrac{1}{h} \\big (v-\\llbracket v \\rrbracket _h\\big ), \\quad \\partial _t \\llbracket v \\rrbracket _{\\bar{h}} =\\tfrac{1}{h} \\big (\\llbracket v \\rrbracket _{\\bar{h}}- v\\big ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1302\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mi>h</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>h</mml:mi></mml:mfrac></mml:mstyle><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>v</mml:mi><mml:mo>-</mml:mo><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"1em\"/><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>h</mml:mi></mml:mfrac></mml:mstyle><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>-</mml:mo><mml:mi>v</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ195\"><alternatives><tex-math id=\"M1303\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _0^T \\partial _t \\llbracket v \\rrbracket _h\\, \\phi \\,\\textrm{d}t=- \\int _0^T \\llbracket v \\rrbracket _{\\bar{h}} \\, \\partial _t\\phi \\,\\textrm{d}t\\quad \\text {for all}\\>\\phi \\in C_o^1(0,T). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1304\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mi>h</mml:mi></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mi>ϕ</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>=</mml:mo><mml:mo>-</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mspace width=\"0.166667em\"/><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mi>ϕ</mml:mi><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mspace width=\"1em\"/><mml:mtext>for all</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:mi>ϕ</mml:mi><mml:mo>∈</mml:mo><mml:msubsup><mml:mi>C</mml:mi><mml:mi>o</mml:mi><mml:mn>1</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq463\"><alternatives><tex-math id=\"M1305\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$v\\in L^q(E_T)$$\\end{document}</tex-math><mml:math id=\"M1306\"><mml:mrow><mml:mi>v</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mi>q</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq464\"><alternatives><tex-math id=\"M1307\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$q\\ge 1$$\\end{document}</tex-math><mml:math id=\"M1308\"><mml:mrow><mml:mi>q</mml:mi><mml:mo>≥</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq465\"><alternatives><tex-math id=\"M1309\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\llbracket v \\rrbracket _h,\\, \\llbracket v \\rrbracket _{\\bar{h}}\\in L^q(E_T)$$\\end{document}</tex-math><mml:math id=\"M1310\"><mml:mrow><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mi>h</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>∈</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mi>q</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq466\"><alternatives><tex-math id=\"M1311\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$h\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1312\"><mml:mrow><mml:mi>h</mml:mi><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ49\"><label>B.2</label><alternatives><tex-math id=\"M1313\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\llbracket v \\rrbracket _h,\\, \\llbracket v \\rrbracket _{\\bar{h}}\\rightarrow v\\quad \\text {in}\\> L^q(E_T). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1314\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mi>h</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mo>〚</mml:mo><mml:mi>v</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo stretchy=\"false\">→</mml:mo><mml:mi>v</mml:mi><mml:mspace width=\"1em\"/><mml:mtext>in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msup><mml:mi>L</mml:mi><mml:mi>q</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq467\"><alternatives><tex-math id=\"M1315\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$u\\in C\\big ([0,T];L^2_{{\\text {loc}}}(E)\\big )$$\\end{document}</tex-math><mml:math id=\"M1316\"><mml:mrow><mml:mi>u</mml:mi><mml:mo>∈</mml:mo><mml:mi>C</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">[</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">]</mml:mo></mml:mrow><mml:mo>;</mml:mo><mml:msubsup><mml:mi>L</mml:mi><mml:mtext>loc</mml:mtext><mml:mn>2</mml:mn></mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>E</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ196\"><alternatives><tex-math id=\"M1317\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathcal {A}\\equiv K(x,y,t)\\big \|u(x,t) - u(y,t)\\big \|^{p-2} \\big (u(x,t) - u(y,t)\\big ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1318\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi mathvariant=\"script\">A</mml:mi><mml:mo>≡</mml:mo><mml:mi>K</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq468\"><alternatives><tex-math id=\"M1319\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta $$\\end{document}</tex-math><mml:math id=\"M1320\"><mml:mi>ζ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq469\"><alternatives><tex-math id=\"M1321\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\psi _\\varepsilon (t),\\,\\varepsilon >0$$\\end{document}</tex-math><mml:math id=\"M1322\"><mml:mrow><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>,</mml:mo><mml:mspace width=\"0.166667em\"/><mml:mi>ε</mml:mi><mml:mo>></mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq470\"><alternatives><tex-math id=\"M1323\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\chi _{\\{t_o-S<t<t_o\\}}$$\\end{document}</tex-math><mml:math id=\"M1324\"><mml:msub><mml:mi>χ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo><</mml:mo><mml:mi>t</mml:mi><mml:mo><</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq471\"><alternatives><tex-math id=\"M1325\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\psi _\\varepsilon =1$$\\end{document}</tex-math><mml:math id=\"M1326\"><mml:mrow><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq472\"><alternatives><tex-math id=\"M1327\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(t_o-S+\\varepsilon , t_o-\\varepsilon )$$\\end{document}</tex-math><mml:math id=\"M1328\"><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>+</mml:mo><mml:mi>ε</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>ε</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq473\"><alternatives><tex-math id=\"M1329\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\psi _\\varepsilon =0$$\\end{document}</tex-math><mml:math id=\"M1330\"><mml:mrow><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq474\"><alternatives><tex-math id=\"M1331\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$(t_o-S,t_o)$$\\end{document}</tex-math><mml:math id=\"M1332\"><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi><mml:mo>,</mml:mo><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ197\"><alternatives><tex-math id=\"M1333\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varphi _h=\\big (\\llbracket u \\rrbracket _{\\bar{h}}-k\\big )_+\\zeta ^p\\psi _{\\varepsilon }; \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1334\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub><mml:mo>;</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ50\"><label>B.3</label><alternatives><tex-math id=\"M1335\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} -\\int _0^T\\int _E u \\partial _t \\varphi _h\\,\\textrm{d}x\\textrm{d}t+\\int _0^T\\int _{\\mathbb {R}^N}\\int _{\\mathbb {R}^N} \\mathcal {A} \\cdot \\big (\\varphi _h(x,t)-\\varphi _h(y,t)\\big )\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\le 0. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1336\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>-</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:mi>E</mml:mi></mml:msub><mml:mi>u</mml:mi><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mi mathvariant=\"script\">A</mml:mi><mml:mo>·</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>≤</mml:mo><mml:mn>0</mml:mn><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ198\"><alternatives><tex-math id=\"M1337\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} -\\int _0^T\\int _E u \\partial _t \\varphi _h\\,\\textrm{d}x\\textrm{d}t&= -\\int _0^T\\int _E \\llbracket u \\rrbracket _{\\bar{h}} \\partial _t \\varphi _h\\,\\textrm{d}x\\textrm{d}t+\\int _0^T\\int _E \\big (\\llbracket u \\rrbracket _{\\bar{h}} - u\\big )\\partial _t \\varphi _h\\,\\textrm{d}x\\textrm{d}t\\\\&=\\tfrac{1}{2}\\int _0^T\\int _E \\partial _t\\big (\\llbracket u \\rrbracket _{\\bar{h}} -k\\big )_+^2 \\zeta ^p\\psi _{\\varepsilon }\\,\\textrm{d}x\\textrm{d}t\\\\&\\quad +\\tfrac{1}{h}\\int _0^T\\int _E \\big (\\llbracket u \\rrbracket _{\\bar{h}} - u\\big )^2 \\chi _{\\{\\llbracket u \\rrbracket _{\\bar{h}}>k\\}}\\zeta ^p\\psi _{\\varepsilon }\\,\\textrm{d}x\\textrm{d}t\\\\&\\quad + \\int _0^T\\int _E \\big (\\llbracket u \\rrbracket _{\\bar{h}} - u\\big )\\big (\\llbracket u \\rrbracket _{\\bar{h}} -k\\big )_+ \\partial _t\\big (\\zeta ^p\\psi _{\\varepsilon }\\big )\\,\\textrm{d}x\\textrm{d}t. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1338\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mo>-</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:mi>E</mml:mi></mml:msub><mml:mi>u</mml:mi><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:mo>-</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:mi>E</mml:mi></mml:msub><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:mi>E</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>=</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:mi>E</mml:mi></mml:msub><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>h</mml:mi></mml:mfrac></mml:mstyle><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:mi>E</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mn>2</mml:mn></mml:msup><mml:msub><mml:mi>χ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">{</mml:mo><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>></mml:mo><mml:mi>k</mml:mi><mml:mo stretchy=\"false\">}</mml:mo></mml:mrow></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mspace width=\"1em\"/><mml:mo>+</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:mi>E</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq475\"><alternatives><tex-math id=\"M1339\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$h\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1340\"><mml:mrow><mml:mi>h</mml:mi><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq476\"><alternatives><tex-math id=\"M1341\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$h\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1342\"><mml:mrow><mml:mi>h</mml:mi><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq477\"><alternatives><tex-math id=\"M1343\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varepsilon \\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1344\"><mml:mrow><mml:mi>ε</mml:mi><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ199\"><alternatives><tex-math id=\"M1345\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\tfrac{1}{2}\\int _{K_R}\\big (u-k\\big )_+^2\\zeta ^p\\,\\textrm{d}x\\bigg \|_{t_o-S}^{t_o} - \\tfrac{1}{2}\\iint _{Q(R,S)}\\big (u-k\\big )_+^2\\partial _t\\zeta ^p\\,\\textrm{d}x\\textrm{d}t. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1346\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:msubsup><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>S</mml:mi></mml:mrow><mml:msub><mml:mi>t</mml:mi><mml:mi>o</mml:mi></mml:msub></mml:msubsup><mml:mo>-</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo><mml:mn>2</mml:mn></mml:msubsup><mml:msub><mml:mi>∂</mml:mi><mml:mi>t</mml:mi></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ200\"><alternatives><tex-math id=\"M1347\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _0^T\\int _{\\mathbb {R}^N}\\int _{\\mathbb {R}^N} \\mathcal {A} \\cdot \\big (\\varphi (x,t)-\\varphi (y,t)\\big )\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1348\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup></mml:msub><mml:mi mathvariant=\"script\">A</mml:mi><mml:mo>·</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq478\"><alternatives><tex-math id=\"M1349\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$h\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1350\"><mml:mrow><mml:mi>h</mml:mi><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ201\"><alternatives><tex-math id=\"M1351\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\varphi =\\big ( u -k\\big )_+\\zeta ^p\\psi _{\\varepsilon }. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1352\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mi>φ</mml:mi><mml:mo>=</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>-</mml:mo><mml:mi>k</mml:mi><mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>+</mml:mo></mml:msub><mml:msup><mml:mi>ζ</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ202\"><alternatives><tex-math id=\"M1353\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned}&I_1:= \\int _0^T\\int _{K_{2R}}\\int _{K_{2R}}\\mathcal {A} \\cdot \\left( \\big [\\varphi _h(x,t)-\\varphi _h(y,t)\\big ] - \\big [\\varphi (x,t)-\\varphi (y,t)\\big ]\\right) \\,\\textrm{d}y\\textrm{d}x\\textrm{d}t,\\\\&I_2:=2\\int _0^T\\int _{K_{2R}}\\int _{\\mathbb {R}^N\\setminus K_{2R}}\\mathcal {A} \\cdot \\big [\\varphi _h(x,t)- \\varphi (x,t) \\big ]\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1354\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd/><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mi>I</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mi mathvariant=\"script\">A</mml:mi><mml:mo>·</mml:mo><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow></mml:mfenced><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo>:</mml:mo><mml:mo>=</mml:mo><mml:mn>2</mml:mn><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub><mml:mi mathvariant=\"script\">A</mml:mi><mml:mo>·</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq479\"><alternatives><tex-math id=\"M1355\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varphi _h(y,t)=\\varphi (y,t)=0$$\\end{document}</tex-math><mml:math id=\"M1356\"><mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq480\"><alternatives><tex-math id=\"M1357\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$y\\in \\mathbb {R}^N{\\setminus } K_{2R}$$\\end{document}</tex-math><mml:math id=\"M1358\"><mml:mrow><mml:mi>y</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq481\"><alternatives><tex-math id=\"M1359\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_2$$\\end{document}</tex-math><mml:math id=\"M1360\"><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq482\"><alternatives><tex-math id=\"M1361\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_1$$\\end{document}</tex-math><mml:math id=\"M1362\"><mml:msub><mml:mi>I</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq483\"><alternatives><tex-math id=\"M1363\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_2$$\\end{document}</tex-math><mml:math id=\"M1364\"><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq484\"><alternatives><tex-math id=\"M1365\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$h\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1366\"><mml:mrow><mml:mi>h</mml:mi><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq485\"><alternatives><tex-math id=\"M1367\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_1$$\\end{document}</tex-math><mml:math id=\"M1368\"><mml:msub><mml:mi>I</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ51\"><label>B.4</label><alternatives><tex-math id=\"M1369\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _0^T\\int _{K_{2R}}\\int _{K_{2R}} \\frac{ \\big \|\\varphi _h(x,t)-\\varphi _h(y,t)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\le C \\Vert u\\Vert ^p_{L^p(0,T; W^{s,p}(K_{2R}))}, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1370\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>≤</mml:mo><mml:mi>C</mml:mi><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">‖</mml:mo></mml:mrow><mml:mrow><mml:msup><mml:mi>L</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo>;</mml:mo><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:mi>p</mml:mi></mml:msubsup><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq486\"><alternatives><tex-math id=\"M1371\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$C=C(s,p,N, R, \\Vert D\\zeta \\Vert _{\\infty } )$$\\end{document}</tex-math><mml:math id=\"M1372\"><mml:mrow><mml:mi>C</mml:mi><mml:mo>=</mml:mo><mml:mi>C</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>D</mml:mi><mml:mi>ζ</mml:mi><mml:msub><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>∞</mml:mi></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq487\"><alternatives><tex-math id=\"M1373\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\varphi _h\\rightarrow \\varphi $$\\end{document}</tex-math><mml:math id=\"M1374\"><mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mo stretchy=\"false\">→</mml:mo><mml:mi>φ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq488\"><alternatives><tex-math id=\"M1375\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$E_T$$\\end{document}</tex-math><mml:math id=\"M1376\"><mml:msub><mml:mi>E</mml:mi><mml:mi>T</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ203\"><alternatives><tex-math id=\"M1377\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\frac{ \\varphi _h(x,t)-\\varphi _h(y,t)}{\|x-y\|^{\\frac{N}{p}+s}} \\rightharpoonup \\frac{ \\varphi (x,t)-\\varphi (y,t)}{\|x-y\|^{\\frac{N}{p}+s}}\\quad \\text {weakly in}\\>L^p\\big ((0,T)\\times K_{2R}\\times K_{2R}\\big ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1378\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mfrac><mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mfrac><mml:mi>N</mml:mi><mml:mi>p</mml:mi></mml:mfrac><mml:mo>+</mml:mo><mml:mi>s</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mo>⇀</mml:mo><mml:mfrac><mml:mrow><mml:mi>φ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mfrac><mml:mi>N</mml:mi><mml:mi>p</mml:mi></mml:mfrac><mml:mo>+</mml:mo><mml:mi>s</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"1em\"/><mml:mtext>weakly in</mml:mtext><mml:mspace width=\"0.222222em\"/><mml:msup><mml:mi>L</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq489\"><alternatives><tex-math id=\"M1379\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_1\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1380\"><mml:mrow><mml:msub><mml:mi>I</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ204\"><alternatives><tex-math id=\"M1381\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\mathcal {A}\\cdot \|x-y\|^{\\frac{N}{p}+s}\\in L^{\\frac{p}{p-1}}\\big ((0,T)\\times K_{2R}\\times K_{2R}\\big ). \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1382\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"script\">A</mml:mi><mml:mo>·</mml:mo><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mfrac><mml:mi>N</mml:mi><mml:mi>p</mml:mi></mml:mfrac><mml:mo>+</mml:mo><mml:mi>s</mml:mi></mml:mrow></mml:msup><mml:mo>∈</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mfrac><mml:mi>p</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mo>×</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq490\"><alternatives><tex-math id=\"M1383\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\zeta $$\\end{document}</tex-math><mml:math id=\"M1384\"><mml:mi>ζ</mml:mi></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq491\"><alternatives><tex-math id=\"M1385\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\psi _\\varepsilon $$\\end{document}</tex-math><mml:math id=\"M1386\"><mml:msub><mml:mi>ψ</mml:mi><mml:mi>ε</mml:mi></mml:msub></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ205\"><alternatives><tex-math id=\"M1387\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big \|\\varphi _h(x,t)-\\varphi _h(y,t)\\big \|^p\\le c \\big \|\\llbracket u \\rrbracket _{\\bar{h}}(x,t) - \\llbracket u \\rrbracket _{\\bar{h}}(y,t)\\big \|^p + c\\big \| \\llbracket u \\rrbracket _{\\bar{h}}(y,t)\\big \|^p \\big \|\\zeta (x,t)-\\zeta (y,t)\\big \|^p \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1388\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo>≤</mml:mo><mml:mi>c</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo>+</mml:mo><mml:mi>c</mml:mi><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq492\"><alternatives><tex-math id=\"M1389\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$c=c(p)$$\\end{document}</tex-math><mml:math id=\"M1390\"><mml:mrow><mml:mi>c</mml:mi><mml:mo>=</mml:mo><mml:mi>c</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>p</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ206\"><alternatives><tex-math id=\"M1391\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\big \|\\llbracket u \\rrbracket _{\\bar{h}}(x,t) - \\llbracket u \\rrbracket _{\\bar{h}}(y,t)\\big \|^p&\\le \\left( \\tfrac{1}{h} \\int _t^T \\mathrm e^{\\frac{t-\\tau }{h}} \\, \\textrm{d}\\tau \\right) ^{p-1}\\left( \\tfrac{1}{h} \\int _t^T \\mathrm e^{\\frac{t-\\tau }{h}} \\big \| u(x,\\tau ) - u(y,\\tau )\\big \|^p \\, \\textrm{d}\\tau \\right) \\\\&\\le \\tfrac{1}{h} \\int _t^T \\mathrm e^{\\frac{t-\\tau }{h}} \\big \| u(x,\\tau ) - u(y,\\tau )\\big \|^p \\, \\textrm{d}\\tau . \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1392\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>h</mml:mi></mml:mfrac></mml:mstyle><mml:msubsup><mml:mo>∫</mml:mo><mml:mi>t</mml:mi><mml:mi>T</mml:mi></mml:msubsup><mml:msup><mml:mi mathvariant=\"normal\">e</mml:mi><mml:mfrac><mml:mrow><mml:mi>t</mml:mi><mml:mo>-</mml:mo><mml:mi>τ</mml:mi></mml:mrow><mml:mi>h</mml:mi></mml:mfrac></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>τ</mml:mi></mml:mfenced><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mfenced close=\")\" open=\"(\"><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>h</mml:mi></mml:mfrac></mml:mstyle><mml:msubsup><mml:mo>∫</mml:mo><mml:mi>t</mml:mi><mml:mi>T</mml:mi></mml:msubsup><mml:msup><mml:mi mathvariant=\"normal\">e</mml:mi><mml:mfrac><mml:mrow><mml:mi>t</mml:mi><mml:mo>-</mml:mo><mml:mi>τ</mml:mi></mml:mrow><mml:mi>h</mml:mi></mml:mfrac></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>τ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>τ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>τ</mml:mi></mml:mfenced></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mi>h</mml:mi></mml:mfrac></mml:mstyle><mml:msubsup><mml:mo>∫</mml:mo><mml:mi>t</mml:mi><mml:mi>T</mml:mi></mml:msubsup><mml:msup><mml:mi mathvariant=\"normal\">e</mml:mi><mml:mfrac><mml:mrow><mml:mi>t</mml:mi><mml:mo>-</mml:mo><mml:mi>τ</mml:mi></mml:mrow><mml:mi>h</mml:mi></mml:mfrac></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>τ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>τ</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>τ</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ207\"><alternatives><tex-math id=\"M1393\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _0^T \\big \|\\llbracket u \\rrbracket _{\\bar{h}}(x,t) - \\llbracket u \\rrbracket _{\\bar{h}}(y,t)\\big \|^p\\,\\textrm{d}t&\\le \\int _0^T\\big (1-\\mathrm e^{-\\frac{t}{h}}\\big ) \\big \| u(x,t) - u(y,t)\\big \|^p\\,\\textrm{d}t\\\\&\\le \\int _0^T \\big \| u(x,t) - u(y,t)\\big \|^p\\,\\textrm{d}t. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1394\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:msup><mml:mi mathvariant=\"normal\">e</mml:mi><mml:mrow><mml:mo>-</mml:mo><mml:mfrac><mml:mi>t</mml:mi><mml:mi>h</mml:mi></mml:mfrac></mml:mrow></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ52\"><label>B.5</label><alternatives><tex-math id=\"M1395\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _0^T\\int _{K_{2R}}\\int _{K_{2R}} \\frac{\\big \|\\llbracket u \\rrbracket _{\\bar{h}}(x,t) - \\llbracket u \\rrbracket _{\\bar{h}}(y,t)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\le \\Vert u\\Vert ^p_{L^p(0,T; W^{s,p}(K_{2R}))}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1396\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>≤</mml:mo><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">‖</mml:mo></mml:mrow><mml:mrow><mml:msup><mml:mi>L</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo>;</mml:mo><mml:msup><mml:mi>W</mml:mi><mml:mrow><mml:mi>s</mml:mi><mml:mo>,</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:mi>p</mml:mi></mml:msubsup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ208\"><alternatives><tex-math id=\"M1397\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\int _0^T \\big \| \\llbracket u \\rrbracket _{\\bar{h}}(y,t)\\big \|^p\\,\\textrm{d}t\\le \\int _0^T \\big \| u(y,t)\\big \|^p\\,\\textrm{d}t, \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1398\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>≤</mml:mo><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:mo>,</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ53\"><label>B.6</label><alternatives><tex-math id=\"M1399\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \\begin{aligned} \\int _0^T&\\int _{K_{2R}}\\int _{K_{2R}} \\frac{\\big \| \\llbracket u \\rrbracket _{\\bar{h}}(y,t)\\big \|^p \\big \|\\zeta (x,t)-\\zeta (y,t)\\big \|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\\\&\\le \\Vert D\\zeta \\Vert ^p_{\\infty } \\int _0^T\\int _{K_{2R}}\\int _{K_{2R}} \\frac{\\big \|\\llbracket u \\rrbracket _{\\bar{h}}(y,t)\\big \|^p \|x-y\|^p}{\|x-y\|^{N+sp}}\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\\\&\\le \\Vert D\\zeta \\Vert ^p_{\\infty } \\int _0^T\\int _{K_{2R}}\\int _{K_{2R}} \\frac{\\big \|u(y,t)\\big \|^p }{\|x-y\|^{N+(s-1)p}}\\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\\\&\\le \\varvec{\\gamma } \\Vert D\\zeta \\Vert ^p_{\\infty } R^{(1-s)p} \\Vert u\\Vert ^p_{L^p(0,T; L^{p}(K_{2R}))}. \\end{aligned} \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1400\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>ζ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>D</mml:mi><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">‖</mml:mo></mml:mrow><mml:mi>∞</mml:mi><mml:mi>p</mml:mi></mml:msubsup><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mo>〚</mml:mo><mml:mi>u</mml:mi><mml:msub><mml:mo>〛</mml:mo><mml:mover accent=\"true\"><mml:mrow><mml:mi>h</mml:mi></mml:mrow><mml:mrow><mml:mo stretchy=\"false\">¯</mml:mo></mml:mrow></mml:mover></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>D</mml:mi><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">‖</mml:mo></mml:mrow><mml:mi>∞</mml:mi><mml:mi>p</mml:mi></mml:msubsup><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mfrac><mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>s</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:msubsup><mml:mrow><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>D</mml:mi><mml:mi>ζ</mml:mi><mml:mo stretchy=\"false\">‖</mml:mo></mml:mrow><mml:mi>∞</mml:mi><mml:mi>p</mml:mi></mml:msubsup><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mi>s</mml:mi><mml:mo stretchy=\"false\">)</mml:mo><mml:mi>p</mml:mi></mml:mrow></mml:msup><mml:msubsup><mml:mrow><mml:mo stretchy=\"false\">‖</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">‖</mml:mo></mml:mrow><mml:mrow><mml:msup><mml:mi>L</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mn>0</mml:mn><mml:mo>,</mml:mo><mml:mi>T</mml:mi><mml:mo>;</mml:mo><mml:msup><mml:mi>L</mml:mi><mml:mi>p</mml:mi></mml:msup><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:mrow><mml:mi>p</mml:mi></mml:msubsup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq493\"><alternatives><tex-math id=\"M1401\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_2$$\\end{document}</tex-math><mml:math id=\"M1402\"><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq494\"><alternatives><tex-math id=\"M1403\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\|x-y\|\\ge \\tfrac{1}{2} \|y\|$$\\end{document}</tex-math><mml:math id=\"M1404\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mo>≥</mml:mo><mml:mstyle displaystyle=\"false\" scriptlevel=\"0\"><mml:mfrac><mml:mn>1</mml:mn><mml:mn>2</mml:mn></mml:mfrac></mml:mstyle><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq495\"><alternatives><tex-math id=\"M1405\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$y\\in \\mathbb {R}^N{\\setminus } K_{2R}$$\\end{document}</tex-math><mml:math id=\"M1406\"><mml:mrow><mml:mi>y</mml:mi><mml:mo>∈</mml:mo><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq496\"><alternatives><tex-math id=\"M1407\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$x\\in K_{R}$$\\end{document}</tex-math><mml:math id=\"M1408\"><mml:mrow><mml:mi>x</mml:mi><mml:mo>∈</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:mrow></mml:math></alternatives></inline-formula>", "<disp-formula id=\"Equ209\"><alternatives><tex-math id=\"M1409\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\begin{aligned} \| I_2 \|&\\le 2 \\int _0^T\\int _{K_{2R}}\\int _{\\mathbb {R}^N\\setminus K_{2R}} \\Big \| \\mathcal {A} \\cdot \\big (\\varphi _h(x,t)-\\varphi (x,t)\\big ) \\Big \| \\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\\\&\\le 2C_1 \\int _0^T\\int _{K_{2R}}\\int _{\\mathbb {R}^N\\setminus K_{2R}} \\frac{\|u(x,t) - u(y,t)\|^{p-1}}{\|x-y\|^{N+sp}} \\big \| \\varphi _h(x,t)-\\varphi (x,t) \\big \| \\,\\textrm{d}y\\textrm{d}x\\textrm{d}t\\\\&\\le \\varvec{\\gamma } \\int _0^T\\int _{K_{2R}} \\big \| \\varphi _h(x,t)-\\varphi (x,t) \\big \| \\,\\textrm{d}x\\textrm{d}t\\int _{\\mathbb {R}^N\\setminus K_{2R}} \\frac{\|u(x,t)\|^{p-1} + \|u(y,t)\|^{p-1}}{\|y\|^{N+sp}}\\,\\textrm{d}y\\\\&\\le \\frac{\\varvec{\\gamma }}{R^{sp}} \\int _0^T\\int _{K_{R}} \\big \| \\varphi _h(x,t)-\\varphi (x,t) \\big \| \\left( \|u(x,t)\|^{p-1} + \\big [\\textrm{Tail}\\big (u; Q(R,S)\\big )\\big ]^{p-1}\\right) \\,\\textrm{d}x\\textrm{d}t\\\\&\\le \\frac{\\varvec{\\gamma }}{R^{sp}} \\bigg [\\iint _{Q(R,S)} \\big \| \\varphi _h -\\varphi \\big \|^p\\,\\textrm{d}x\\textrm{d}t\\bigg ]^{\\frac{1}{p}} \\bigg [\\iint _{Q(R,S)} \\left( \|u \|^{p } + \\big [\\textrm{Tail}\\big (u; Q(R,S)\\big )\\big ]^{p}\\right) \\,\\textrm{d}x\\textrm{d}t\\bigg ]^{\\frac{p-1}{p}}. \\end{aligned}$$\\end{document}</tex-math><mml:math id=\"M1410\" display=\"block\"><mml:mrow><mml:mtable><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow></mml:mrow></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mn>2</mml:mn><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi mathvariant=\"script\">A</mml:mi><mml:mo>·</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.623em\" minsize=\"1.623em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mn>2</mml:mn><mml:msub><mml:mi>C</mml:mi><mml:mn>1</mml:mn></mml:msub><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>x</mml:mi><mml:mo>-</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:msub><mml:mo>∫</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mi mathvariant=\"double-struck\">R</mml:mi></mml:mrow><mml:mi>N</mml:mi></mml:msup><mml:mo lspace=\"0.15em\" rspace=\"0.15em\" stretchy=\"false\">\\</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mn>2</mml:mn><mml:mi>R</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:msub><mml:mfrac><mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>y</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mrow><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>y</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>N</mml:mi><mml:mo>+</mml:mo><mml:mi>s</mml:mi><mml:mi>p</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>y</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:msubsup><mml:mo>∫</mml:mo><mml:mn>0</mml:mn><mml:mi>T</mml:mi></mml:msubsup><mml:msub><mml:mo>∫</mml:mo><mml:msub><mml:mi>K</mml:mi><mml:mi>R</mml:mi></mml:msub></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>x</mml:mi><mml:mo>,</mml:mo><mml:mi>t</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup><mml:mo>+</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>;</mml:mo><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:msup></mml:mfenced><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi></mml:mrow></mml:mtd></mml:mtr><mml:mtr><mml:mtd columnalign=\"right\"><mml:mrow/></mml:mtd><mml:mtd columnalign=\"left\"><mml:mrow><mml:mo>≤</mml:mo><mml:mfrac><mml:mrow><mml:mi mathvariant=\"bold-italic\">γ</mml:mi></mml:mrow><mml:msup><mml:mi>R</mml:mi><mml:mrow><mml:mi mathvariant=\"italic\">sp</mml:mi></mml:mrow></mml:msup></mml:mfrac><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:msub><mml:mi>φ</mml:mi><mml:mi>h</mml:mi></mml:msub><mml:mo>-</mml:mo><mml:mi>φ</mml:mi><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:msup><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mfrac><mml:mn>1</mml:mn><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:msub><mml:mo>∬</mml:mo><mml:mrow><mml:mi>Q</mml:mi><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:msub><mml:mfenced close=\")\" open=\"(\"><mml:msup><mml:mrow><mml:mo stretchy=\"false\">\|</mml:mo><mml:mi>u</mml:mi><mml:mo stretchy=\"false\">\|</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup><mml:mo>+</mml:mo><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">[</mml:mo></mml:mrow><mml:mtext>Tail</mml:mtext><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">(</mml:mo></mml:mrow><mml:mi>u</mml:mi><mml:mo>;</mml:mo><mml:mi>Q</mml:mi><mml:mrow><mml:mo stretchy=\"false\">(</mml:mo><mml:mi>R</mml:mi><mml:mo>,</mml:mo><mml:mi>S</mml:mi><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">)</mml:mo></mml:mrow><mml:msup><mml:mrow><mml:mo maxsize=\"1.2em\" minsize=\"1.2em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mi>p</mml:mi></mml:msup></mml:mfenced><mml:mspace width=\"0.166667em\"/><mml:mtext>d</mml:mtext><mml:mi>x</mml:mi><mml:mtext>d</mml:mtext><mml:mi>t</mml:mi><mml:msup><mml:mrow><mml:mo maxsize=\"2.047em\" minsize=\"2.047em\" stretchy=\"true\">]</mml:mo></mml:mrow><mml:mfrac><mml:mrow><mml:mi>p</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mi>p</mml:mi></mml:mfrac></mml:msup><mml:mo>.</mml:mo></mml:mrow></mml:mtd></mml:mtr></mml:mtable></mml:mrow></mml:math></alternatives></disp-formula>", "<inline-formula id=\"IEq497\"><alternatives><tex-math id=\"M1411\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$I_2\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1412\"><mml:mrow><mml:msub><mml:mi>I</mml:mi><mml:mn>2</mml:mn></mml:msub><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>", "<inline-formula id=\"IEq498\"><alternatives><tex-math id=\"M1413\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$h\\rightarrow 0$$\\end{document}</tex-math><mml:math id=\"M1414\"><mml:mrow><mml:mi>h</mml:mi><mml:mo stretchy=\"false\">→</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:math></alternatives></inline-formula>" ]	[]	[]	[]	[]	[]	[ "<fn-group><fn id=\"Fn1\"><label>1</label><p id=\"Par13\">After completion of the paper, we noticed a similar result in the recent preprint [##UREF##0##1##], via exponential change of variables.</p></fn><fn id=\"Fn2\"><label>2</label><p id=\"Par33\">The reader is advised to compare the either-or statement with Lemma 3.1 of [##UREF##10##11##, Chapter 3]. There, the constant <italic>C</italic> in (3.2) information of lower order terms; Here, we treat the tail as a kind of lower order term.</p></fn><fn><p><bold>Publisher's Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"526_2023_2627_Article_Equ1.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq1.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq2.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq3.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq4.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ2.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq5.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq6.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq7.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ3.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq8.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq9.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq10.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq11.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq12.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq13.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq14.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq15.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq16.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq17.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq18.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ54.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq19.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq20.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ55.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq21.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq22.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq23.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ56.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq24.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq25.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq26.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq27.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq28.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq29.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq30.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq31.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq32.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq33.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq34.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq35.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ4.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ5.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq36.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq37.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ57.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq38.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq39.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq40.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq41.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ58.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ59.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq42.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq43.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ60.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq44.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ61.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq45.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq46.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ6.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ7.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ62.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ8.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq47.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq48.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq49.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq50.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq51.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq52.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq53.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq54.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq55.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ63.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq56.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq57.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ9.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq58.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq59.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ64.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq60.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq61.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq62.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq63.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq64.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq65.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq66.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq67.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq68.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ65.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq69.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq70.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq71.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ66.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq72.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq73.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq74.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq75.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq76.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ10.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq77.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq78.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ11.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq79.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ12.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq80.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ67.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq81.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ68.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ13.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ69.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq82.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq83.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ70.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ71.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq84.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq85.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ72.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq86.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ73.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ74.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq87.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq88.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq89.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq90.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq91.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq92.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq93.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq94.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq95.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ75.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ76.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq96.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq97.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq98.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq99.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq100.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq101.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ77.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq102.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq103.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq104.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq105.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq106.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq107.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq108.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq109.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq110.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ78.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ79.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ80.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq111.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq112.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq113.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq114.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ81.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ82.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ83.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq115.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq116.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq117.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq118.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq119.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq120.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ84.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ85.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq121.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq122.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq123.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq124.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ86.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ87.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq125.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ88.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq126.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq127.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq128.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ89.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq129.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq130.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ90.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ91.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ92.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ93.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq131.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq132.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq133.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq134.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq135.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq136.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Equ210_HTML.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq137.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ94.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq138.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ95.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ96.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq139.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ97.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq140.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq141.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq142.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq143.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq144.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq145.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq146.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq147.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq148.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq149.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ98.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ99.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ100.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq150.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq151.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq152.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq153.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq154.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq155.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq156.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq157.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq158.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq159.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq160.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq161.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq162.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq163.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq164.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq165.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq166.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ101.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq167.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq168.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq169.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq170.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq171.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq172.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq173.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq174.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq175.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq176.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq177.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq178.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq179.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq180.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq181.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq182.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq183.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq184.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq185.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq186.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq187.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq188.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq189.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq190.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq191.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq192.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq193.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ102.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ103.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq194.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ104.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq195.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq196.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq197.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ105.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq198.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq199.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq200.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq201.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq202.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq203.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq204.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq205.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq206.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq207.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ106.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ107.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ108.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq208.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq209.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq210.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq211.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq212.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq213.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ109.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq214.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq215.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq216.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq217.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq218.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq219.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ110.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ111.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq220.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq221.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ112.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ113.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ114.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq222.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ115.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ116.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ117.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ118.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq223.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ119.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq224.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq225.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq226.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ120.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ121.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq227.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq228.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq229.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq230.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq231.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq232.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq233.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq234.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq235.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ122.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq236.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq237.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq238.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq239.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ123.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ124.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq240.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq241.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq242.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq243.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq244.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ125.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq245.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq246.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq247.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq248.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq249.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ126.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ127.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq250.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq251.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq252.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ128.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ129.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ130.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq253.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ131.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq254.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq255.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ132.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq256.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq257.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq258.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ133.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq259.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq260.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq261.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq262.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq263.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq264.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq265.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq266.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq267.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ134.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq268.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq269.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq270.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ135.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ136.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ137.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq271.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq272.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq273.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq274.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq275.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq276.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq277.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq278.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ138.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ139.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ140.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq279.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq280.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq281.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq282.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq283.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq284.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq285.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq286.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq287.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ141.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq288.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq289.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq290.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ142.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq291.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq292.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq293.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq294.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq295.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq296.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq297.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq298.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ143.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq299.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq300.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq301.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq302.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq303.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ144.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq304.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq305.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ145.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq306.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq307.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq308.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq309.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq310.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq311.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ146.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq312.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq313.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq314.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq315.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq316.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq317.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ147.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq318.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq319.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ148.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq320.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ14.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq321.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq322.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq323.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq324.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ149.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ150.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq325.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq326.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq327.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq328.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq329.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq330.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ15.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ151.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ16.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ17.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq331.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ152.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ18.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq332.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq333.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ19.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ153.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq334.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ154.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq335.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq336.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq337.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq338.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq339.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq340.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq341.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ155.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ156.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq342.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq343.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq344.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq345.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq346.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq347.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq348.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ20.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ157.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ21.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ22.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ158.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq349.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq350.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq351.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ159.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq352.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ160.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq353.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ161.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ162.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq354.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq355.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ163.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ23.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq356.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq357.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ24.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq358.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq359.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ164.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ165.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq360.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq361.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ166.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq362.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq363.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq364.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq365.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ167.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq366.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ25.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq367.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq368.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq369.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ26.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq370.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq371.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq372.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq373.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ27.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq374.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq375.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq376.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq377.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq378.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ28.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ29.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq379.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ168.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ30.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq380.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq381.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq382.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ31.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ32.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq383.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ33.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq384.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ34.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq385.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq386.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ169.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq387.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ35.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq388.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ36.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq389.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ170.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq390.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ171.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ172.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq391.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq392.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq393.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq394.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq395.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq396.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ37.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ38.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq397.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ173.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq398.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq399.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ174.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ39.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ40.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq400.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq401.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq402.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq403.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq404.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq405.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq406.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ175.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq407.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq408.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ41.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ176.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ42.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ177.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq409.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ178.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ43.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq410.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ179.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ44.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ45.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ180.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq411.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq412.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ181.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ182.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq413.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ183.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq414.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq415.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq416.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq417.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq418.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq419.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq420.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ46.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq421.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq422.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ184.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ185.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ186.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq423.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq424.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq425.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq426.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq427.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq428.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ187.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq429.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq430.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq431.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq432.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq433.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq434.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq435.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Equ211_HTML.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq436.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ188.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq437.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq438.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq439.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq440.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ47.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq441.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq442.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq443.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq444.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq445.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq446.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq447.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq448.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ189.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq449.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq450.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq451.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq452.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq453.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq454.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ190.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ191.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq455.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq456.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq457.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Equ212_HTML.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq458.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ192.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq459.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq460.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ193.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq461.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq462.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ194.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ48.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ195.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq463.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq464.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq465.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq466.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ49.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq467.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ196.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq468.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq469.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq470.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq471.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq472.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq473.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq474.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ197.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ50.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ198.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq475.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq476.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq477.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ199.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ200.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq478.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ201.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ202.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq479.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq480.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq481.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq482.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq483.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq484.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq485.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ51.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq486.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq487.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq488.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ203.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq489.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ204.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq490.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq491.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ205.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq492.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ206.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ207.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ52.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ208.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ53.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq493.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq494.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq495.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq496.gif\"/>", "<graphic xlink:href=\"526_2023_2627_Article_Equ209.gif\" position=\"anchor\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq497.gif\"/>", "<inline-graphic xlink:href=\"526_2023_2627_Article_IEq498.gif\"/>" ]	[]	[{"label": ["1."], "mixed-citation": ["Adimurthi, K., Prasad, H., Tewary, V.: Local H\u00f6lder regularity for nonlocal parabolic "], "tex-math": ["\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p$$\\end{document}"], "{http://www.w3.org/1998/Math/MathML}mi": ["p"], "ext-link": ["arXiv:2205.09695"]}, {"label": ["2."], "surname": ["Banerjee", "Garain", "Kinnunen"], "given-names": ["A ", "P", "J"], "article-title": ["Some local properties of subsolutons and supersolutions for a doubly nonlinear nonlocal parabolic p-Laplace equation"], "source": ["Ann. Mat. Pura Appl."], "year": ["2022"], "volume": ["201"], "issue": ["4"], "fpage": ["1717"], "lpage": ["1751"], "pub-id": ["10.1007/s10231-021-01177-4"]}, {"label": ["3."], "surname": ["Banerjee", "Garain", "Kinnunen"], "given-names": ["A", "P", "J"], "article-title": ["Lower semicontinuity and pointwise behavior of supersolutions for some doubly nonlinear nonlocal parabolic "], "tex-math": ["\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p$$\\end{document}"], "{http://www.w3.org/1998/Math/MathML}mi": ["p"], "source": ["Commun. Contemp. Math."], "year": ["2023"], "volume": ["25"], "issue": ["8"], "fpage": ["2250032"], "pub-id": ["10.1142/S0219199722500328"]}, {"label": ["4."], "surname": ["Brasco", "Lindgren", "Str\u00f6mqvist"], "given-names": ["L", "E", "M"], "article-title": ["Continuity of solutions to a nonlinear fractional diffusion equation"], "source": ["J. Evol. Equ."], "year": ["2021"], "volume": ["21"], "issue": ["4"], "fpage": ["4319"], "lpage": ["4381"], "pub-id": ["10.1007/s00028-021-00721-2"]}, {"label": ["5."], "mixed-citation": ["Caffarelli, L.A.: Non-local diffusions, drifts and games. Nonlinear partial differential equations, In: The Abel Symposium, Springer, Heidelberg "], "bold": ["7"]}, {"label": ["6."], "surname": ["Caffarelli", "Chan", "Vasseur"], "given-names": ["LA", "CH", "A"], "article-title": ["Regularity theory for parabolic nonlinear integral operators"], "source": ["J. Am. Math. Soc."], "year": ["2011"], "volume": ["24"], "issue": ["3"], "fpage": ["849"], "lpage": ["869"], "pub-id": ["10.1090/S0894-0347-2011-00698-X"]}, {"label": ["7."], "surname": ["Chen", "DiBenedetto"], "given-names": ["Y-Z", "E"], "article-title": ["H\u00f6lder estimates of solutions of singular parabolic equations with measurable coefficients"], "source": ["Arch. Ration. Mech. Anal."], "year": ["1992"], "volume": ["118"], "issue": ["3"], "fpage": ["257"], "lpage": ["271"], "pub-id": ["10.1007/BF00387898"]}, {"label": ["8."], "surname": ["Cozzi"], "given-names": ["M"], "article-title": ["Regularity results and Harnack inequalities for minimizers and solutions of nonlocal problems: a unified approach via fractional De Giorgi classes"], "source": ["J. Funct. Anal."], "year": ["2017"], "volume": ["272"], "fpage": ["4762"], "lpage": ["4837"], "pub-id": ["10.1016/j.jfa.2017.02.016"]}, {"label": ["9."], "surname": ["DiBenedetto"], "given-names": ["E"], "source": ["Degenerate Parabolic Equations"], "year": ["1993"], "publisher-loc": ["New York"], "publisher-name": ["Springer-Verlag"]}, {"label": ["10."], "surname": ["DiBenedetto"], "given-names": ["E"], "article-title": ["On the local behaviour of solutions of degenerate parabolic equations with measurable coefficients"], "source": ["Ann. Scuola Norm. Sup. Pisa Cl. Sci."], "year": ["1986"], "volume": ["13"], "issue": ["3"], "fpage": ["487"], "lpage": ["535"]}, {"label": ["11."], "surname": ["DiBenedetto", "Gianazza", "Vespri"], "given-names": ["E", "U", "V"], "source": ["Harnack\u2019s Inequality for Degenerate and Singular Parabolic Equations"], "year": ["2012"], "publisher-loc": ["New York"], "publisher-name": ["Springer-Verlag"]}, {"label": ["12."], "surname": ["Di Castro", "Kuusi", "Palatucci"], "given-names": ["A", "T", "G"], "article-title": ["Local behavior of fractional "], "tex-math": ["\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p$$\\end{document}"], "{http://www.w3.org/1998/Math/MathML}mi": ["p"], "source": ["Ann. Inst. H. Poincar\u00e9 Anal. Non Lin\u00e9aire"], "year": ["2016"], "volume": ["33"], "fpage": ["1279"], "lpage": ["1299"], "pub-id": ["10.1016/j.anihpc.2015.04.003"]}, {"label": ["13."], "surname": ["Di Castro", "Kuusi", "Palatucci"], "given-names": ["A", "T", "G"], "article-title": ["Nonlocal Harnack inequalities"], "source": ["J. Funct. Anal."], "year": ["2014"], "volume": ["267"], "fpage": ["1807"], "lpage": ["1836"], "pub-id": ["10.1016/j.jfa.2014.05.023"]}, {"label": ["14."], "surname": ["Di Nezza", "Palatucci", "Valdinoci"], "given-names": ["E", "G", "E"], "article-title": ["Hitchhiker\u2019s guide to the fractional Sobolev spaces"], "source": ["Bull. Sci. Math."], "year": ["2012"], "volume": ["136"], "issue": ["5"], "fpage": ["521"], "lpage": ["573"], "pub-id": ["10.1016/j.bulsci.2011.12.004"]}, {"label": ["15."], "surname": ["Ding", "Zhang", "Zhou"], "given-names": ["M", "C", "S"], "article-title": ["Local boundedness and H\u00f6lder continuity for the parabolic fractional "], "tex-math": ["\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p$$\\end{document}"], "{http://www.w3.org/1998/Math/MathML}mi": ["p"], "source": ["Calc. Var. Partial Differ. Equ."], "year": ["2021"], "volume": ["60"], "issue": ["1"], "fpage": ["38"], "lpage": ["45"], "pub-id": ["10.1007/s00526-020-01870-x"]}, {"label": ["16."], "surname": ["Felsinger", "Kassmann"], "given-names": ["M", "M"], "article-title": ["Local regularity for parabolic nonlocal operators"], "source": ["Comm. Partial Differ. Equ."], "year": ["2013"], "volume": ["38"], "issue": ["9"], "fpage": ["1539"], "lpage": ["1573"], "pub-id": ["10.1080/03605302.2013.808211"]}, {"label": ["17."], "surname": ["Kassmann"], "given-names": ["M"], "article-title": ["A priori estimates for integro-differential operators with measurable kernels"], "source": ["Calc. Var. Partial Differ. Equ."], "year": ["2009"], "volume": ["34"], "fpage": ["1"], "lpage": ["21"], "pub-id": ["10.1007/s00526-008-0173-6"]}, {"label": ["18."], "surname": ["Kim"], "given-names": ["Y-C"], "article-title": ["Nonlocal Harnack inequalities for nonlocal heat equations"], "source": ["J. Differ. Equ."], "year": ["2019"], "volume": ["267"], "issue": ["11"], "fpage": ["6691"], "lpage": ["6757"], "pub-id": ["10.1016/j.jde.2019.07.006"]}, {"label": ["19."], "surname": ["Kim"], "given-names": ["Y-C"], "article-title": ["Local properties for weak solutions of nonlocal heat equations"], "source": ["Nonlinear Anal."], "year": ["2020"], "volume": ["192"], "issue": ["30"], "fpage": ["111689, 30"]}, {"label": ["20."], "surname": ["Kinnunen", "Lindqvist"], "given-names": ["J", "P"], "article-title": ["Pointwise behaviour of semicontinuous supersolutions to a quasilinear parabolic equation"], "source": ["Ann. Mat. Pura Appl."], "year": ["2006"], "volume": ["185"], "issue": ["3"], "fpage": ["411"], "lpage": ["435"], "pub-id": ["10.1007/s10231-005-0160-x"]}, {"label": ["21."], "surname": ["Maz\u00f3n", "Rossi", "Toledo"], "given-names": ["JM", "JD", "J"], "article-title": ["Fractional "], "tex-math": ["\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p$$\\end{document}"], "{http://www.w3.org/1998/Math/MathML}mi": ["p"], "source": ["J. Math. Pures Appl."], "year": ["2016"], "volume": ["105"], "issue": ["6"], "fpage": ["810"], "lpage": ["844"], "pub-id": ["10.1016/j.matpur.2016.02.004"]}, {"label": ["22."], "surname": ["Silvestre"], "given-names": ["L"], "article-title": ["H\u00f6lder estimates for solutions of integro-differential equations like the fractional Laplace"], "source": ["Indiana Univ. Math. J."], "year": ["2006"], "volume": ["55"], "issue": ["3"], "fpage": ["1155"], "lpage": ["1174"], "pub-id": ["10.1512/iumj.2006.55.2706"]}, {"label": ["23."], "surname": ["Str\u00f6mqvist"], "given-names": ["M"], "article-title": ["Local boundedness of solutions to nonlocal parabolic equations modeled on the fractional "], "tex-math": ["\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p$$\\end{document}"], "{http://www.w3.org/1998/Math/MathML}mi": ["p"], "source": ["J. Differ. Equ."], "year": ["2019"], "volume": ["266"], "fpage": ["7948"], "lpage": ["7979"], "pub-id": ["10.1016/j.jde.2018.12.021"]}, {"label": ["24."], "surname": ["Str\u00f6mqvist"], "given-names": ["M"], "article-title": ["Harnack\u2019s inequality for parabolic nonlocal equations"], "source": ["Ann. Inst. H. Poincar\u00e9 Anal. Non Lin\u00e9aire"], "year": ["2019"], "volume": ["36"], "fpage": ["1709"], "lpage": ["1745"], "pub-id": ["10.1016/j.anihpc.2019.03.003"]}, {"label": ["25."], "mixed-citation": ["Urbano, J.M.: The method of intrinsic scaling. A systematic approach to regularity for degenerate and singular PDEs, Lecture Notes in Mathematics, 1930. Springer-Verlag, Berlin (2008)"]}, {"label": ["26."], "surname": ["V\u00e1zquez"], "given-names": ["JL"], "article-title": ["The Dirichlet problem for the fractional "], "tex-math": ["\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p$$\\end{document}"], "{http://www.w3.org/1998/Math/MathML}mi": ["p"], "source": ["J. Differ. Equ."], "year": ["2016"], "volume": ["260"], "issue": ["7"], "fpage": ["6038"], "lpage": ["6056"], "pub-id": ["10.1016/j.jde.2015.12.033"]}, {"label": ["27."], "surname": ["V\u00e1zquez"], "given-names": ["JL "], "article-title": ["The evolution fractional "], "tex-math": ["\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$p$$\\end{document}", "\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$$\\mathbb{R} ^{N}$$\\end{document}"], "{http://www.w3.org/1998/Math/MathML}mi": ["p", "R", "N"], "source": ["Nonlinear Anal."], "year": ["2020"], "volume": ["199"], "fpage": ["112034"], "pub-id": ["10.1016/j.na.2020.112034"]}]	{ "acronym": [], "definition": [] }	27	CC BY	no	2024-01-13 23:36:43	Calc Var Partial Differ Equ. 2024 Dec 19; 63(1):22	oa_package/1b/ce/PMC10730649.tar.gz
PMC10746543	37679459	[]	[ "<title>Methods</title>", "<title>Mammalian cell culture</title>", "<p id=\"Par38\">The human HEK293T cell lines were provided by the Genetic Perturbation Platform, Broad Institute, MDA-MB-231 cells were purchased from ATCC and HEK293T<sub>Cas9</sub> were previously published<sup>##REF##30385546##33##</sup>. HEK293T cells were cultured in Dulbecco’s modified Eagle medium (Gibco) and MDA-MB-231 in RPMI (Gibco), with 10% fetal bovine serum (Invitrogen), glutamine (Invitrogen) and penicillin–streptomycin (Invitrogen) at 37 °C and 5% CO<sub>2</sub>.</p>", "<title>Compounds</title>", "<p id=\"Par39\">The majority of compound bearing the ‘DS’ prefix were synthesized in-house (for synthetic chemistry methods, see ##SUPPL##0##Supplementary Note: Synthetic Procedures##) on the basis of published synthetic procedures for related small molecules<sup>##UREF##12##42##–##UREF##13##44##</sup>. Compounds DS22, DS47, DS74, WX3 and WX4-INT were synthesized by WuXi AppTec. Other small molecules were obtained from the following commercial vendors: Tocris, Enzo Life Sciences, MedChemExpress, Cayman Chemical Company, ProbeChem, Sigma and LabNetwork, Enamine (Supplementary Table ##SUPPL##0##3##).</p>", "<title>Reporter vectors</title>", "<p id=\"Par40\">The following reporters were used in this study: Cilantro 2 (PGK.BsmBICloneSite-10aaFlexibleLinker-eGFP.IRES.mCherry.cppt.EF1α.PuroR, Addgene #74450) for cyclin K degradation assay as previously reported<sup>##UREF##5##15##</sup>.</p>", "<title>Protein expression and purification</title>", "<p id=\"Par41\">Human wild-type and mutant versions of DDB1 (Uniprot entry <ext-link ext-link-type=\"uri\" xlink:href=\"https://www.uniprot.org/uniprot/Q16531\">Q16531</ext-link>), CDK12 (<ext-link ext-link-type=\"uri\" xlink:href=\"https://www.uniprot.org/uniprot/Q9NYV4\">Q9NYV4</ext-link>, K965R) and CCNK (<ext-link ext-link-type=\"uri\" xlink:href=\"https://www.uniprot.org/uniprot/O75909\">O75909</ext-link>) were subcloned into pAC-derived vectors<sup>##REF##19061853##45##</sup> and recombinant proteins were expressed as N-terminal His<sub>6</sub>, His<sub>6</sub>–Spy, StrepII or StrepII–Avi fusions in <italic>Trichoplusia ni</italic> High Five insect cells using the baculovirus expression system (Invitrogen)<sup>##UREF##14##46##</sup>.</p>", "<title>Expression and purification of DDB1 constructs</title>", "<p id=\"Par42\">Wild-type or mutant forms of full-length or beta-propeller B domain deletion (ΔBPB: a.a. 396–705 deleted) constructs of His<sub>6</sub>–DDB1<sub>ΔBPB</sub>, StrepII–Avi–DDB1, or His6–Spy–DDB1 were purified as previously described for DDB1–DCAF complexes<sup>##REF##25043012##47##</sup>. Briefly, for His-tagged constructs, High Five insect cells expressing the above-mentioned proteins were lysed by sonication in 50 mM Tris–HCl (pH 8.0), 500 mM NaCl, 10% (v/v) glycerol, 10 mM imidazole, 0.25 mM tris(2-carboxyethyl)phosphine (TCEP), 0.1% (v/v) Triton X-100, 1 mM phenylmethylsulfonylfluoride (PMSF), and 1× protease inhibitor cocktail (Sigma). Following ultracentrifugation, the soluble fraction was passed over HIS-Select Ni<sup>2+</sup> affinity resin (Sigma), washed first with 50 mM Tris–HCl pH 8.0, 500 mM NaCl, 10% glycerol, 0.5 mM TCEP and 10 mM imidazole, then with 50 mM Tris–HCl pH 8.0, 200 mM NaCl, 10% glycerol, 0.5 mM TCEP and 10 mM imidazole, and finally eluted in 50 mM Tris–HCl (pH 8.0), 200 mM NaCl, 10% (v/v) glycerol, 0.5 mM TCEP and 250 mM imidazole. For crystallography, affinity tags were removed by overnight Tobacco Etch Virus (TEV) protease treatment at a 1:50 (w/w) ratio. StrepII-tagged versions of DDB1 were affinity purified using Strep-Tactin Sepharose (IBA) omitting imidazole in lysis, wash and elution buffers, supplementing the elution buffer with 2.5 mM desthiobiotin (IBA), and using 50 mM Tris–HCl (pH 6.8) throughout. For ion exchange chromatography, affinity-purified proteins were diluted in a 1:1 ratio with buffer <italic>A</italic> (50 mM Tris–HCl (pH 8.0), 10 mM NaCl, 2.5% (v/v) glycerol and 0.5 mM TCEP) and passed over an 8 ml Poros 50HQ column. Bound DDB1 was eluted by a linear salt gradient mixing buffer A and buffer B (50 mM Tris–HCl (pH 8.0), 1 M NaCl, 2.5% (v/v) glycerol and 0.5 mM TCEP) over 15 column volumes to a final ratio of 60% buffer B. DDB1-containing fractions were concentrated and subjected to size exclusion chromatography in 50 mM HEPES (pH 7.4), 200 mM NaCl, 2.5% (v/v) glycerol and 0.5 mM TCEP. Peak fractions were concentrated (to a final concentration of approximately 200 µM for DDB1ΔB and 30 µM for full-length DDB1), flash frozen in liquid nitrogen and stored at −80 °C or directly used in crystallization trials.</p>", "<title>Expression and purification of CDK12-cyclin K for biophysical assays</title>", "<p id=\"Par43\">High Five insect cells were infected with CDK12 and cyclin K viruses at a 2:1 ratio to avoid excess expression of cyclin K alone. Cells co-expressing truncated versions of wild-type or mutant His<sub>6</sub>–CDK12 (a.a. 713–1,052 or 713–1,032) and His<sub>6</sub>–Avi-tagged cycK (a.a. 1–267) were lysed by sonication in 50 mM Tris–HCl (pH 6.8), 500 mM NaCl, 10% (v/v) glycerol, 10 mM MgCl<sub>2</sub>, 10 mM imidazole, 0.25 mM TCEP, 0.1% (v/v) Triton X-100, 1 mM PMSF and 1× protease inhibitor cocktail (Sigma). Following ultracentrifugation, the soluble fraction was passed over HIS-Select Ni<sup>2+</sup> affinity resin (Sigma), washed first with 50 mM Tris–HCl (pH 6.8), 1 M NaCl, 10% (v/v) glycerol, 0.5 mM TCEP and 10 mM imidazole, then with 50 mM Tris–HCl pH 6.8, 500 mM NaCl, 10 % (v/v) glycerol, 0.5 mM TCEP and 10 mM imidazole, and eluted in 50 mM Tris–HCl (pH 6.8), 200 mM NaCl, 10% (v/v) glycerol, 0.25 mM TCEP and 250 mM imidazole. For biophysical assays, the eluted fractions were directly concentrated and passed over a gel filtration column in 50 mM HEPES pH 7.4, 200 mM NaCl, 0.5 mM TCEP and 2.5% (v/v) glycerol. Peak fractions were concentrated to approximately 20 µM, flash frozen in liquid nitrogen and stored at −80 °C</p>", "<title>Expression and purification of CDK12–cyclin K for crystallography</title>", "<p id=\"Par44\">High Five insect cells were infected with CDK12 and cyclin K viruses at a 2:1 ratio as described above. Cells co-expressing truncated versions of wild-type or mutant StrepII–CDK12 (a.a. 713–1,052) and StrepII–cycK (a.a. 1–267) were lysed by sonication in 50 mM Tris–HCl (pH 6.8), 500 mM NaCl, 10% (v/v) glycerol, 10 mM MgCl<sub>2</sub>, 10 mM imidazole, 0.25 mM TCEP, 0.1% (v/v) Triton X-100, 1 mM PMSF and 1× protease inhibitor cocktail (Sigma). Following ultracentrifugation, the soluble fraction was passed over Strep-Tactin Sepharose affinity resin (IBA), washed first with 50 mM Tris-HCl (pH 6.8), 1 M NaCl, 10% (v/v) glycerol and 0.5 mM TCEP, then with 50 mM Tris–HCl pH 6.8, 500 mM NaCl, 10 % (v/v) glycerol and 0.5 mM TCEP, and eluted in 50 mM Tris–HCl (pH 6.8), 200 mM NaCl, 10% (v/v) glycerol, 0.5 mM TCEP and 2.5 mM desthiobiotin (IBA). Affinity tags were subsequently removed by overnight incubation with TEV protease at 1:50 (w/w). Before ion-exchange chromatography, the protein solution was diluted in a 1:1 ratio with buffer A (50 mM Tris–HCl pH 6.8, 10 mM NaCl, 2.5 % (v/v) glycerol and 0.5 mM TCEP) and passed over an 8 ml Poros 50HQ column to remove contaminants. The flow-through was then again diluted in a 1:1 ratio with buffer A and loaded onto an 8 ml Poros 50HS column. Bound proteins were eluted by a linear salt gradient mixing buffer A and buffer B (50 mM Tris–HCl (pH 6.8), 1 M NaCl, 2.5% (v/v) glycerol and 0.25 mM TCEP) over 15 column volumes to a final ratio of 80% buffer B. Poros 50HS peak fractions containing the CDK12–cycK complex were concentrated and subjected to size exclusion chromatography in 50 mM HEPES (pH 7.4), 200 mM NaCl, 2.5% (v/v) glycerol and 0.25 mM TCEP. The concentrated proteins (at approximatel<italic>y</italic> 200 µM) were flash frozen in liquid nitrogen and stored at −80 °C or used directly in crystallization trials.</p>", "<title>Protein labeling</title>", "<title>Labeling with fluorophore-conjugated maleimides</title>", "<p id=\"Par45\">The SpyTag/SpyCatcher system was employed as a mean of conjugation of the TR-FRET acceptor (Alexa<sub>488</sub> in a maleimide form) to the protein of interest as described before<sup>##UREF##5##15##,##REF##30385546##33##</sup>. For this, mutant (S50C) SpyCatcher protein was purified according to published procedures<sup>##REF##22366317##48##</sup> and was reduced by incubation with dithiothreitol (DTT) (8 mM) at 4 °C for 1 h. DTT was subsequently removed during a gel filtration step in 50 mM HEPES pH 7.4, 200 mM NaCl. Alexa<sub>488</sub>–C5–maleimide was dissolved in 100% dimethyl sulfoxide (DMSO), mixed with the reduced SpyCatcher at a 4:1 ratio, and incubated for 3 h in a vacuum desiccator. The reaction was subsequently quenched with DTT (8 mM), and labeled SpyCatcher was purified through size exclusion chromatography in 50 mM HEPES pH 7.4, 200 mM NaCl and 0.5 mM TCEP. SpyCatcher<sub>Alexa488</sub> was concentrated to ~50 μM, flash frozen in liquid nitrogen and stored at −80 °C. Purified Spy-tagged DDB1 was mixed with an equimolar concentration of labeled SpyCatcher, incubated for 1 h at room temperature and the labeling efficiency was monitored via sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Labeled protein was flash frozen and stored at −80 °C (~20 μM).</p>", "<title>Biotinylation</title>", "<p id=\"Par46\">Conjugation of the TR-FRET donor (Strep-Tb) to CDK12–cyclin K was achieved through enzymatic biotinylation. For the biotinylation of His<sub>6</sub>–CDK12 His<sub>6</sub>/cyclin K–Avi, the complex at 20–50 μM was incubated with final concentrations of 2.5 μM BirA enzyme, 0.2 mM <sc>d</sc>-biotin and 20 mM ATP in 50 mM HEPES (pH 7.4), 200 mM NaCl, 10 mM MgCl<sub>2</sub> and 0.5 mM TCEP. The reaction was incubated for 10–12 h at 4 °C and biotinylated complex was purified by gel filtration chromatography (in 50 mM HEPES pH 7.4, 200 mM NaCl, 0.5 mM TCEP), concentrated to ~10–20 μM, flash frozen and stored at −80 °C in small aliquots.</p>", "<title>TR-FRET assay</title>", "<p id=\"Par47\">For TR-FRET-based compound evaluation, a mixture of CDK12–cyclin K<sub>biotin</sub> (50 nM), <sub>Alexa488</sub>DDB1 (100 nM), terbium-coupled streptavidin (Invitrogen) (4 nM) in a TR-FRET assay buffer (50 mM HEPES pH 7.4, 150 mM NaCl, 0.005% Tween 20, 0.5% DMSO, 0.05% bovine serum albumin, 1 mM TCEP and 2 mM ethylenediaminetetraacetic acid) was plated in a white 384-well microplate (Greiner, 784075) at a volume of 6 µl per well. Compounds were then dispensed digitally from DMSO stocks using the D300 dispenser (Tecan) to yield a 13-point dilution series of each small molecule, with the highest final concentration of 20 µM for poor molecular glues and 2 µM for potent compounds.</p>", "<p id=\"Par48\">TR-FRET measurements were carried out using a PHERAstar FS microplate reader (BMG Labtech) equipped with a 337-520-490 filter set and 60 cycles were recorded over 1 h. A 70 μs delay was employed to reduce background fluorescence. The TR-FRET signal was obtained through calculating the ratio of 520 nm to 490 nm fluorescence, and Prism 9 (GraphPad) was used for further data analysis. The curves resulting from plotting the TR-FRET against compound concentration were fitted using equation (##FORMU##0##1##) to determine the half-maximal effective concentrations (EC<sub>50</sub>).</p>", "<p id=\"Par49\">Equation (##FORMU##0##1##) shows [Agonist] versus the response from GraphPad Prism 9, where Top and Bottom refer to the curve plateaus.</p>", "<p id=\"Par50\">Over 30 of the tested small molecules showed in vitro TR-FRET EC<sub>50</sub> values below 50 nM. As the differences between such tight binders cannot be adequately judged using the current assay setup, we repeated the TR-FRET assay for selected compounds at a lower protein concentration (10 nM of CDK12–cyclin K) and determined their dissociation constants (<italic>K</italic><sub>d</sub>) using a quadratic equation fit appropriate for cases where the expected dissociation constant value is below the protein concentration used (equation (##FORMU##1##2##)):</p>", "<p id=\"Par51\">Equation (##FORMU##1##2##) is a quadratic binding equation used for <italic>K</italic><sub>d</sub> determination,where Top and Bottom refer to the curve plateaus. Ligand concentration (<italic>L</italic>) was constrained to 50 nM.</p>", "<p id=\"Par52\">Lowering of the CDK12–cyclin K concentration from 50 nM to 10 nM resulted in a much smaller assay window but yielded <italic>K</italic><sub>d</sub> values in the subnanomolar range for the top compounds (DS17 and DS73), while showing no difference for the weak recruiter roscovitine (Extended Data Fig. ##FIG##10##6b##). This indicates that the tightest glues, which recruit DDB1 with picomolar affinities, lie below the limit of detection of the TR-FRET assay, with DS17 showing binding so tight that it cannot be adequately quantified in either setup. Nonetheless, the reported affinity measurements still allow us to establish an approximate rank order of the compounds’ in vitro activities, and we note that the EC<sub>50</sub> values are overestimated for the most potent molecular glues.</p>", "<title>DDB1–CUL4–RBX1 reconstitution and in vitro CUL4 neddylation</title>", "<p id=\"Par53\">In vitro CRL4 reconstitution and CUL4 neddylation were performed as described before<sup>##REF##26909574##49##</sup>. Briefly, His<sub>6</sub>–CUL4A/His<sub>6</sub>–RBX1 at 3.5 µM was incubated with His<sub>6</sub>–DDB1 at 3 µM in a reaction mixture containing 3.8 μM NEDD8, 50 nM NAE1/UBA3 (E1), 30 nM UBC12 (E2), 1 mM ATP, 50 mM Tris (pH 7.5), 100 mM NaCl, 2.5 mM MgCl<sub>2</sub>, 0.5 mM DTT and 5% (v/v) glycerol for 1.5 h at room temperature. Neddylated and gel filtration-purified DDB1–CUL4–RBX1 (<sub>N8</sub>DDB1–CUL4–RBX1) was concentrated to 5–15 μM, flash frozen and stored at −80 °C.</p>", "<title>Crystallization and data collection</title>", "<p id=\"Par54\">A crystallization solution of purified and TEV-cleaved DDB1ΔB (70 µM), CDK12–cyclin K (80 µM) and compound (80–120 µM) in SEC buffer (50 mM HEPES 7.4, 200 mM NaCl and 0.25 mM TCEP) was set up in two-drop 96-well plates (Swissci) for sitting-drop crystallization. A liquid handling system Phoenix (Art Robbins Instruments, Dunn Labortechnik GmbH) was used to pipette crystallization drops containing 200 nl of the protein complex solution mixed with 200 nl of reservoir solution. Fine screens and additive screens were formulated around the two conditions in which the DDB1ΔB–CDK12–cyclin K-CR8 complex originally crystallized (0.9 M ammonium citrate tribasic pH 7.0 or 1.4 M ammonium sulfate and 70 mM HEPES pH 7.0) (ref. <sup>##UREF##5##15##</sup>). The plates were incubated at 20 °C, and initial crystal formation was usually observed within 2–5 days.</p>", "<p id=\"Par55\">Crystals designated for data collection were cryoprotected by supplementing the 400 nl drop with 1 µl of reservoir solution containing ethylene glycol (25 % (v/v)) as cryoprotectant. Crystals were flash frozen in liquid nitrogen. Diffraction data collection was performed at the Swiss Light Source (Paul-Scherrer-Institute, Villigen, Switzerland) beamline PXII (X10SA) equipped with an Eiger2 16M detector (Dectris). The wavelength was set to 1 Å and the crystal was cooled to 100 K in a liquid nitrogen cryo-jet.</p>", "<title>Structure determination and model building</title>", "<p id=\"Par56\">Pipedream (GlobalPhasing) was used to execute the following steps automatically. Data processing was performed using X-ray Detector Software<sup>##REF##20124693##50##</sup>. Space group determination was done with POINTLESS<sup>##REF##21460441##51##</sup>, and datasets were merged and scaled with AIMLESS<sup>##REF##21460441##51##</sup>. Intensities were converted into structure factor amplitudes with STARANISO (Global Phasing)<sup>##UREF##15##52##</sup> by applying a weighted CC<sub>1/2</sub> of 0.3 resolution cutoff.</p>", "<p id=\"Par57\">The structures of the different DDB1ΔB–CDK12–cyclin K-compound complexes were solved by means of molecular replacement with PHASER<sup>##REF##19461840##53##</sup> using a previously solved structure of the complex induced by CR8 (Protein Data Bank (PDB) <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb6TD3/pdb\">6TD3</ext-link> (ref. <sup>##UREF##5##15##</sup>); with ligand deleted) as the search model. Reciprocal space refinement was performed using phenix.refine<sup>##REF##22505256##54##</sup>, followed by iterative real space refinement in COOT<sup>##REF##20383002##55##</sup>. Ligand restrains were generated with jligand<sup>##REF##22505263##56##</sup>. In case of ambiguities in the density in ligand-proximal regions (compounds dCeMM3, dCeMM4, HQ461, DS15, DS30, roscovitine and DS59), additional restrained refinement (Molecular Dynamics Flexible Fitting) based on available density maps was performed with ISOLDE<sup>##UREF##16##57##</sup> to inform on the preferred ligand conformation, which was followed by a phenix refinement in each case. We acknowledge that in certain cases ambiguities persist, and we therefore suggest appropriate caution when interpreting the ternary complex structures, as well as refer the readers to Supplementary Figs. ##SUPPL##0##1## and ##SUPPL##0##2## where the density maps and omit maps are shown for each structure. When no density was present for certain ligand regions (DS50 and DS06), those regions were set to zero occupancy, which is clearly indicated in figure panels and legends throughout.</p>", "<p id=\"Par58\">Omit maps were generated through three refinement macrocycles with one cycle of simulated annealing during the second macrocycle. The ligand was set to zero occupancy and atoms in 5 Å radius around the ligand were restrained to avoid refinement into the ligand density.</p>", "<p id=\"Par59\">Structure validation was carried out with Molprobity<sup>##REF##29067766##58##</sup>, and visualizations were generated with PyMol (Schrödinger). Interface analysis was performed using PISA<sup>##REF##17681537##59##</sup> and pocket dimensions were evaluated using CASTp (ref. <sup>##REF##29860391##60##</sup>).</p>", "<title>Ligand docking</title>", "<p id=\"Par60\">Ligand docking at the DDB1–CDK12 interface (structure 6TD3 (ref. <sup>##UREF##5##15##</sup>) minimized using OPLS3e force field, processed for receptor grid generation using default settings, and with the CR8 ligand removed) was performed with Glide (Schrödinger)<sup>##REF##15027865##61##</sup>. For docking of the cyclin K degrader set evaluated in the study, ligands were input as a SMILE strings, prepared using LigPrep (OPLS3e force field) and docked using XP precision<sup>##REF##17034125##62##</sup>.</p>", "<p id=\"Par61\">For the R<sub>2</sub> group screen, CR8 derivatives with a library of 26,736 R<sub>2</sub> groups possessing commercially available precursors was docked at the DDB1–CDK12 interface. Briefly, the ‘In-Stock Decorators’ library was downloaded from Chemspace and filtered for aliphatic primary amines with the ligfilter module using LigPrep. The r_group_enumeration tool was then used to exchange the R<sub>2</sub> aminobutanol moiety in the CR8 ligand for the generated primary amine fragments from the previous LigPrep step. Docking was performed with SP precision.</p>", "<p id=\"Par62\">For the docking of a kinase inhibitor library, a kinase inhibitor catalog containing commercially available compounds was downloaded from ZINC, prepared using LigPrep (OPLS3e force field), and a database was created using Phase (Schrödinger). The library was docked with HTVS precision.</p>", "<title>Lanthascreen kinase binding assay</title>", "<p id=\"Par63\">Lanthascreen experiments were performed using commercially available reagents (Thermo Fisher) and according to the manufacturer’s instructions. Briefly, a His-tagged kinase (CDK2–cyclin A, CDK9–cyclin T or CDK12–cyclin K at a final concentration of 5 nM) was mixed with a biotin anti-His antibody (PV6089; final concentration of 2 nM), Lanthascreen Europium-Streptavidin (PV5899; 2 nM) and Tracer 236 (PV5899; final concentration of 30 nM for CDK9, 100 nM for CDK2 and 200 nM for CDK12) in kinase buffer A (PV3189). A serial dilution of a test compound from a DMSO stock was prepared in kinase buffer A. The kinase solution and compound dilution series were mixed in a black 384-well microplate (Greiner, 784076) to a final volume of 12–15 µl. After excitation of europium (Eu) fluorescence at 337 nm, emissions at 665 nm (Eu) and 620 nm (Alexa647) were measured with a 100 μs delay to reduce background fluorescence and the reactions were followed over 60 min using a PHERAstar FS microplate reader (BMG Labtech). TR-FRET signal was calculated through the 665:620 nm ratio, and data were analyzed with Prism 9 (GraphPad) using equation (##FORMU##2##3##):</p>", "<p id=\"Par64\">Equation (##FORMU##2##3##) shows [Inhibitor] versus the response from GraphPad Prism 9, where Top and Bottom refer to the curve plateaus.</p>", "<title>Cyclin K reporter stability analysis</title>", "<p id=\"Par65\">HEK293T–Cas9 cells expressing the cyclin K–eGFP degradation reporter were resuspended at 1 × 10<sup>6</sup> ml<sup>−1</sup> and 50 µl of cell suspension was seeded in non-cell-culture-treated 384-well plates. Shortly after, cells were treated with drug or DMSO for 5 h. Subsequently, cells were fixed with 50 µl of 4% paraformaldehyde solution (Chem Cruz, sc-281692) and stored at 4 °C. The fluorescent signal was quantified by flow cytometry (LSRFortessa flow cytometer, BD Biosciences). Using FlowJo (flow cytometry analysis software, BD Biosciences), the geometric mean of the eGFP and mCherry fluorescent signal for round and mCherry-positive cells was calculated. The ratio of eGFP to mCherry was normalized to the average of three DMSO-treated controls.</p>", "<title>Drug sensitivity assays</title>", "<p id=\"Par66\">HEK293T–Cas9 cells were resuspended at 0.15 × 10<sup>6</sup> ml<sup>−1</sup> treated with DMSO or 100 nM MLN4924 and plated on 384-well plates. After 2 h, the indicated drugs were dispensed with a D300 digital dispenser (Tecan). After 3 days of drug exposure, cell viability was assessed using the CellTiter-Glo luminescent assay (Promega, G7572) on an CLARIOstar Plus, MARS 3.4 (BMG LabTech). Cell viabilities were calculated relative to DMSO controls. The half-maximum effective concentration (EC<sub>50</sub>) values were derived from standard four-parameter log-logistic curves fitted with the ‘dr4pl’ R package.</p>", "<title>Label-free quantitative mass spectrometry</title>", "<title>Sample preparation</title>", "<p id=\"Par67\">MDA-MB-231 cells were treated with DMSO or a cyclin K degrader compound at 1 µM for 5 h. Cells were collected by centrifugation and washed with phosphate-buffered saline before snap freezing in liquid nitrogen. Cells were lysed by addition of lysis buffer (8 M urea, 50 mM NaCl, 50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (EPPS) pH 8.5, and protease and phosphatase inhibitors) and homogenization by bead beating (BioSpec) for three repeats of 30 s at 2,400 rpm. Bradford assay was used to determine the final protein concentration in the clarified cell lysate. Then 50 µg of protein for each sample was reduced, alkylated and precipitated using methanol/chloroform as previously described<sup>##REF##30067223##63##</sup>, and the resulting washed precipitated protein was allowed to air dry. Precipitated protein was resuspended in 4 M urea, 50 mM HEPES pH 7.4, followed by dilution to 1 M urea with the addition of 200 mM EPPS, pH 8. Proteins were first digested with LysC (1:50; enzyme:protein) for 12 h at room temperature. The LysC digestion was diluted to 0.5 M urea with 200 mM EPPS pH 8 followed by digestion with trypsin (1:50; enzyme:protein) for 6 h at 37 °C. Sample digests were acidified with formic acid to a pH of 2–3 before desalting using C18 solid phase extraction plates (SOLA, Thermo Fisher Scientific). Desalted peptides were dried in a vacuum-centrifuged and reconstituted in 0.1% formic acid for liquid chromatography–mass spectrometry analysis.</p>", "<p id=\"Par68\">Data were collected using a TimsTOF Pro2 (Bruker Daltonics) coupled to a nanoElute LC pump (Bruker Daltonics) via a CaptiveSpray nano-electrospray source. Peptides were separated on a reversed-phase C<sub>18</sub> column (25 cm × 75 µm inner diameter, 1.6 µM, IonOpticks) containing an integrated captive spray emitter. Peptides were separated using a 50 min gradient of 2–30% buffer B (acetonitrile in 0.1% formic acid) with a flow rate of 250 nl min<sup>−1</sup> and column temperature maintained at 50 °C.</p>", "<p id=\"Par69\">Data-dependent acquisition (DDA) was performed in Parallel Accumulation-Serial Fragmentation (PASEF) mode to determine effective ion mobility windows for downstream diaPASEF data collection<sup>##REF##33257825##64##</sup>. The ddaPASEF parameters included: 100% duty cycle using accumulation and ramp times of 50 ms each, one Trapped Ion Mobility Spectrometry(TIMS)-MS scan and ten PASEF ramps per acquisition cycle. The TIMS-MS survey scan was acquired between 100 <italic>m</italic>/<italic>z</italic> and 1,700 <italic>m</italic>/<italic>z</italic> and 1/<italic>K</italic><sub>0</sub> of 0.7–1.3 V s cm<sup>−2</sup>. Precursors with one to five charges were selected, and those that reached an intensity threshold of 20,000 arbitrary units were actively excluded for 0.4 min. The quadrupole isolation width was set to 2 <italic>m</italic>/<italic>z</italic> for <italic>m</italic>/<italic>z</italic> < 700 and 3 <italic>m</italic>/<italic>z</italic> for <italic>m</italic>/<italic>z</italic> > 800, with the <italic>m</italic>/<italic>z</italic> between 700 <italic>m</italic>/<italic>z</italic> and 800 <italic>m/z</italic> being interpolated linearly. The TIMS elution voltages were calibrated linearly with three points (Agilent ESI-L Tuning Mix Ions; 622, 922 and 1,222 <italic>m</italic>/<italic>z</italic>) to determine the reduced ion mobility coefficients (1/<italic>K</italic><sub>0</sub>). To perform diaPASEF, the precursor distribution in the DDA <italic>m</italic>/<italic>z</italic>-ion mobility plane was used to design an acquisition scheme for data-independent acquisition (DIA) data collection that included two windows in each 50 ms diaPASEF scan. Data were acquired using 16 of these 25 Da precursor double window scans (creating 32 windows) that covered the diagonal scan line for doubly and triply charged precursors, with singly charged precursors able to be excluded by their position in the <italic>m</italic>/<italic>z</italic>-ion mobility plane. These precursor isolation windows were defined between 400 <italic>m</italic>/<italic>z</italic> and 1,200 <italic>m</italic>/<italic>z</italic> and 1/<italic>K</italic><sub>0</sub> of 0.7–1.3 V s cm<sup>−2</sup>.</p>", "<title>LC-MS data analysis</title>", "<p id=\"Par70\">The diaPASEF raw file processing and controlling peptide and protein level false discovery rates, assembling proteins from peptides, and protein quantification from peptides was performed using directDIA analysis in Spectronaut 14 (Version 15.5.211111.50606, Biognosys). DirectDIA mode includes first extracting the DIA data into a collection of MS2 spectra which are searched using Spectronaut’s Pulsar search engine. The search results are then used to generate a spectral library which is then employed for the targeted analysis of the DIA data. MS/MS spectra were searched against a Swissprot human database (January 2021). Database search criteria largely followed the default settings for directDIA including: tryptic with two missed cleavages, fixed carbomidomethylation of cysteine, and variable oxidation of methionine and acetylation of protein N-termini and precursor Q-value (FDR) cut-off of 0.01. Precursor quantification was performed using MS1 areas, cross run normalization was set to localised and imputation strategy was set to no imputation. Proteins with poor quality data were excluded from further analysis (summed abundance across channels of < 100 and mean number of precursors used for quantification < 2). Protein abundances were scaled using in-house scripts in the R framework<sup>##UREF##17##65##</sup> and statistical analysis was carried out using the limma package within the R framework<sup>##REF##25605792##66##</sup>.</p>", "<title>RNA-seq</title>", "<title>Library preparation</title>", "<p id=\"Par71\">A total of 300,000 MDA-MB-231 cells (ATCC) per technical replicate were treated with 1 μM of drug (or 10 μM in the case of less toxic compounds—DS20, DS21, DS25, 919278, DS50 and roscovitine) for 6 h. Pretreatment of relevant conditions with 0.1 μM MLN4924 (MedChemExpress) was performed for 2 h before compound treatment. RNA extraction was performed using TRIzol (Life Technologies Company) and quantified using Qubit (Thermo Fisher Scientific). RNA was then treated with DNase I, quantified using Qubit and evaluated using a High Sensitivity RNA kit on a TapeStation (Agilent). ERCC spike-in (Thermo Fisher Scientific) was then added. Total RNA prep, complementary DNA synthesis and library preparation was performed on the basis of Illumina Stranded Total RNA prep, Ligation with Ribo-Zero protocol (Illumina). RNA was rRNA depleted and bead purified using RNAClean XP beads (Beckman Coulter). RNA was then fragmented followed by cDNA synthesis and bead purification using AMPure XP beads (Beckman Coulter). cDNA was then dual indexed, amplified, bead purified, evaluated using a DNA 1000 kit (Agilent) on a TapeStation and quantified using a Qubit. Finally, libraries were pooled and sequenced on a NovaSeqS4 (Illumina), using 150 bp paired-end reads.</p>", "<title>RNA-seq analysis</title>", "<p id=\"Par72\">Sequencing reads were aligned to the human genome (<italic>H.sapiens</italic>-ENSEMBL-GRCh38.r91) and quantified by BrowserGenome<sup>##REF##26513548##67##</sup>. Differential gene expression analysis was performed in R (v4.1.1). In detail, raw counts were imported using the DESeqDataSetFromMatrix function implemented in the DESeq2 package (v.1.32.0) (ref. <sup>##REF##25516281##68##</sup>). After vst transformation and normalization using default parameters, normalized transcripts with an average expression lower than 10 across all replicates as well as a total overall expression lower than 200 across all samples were filtered out. PCA was performed using all transcripts as input and visualized using ggplot2 (v3.4.2). Differentially expressed genes were computed comparing each sample against the DMSO control separately using a significance cutoff of <italic>P</italic> = 0.05, a log<sub>2</sub> fold change threshold of 0 and independent hypothesis weighting. The log<sub>2</sub> fold change shrunken differentially expressed genes passing the filtering criteria corresponding to the figure descriptions were displayed using EnhancedVolcano (v.1.10.0). The following additional packages consitute an essential part of the code but do not infer with data processing directly: useful (v1.2.6), dplyr (v1.0.10), reshape2 (v1.4.4), ggpubr (v0.5.0), vsn (v3.66.0), pheatmap (v1.0.12), pals (v1.7), viridis (v0.6.2), stringr (v1.4.1), tidyr (v1.2.1), tidyverse (v1.3.2), ashr (v2.2), ggrepel (v0.9.2) and IHW (1.26.9).</p>", "<title>Reporting summary</title>", "<p id=\"Par73\">Further information on research design is available in the ##SUPPL##1##Nature Portfolio Reporting Summary## linked to this article.</p>" ]	[ "<title>Results</title>", "<title>CR8 tolerates modifications retaining molecular glue activity</title>", "<p id=\"Par7\">To understand how chemically dissimilar compounds can commit cyclin K for degradation, we first focused on the CR8 scaffold. The DDB1–CR8–CDK12–cyclin K complex crystal structure found the compound bound at the CDK12–DDB1 interface, with the phenylpyridine moiety of CR8 protruding towards DDB1 and bridging this interface (Fig. ##FIG##0##1a,b##)<sup>##UREF##5##15##</sup>. We set out to dissect the CR8 SAR and explore whether moieties other than phenylpyridine (substituents at position R<sub>1</sub>, hereafter referred to as ‘gluing moieties’ (C6 position in the 2,6,9-trisubstituted nomenclature; Fig. ##FIG##0##1b##)) promote CDK12–DDB1 interactions. For this, we developed an optimized time-resolved fluorescence energy transfer (TR-FRET) assay that accurately measured in vitro complex formation between CDK12–cyclin K and DDB1 in the presence of small molecules and confirmed that CR8 induces tight complex formation (EC<sub>50</sub> = 16 ± 1 nM) (Extended Data Fig. ##FIG##5##1a–c##). Biophysical characterization was complemented by crystallization of compound-induced ternary complexes when possible (Supplementary Tables ##SUPPL##2##1## and ##SUPPL##0##2## and Supplementary Figs. ##SUPPL##0##1##–##SUPPL##0##3##).</p>", "<p id=\"Par8\">First, we explored the CR8 SAR through the gradual simplification of its gluing moiety. A derivative bearing a biphenyl substituent (DS16 (<bold>2</bold>)) instead of the phenylpyridine displayed the same binding mode as CR8, with the purine core held in the CDK12 active site by two hydrogen bonds to the kinase hinge (Met816), a region connecting the N- and C-terminal lobes of the catalytic domain (Fig. ##FIG##0##1c##). The compound is enclosed by a CDK12 loop (amino acids (a.a.) 731–743, with Ile733 approaching the ligand (Extended Data Fig. ##FIG##5##1d##); omitted in most figures for clarity), and the gluing moiety engages in π–cation interactions with Arg928 of DDB1 (Fig. ##FIG##0##1c##). Interestingly, DS16 showed activity equivalent to CR8, demonstrating that the hydrogen bond acceptor (HBA) in the ring is not required for robust complex formation in vitro (Extended Data Fig. ##FIG##5##1e##). While a phenyl ring on a propyl chain (DS11 (<bold>3</bold>)) supported robust complex formation (EC<sub>50</sub> = 57 ± 3 nM), shortening the chain by two alkyl carbons yielded roscovitine (<bold>4</bold>), which gave much poorer recruitment (EC<sub>50</sub> = 703 ± 144 nM) (Fig. ##FIG##0##1c## and Extended Data Fig. ##FIG##5##1e##). Strikingly, even an octyl chain (DS06 (<bold>5</bold>)) protruding into DDB1 supported the formation of an analogous complex, albeit with a lower affinity (EC<sub>50</sub> = 1,162 ± 115 nM) (Fig. ##FIG##0##1c## and Extended Data Fig. ##FIG##5##1e##). As the ternary complex appeared surprisingly permissive to changes in the CR8 scaffold, we asked whether simply filling the kinase pocket would be sufficient to facilitate the interaction. However, a di-substituted purine core, with only a methyl in R<sub>1</sub> (DS23 (<bold>6</bold>)), did not appreciably promote the binding (Fig. ##FIG##0##1c## and Extended Data Fig. ##FIG##5##1e##), demonstrating that more extensive engagement of DDB1 residues by the compound is required for molecular glue activity.</p>", "<title>R<sub>1</sub> interactions govern DDB1 recruitment</title>", "<p id=\"Par9\">We then probed the interactions between the DDB1 Arg928 and the solvent-exposed arene moiety of the ligand and noted that compounds featuring aliphatic chains or rings as their gluing moieties did not support high-affinity complex formation (Extended Data Fig. ##FIG##5##1f–h##, <bold>7</bold>–<bold>15</bold>). Further modifications of an otherwise robust recruiter DS11, including extension, shortening or rigidification of the alkyl chain, or introduction of larger π-systems all negatively impacted activity, underscoring the importance of correct arene positioning and identifying steric constraints for bulky compounds that lack conformational plasticity (Fig. ##FIG##0##1d##, Extended Data Figs. ##FIG##5##1i## and ##FIG##6##2a,b##, <bold>16</bold>–<bold>24</bold>; see also ##SUPPL##0##Supplementary Note## for a more detailed discussion of the underlying SAR). Moreover, while exchanging the phenyl rings in the R<sub>1</sub> of CR8 for heterocycles or substituted arenes (for example, DS25 (<bold>25</bold>) and DS43 (<bold>26</bold>)) only led to small changes in affinity, the phenyl group of DS11 was strongly preferred over both electron-rich and electron-poor heterocycles (Extended Data Fig. ##FIG##6##2c–f##; <bold>27</bold>–<bold>30</bold>). Simple derivatization of DS11, such as dimethylation (DS66 (<bold>31</bold>); EC<sub>50</sub> = 18 ± 1 nM) increased in vitro activity to CR8 levels (Extended Data Fig. ##FIG##6##2g–i##, <bold>32</bold>–<bold>37</bold>). Taken together, these results identify interactions between Arg928 and diverse aromatic groups in the ligand’s gluing moiety as key mediators of DDB1–CDK12 molecular glue activity.</p>", "<p id=\"Par10\">Next, we focused on putative hydrogen bonding interactions of the gluing moiety. The pyridine nitrogen in the gluing moiety is a potential HBA (Extended Data Fig. ##FIG##7##3a,b## and ##SUPPL##0##Supplementary Note##, <bold>38</bold>–<bold>40</bold>). We found that changing from a phenylpyridine to biphenyl (CR8 to DS16) (Fig. ##FIG##0##1c## and Extended Data Fig. ##FIG##5##1e##) or methylpyridine to tolyl (DS69 (<bold>35</bold>) to DS30 (<bold>34</bold>)) (Extended Data Fig. ##FIG##6##2g,h##) had no effect on in vitro activity, demonstrating that the HBA is dispensable. Our structural evaluation further highlighted the CDK12 residue Tyr815 as a potential additional hydrogen-bonding contact in the vicinity of the compound. We hence designed WX3 (<bold>41</bold>) bearing a 2-pyridinone ring instead of the first phenyl ring of CR8 (Extended Data Fig. ##FIG##7##3c##). Despite crystallographic analysis revealing the expected binding mode, the binding affinity did not improve (EC<sub>50</sub> = 21 ± 1 nM) (Extended Data Figs. ##FIG##6##2c## and ##FIG##7##3d##). Other modifications, such as a fluorine at this position (DS24, (<bold>42</bold>)), led to decreased affinity (Extended Data Figs. ##FIG##6##2c## and ##FIG##7##3c,d## and ##SUPPL##0##Supplementary Note##).</p>", "<p id=\"Par11\">In summary, exploration of CR8 SAR around the R<sub>1</sub> position demonstrated that surprisingly diverse gluing moieties (arenes and heteroarenes of varying size, but also aliphatic groups—albeit weakly) can engage the Arg928 side chain and therefore facilitate DDB1–CDK12 interactions. We show that, while an HBA is dispensable, appropriate steric and electronic properties for effective π–cation interactions with DDB1 are required for high-affinity complex formation. The position of DDB1 Arg928 remains relatively static in all structures, probably due to its anchoring interaction with CDK12 Asp819 (Fig. ##FIG##0##1e##). We conclude that diverse substituents can be accommodated in this <italic>~</italic>370 Å<sup>3</sup> interfacial cavity in disparate ways, with each proficient molecular glue compound engaging DDB1 Arg928.</p>", "<title>Diverse R<sub>2</sub> modifications are tolerated for complex formation</title>", "<p id=\"Par12\">Next, we explored modifications of other positions on the CR8 scaffold. The R<sub>3</sub> group faces into the kinase pocket and would primarily be expected to govern kinase binding. Instead, we focused on the aminobutanol moiety at the R<sub>2</sub> position, which in the CR8-induced complex is largely solvent-exposed. The inversion at this stereocenter (S-CR8; DS28 (<bold>43</bold>); EC<sub>50</sub> = 32 ± 1 nM) or introducing a morpholino at the R<sub>2</sub> position (DS19 (<bold>44</bold>); EC<sub>50</sub> = 14 ± 0.3 nM) gave rise to compounds with comparable activity to CR8 (R-CR8 is referred to as CR8 throughout) (Extended Data Fig. ##FIG##7##3e,f##), suggesting that hydrogen-bonding interactions between R<sub>2</sub> and the CDK12 backbone do not strongly contribute to binding. Installation of a hydroxyethyl piperidine functionality, present in the potent CDK inhibitor dinaciclib<sup>##REF##20663931##22##</sup>, (DS70, (<bold>45</bold>)) also yielded a potent molecular glue (EC<sub>50</sub> = 18 ± 1 nM) (Extended Data Fig. ##FIG##7##3e,f##). On the other hand, substituting with a dichloropyridine (DS48, (<bold>46</bold>)) or pyrazole (DS52, (<bold>47</bold>)) led to a few-fold reduction in affinity (Extended Data Fig. ##FIG##7##3e,f##). In pursuit of more structurally diverse compounds, we performed R-group docking at this position using Glide (Schrödinger) and evaluated several compounds (DS59 (<bold>48</bold>) and DS50 (<bold>49</bold>)) stipulated to engage in additional interactions, yet their activity was modest (Extended Data Fig. ##FIG##7##3g–j##, <bold>50</bold>–<bold>52</bold>).</p>", "<p id=\"Par13\">Hence, while changes at the R<sub>1</sub> position are the most consequential for gain-of-function glue activity, derivatization at R<sub>2</sub> further affects complex formation, and both R<sub>1</sub> and R<sub>2</sub> can tune important properties of the compound. Substantial changes in the compound structure, size and geometry of the key interaction with DDB1 Arg928 can be accommodated with surprisingly small penalties in glue-induced binding affinity.</p>", "<title>CDK12-selective inhibitors can be cyclin K degraders</title>", "<p id=\"Par14\">Having established that gluing activity is common among CR8 derivatives, we next aimed to explore whether purine-based compounds with more diverse substituents also show gain-of-function molecular glue activity. We turned to published kinase inhibitors (Fig. ##FIG##1##2## and Extended Data Fig. ##FIG##8##4a–c##, <bold>53</bold>–<bold>59</bold>), and first focused on the CDK12-selective inhibitor SR-4835 (refs. <sup>##REF##31668947##18##,##UREF##7##23##</sup>) (<bold>60</bold>), a compound with a CR8-like 2,6,9-trisubstituted purine structure but different R<sub>1–3</sub> substituents. SR-4835 potently recruited DDB1 to CDK12–cyclin K (EC<sub>50</sub> = 16 ± 1 nM) (Fig. ##FIG##1##2a## and Extended Data Fig. ##FIG##8##4d##), consistent with a recent report that it degrades cyclin K (ref. <sup>##REF##34289372##10##</sup>). Crystallization of the ternary complex revealed that SR-4835 binds in a manner similar to CR8, yet it induces conformational changes in the N-lobe of the kinase, most notably in the a.a. 731–743 loop (Extended Data Fig. ##FIG##8##4e##) (root mean square deviation (RMSD) of 1.6 Å). The imidazole ring of the gluing moiety interacts with DDB1 Arg928 and is additionally positioned by hydrogen-bonding interactions with Tyr815 and Asp819 of CDK12 (Fig. ##FIG##1##2a##). Tyr815 is specific to CDK12/13, with a phenylalanine present at this position in other CDKs (Extended Data Fig. ##FIG##8##4f##), which explains the high inhibitory selectivity of SR-4835. We also observed additional CDK12–ligand contacts, with π–π interactions between methylpyrazole and the kinase gatekeeper residue Phe813, a putative halogen bond to DDB1 Asn907, and two C<sub>Ar</sub>-H···O interactions with the backbone carbonyl of Glu814 (Fig. ##FIG##1##2a##).</p>", "<p id=\"Par15\">To further explore the contributions of SR-4835 structural features to its activity, we evaluated various derivatives (Extended Data Fig. ##FIG##8##4g–k##). At R<sub>1</sub>, an unsubstituted benzimidazole gluing moiety (DS55, (<bold>61</bold>)) showed a similar binding mode and only slightly impaired recruitment (EC<sub>50</sub> = 36 ± 2 nM), while exchanging the benzimidazole for an indole (DS56, (<bold>62</bold>)) largely abolished activity (EC<sub>50</sub> = 2114 ± 252 nM), highlighting the importance of the two hydrogen-bonding interactions provided by the imidazole moiety of SR-4835 (Extended Data Fig. ##FIG##8##4g,h##, <bold>63</bold> and <bold>64</bold>). We also synthesized six compounds that are hybrids of SR-4835 and CR8 (DS18 (<bold>65</bold>), DS17 (<bold>66</bold>), DS19, DS22 (<bold>67</bold>), DS21 (<bold>68</bold>) and DS20 (<bold>69</bold>)), yielding a series bearing all possible combination of the R<sub>1-3</sub> substituents (Fig. ##FIG##1##2b##). While DS17–19, DS22, CR8 and SR-4835 promoted very robust in vitro complex formation and yielded crystallizable complexes, compounds DS21 and DS20, carrying the phenylpyridine gluing moiety of CR8 and the SR-4835-derived methylpyrazole in R<sub>3</sub>, were poorer glues (Fig. ##FIG##1##2b## and Extended Data Fig. ##FIG##8##4i##). We conclude that these two bulky substituents cannot be accommodated together, while all other combinations permit effective complex formation, with DS17–19 being among the most potent in vitro recruiters in our series and superior to CR8 (Fig. ##FIG##1##2b## and Extended Data Fig. ##FIG##8##4i##).</p>", "<p id=\"Par16\">Changing the position of one nitrogen atom in the purine ring system was previously reported to increase potency of CR8 (refs. <sup>##REF##28128514##20##,##REF##30023695##24##–##REF##18790752##26##</sup>). We therefore evaluated the effect of such scaffold hopping in the case of SR-4835, while keeping the R<sub>1-3</sub> substituents unchanged (DS74, (<bold>70</bold>)). The resulting compound, however, performed comparably to SR-4835 in TR-FRET (EC<sub>50</sub> = 20 ± 1 nM) (Extended Data Fig. ##FIG##8##4j,k##). Multiple structurally related compounds were disclosed in a recent patent<sup>##UREF##8##27##</sup>, and we selected three of these (DS72 (P25, <bold>71</bold>), DS73 (P342, <bold>72</bold>) and DS71 (P133, <bold>73</bold>)) on the basis of their reported potency and similarity to other small molecules in our series (Extended Data Fig. ##FIG##8##4j##). TR-FRET measurements revealed these molecules facilitate complex formation in vitro with affinities comparable to CR8 and SR-4835 (12 nM < EC<sub>50</sub> < 28 nM), with DS72 performing the best (Extended Data Fig. ##FIG##8##4k##). As compounds DS71 and DS72 feature a difluorobenzimidazole gluing moiety previously reported to enhance CDK12 binding<sup>##UREF##9##28##</sup>, we evaluated substituting the CR8 phenylpyridine for this moiety (DS64, <bold>74</bold>), but found it decreased activity (EC<sub>50</sub> = 41 ± 2 nM) (Extended Data Fig. ##FIG##8##4j,k##). Thus, purine scaffold hopping does not independently enhance gluing activity but can yield highly potent glues (DS71–73) in combination with appropriate R<sub>1</sub>–R<sub>3</sub> substituents.</p>", "<title>Hydrophilic moieties can engage DDB1 to degrade cyclin K</title>", "<p id=\"Par17\">To identify more diverse DDB1–CDK12 molecular glues, we performed virtual screening of the ZINC kinase inhibitor library against the DDB1–CDK12 interface<sup>##REF##26479676##29##</sup>. We reasoned that kinase binders constitute a promising pool of putative cyclin K degraders, potentially with diverse exit vectors for DDB1 engagement. One prominent hit was the CRK inhibitor 21195 (RGB-286147, (<bold>75</bold>)) (ref. <sup>##REF##16242653##30##</sup>) (Fig. ##FIG##1##2c##). Crystallographic analysis showed that, despite a seemingly different chemical structure, 21195 displays a similar binding mode to CR8 and potently promotes ternary complex formation (EC<sub>50</sub> = 12 ± 0.4 nM) (Fig. ##FIG##1##2c## and Extended Data Fig. ##FIG##9##5a##). The pyrazolopyrimidone core is rotated by 90° with respect to the CR8 purine to allow favorable hinge interactions, while the three substituents occupy equivalent positions to R<sub>1-3</sub> of CR8 (Fig. ##FIG##1##2c##). Remarkably, the gluing moiety of 21195, while still bearing a benzene ring capable of the key π–cation interaction with Arg928, has an otherwise hydrophilic character, with a hydroxy group pointing directly towards DDB1 and hydrogen bonding with Asn907 (Fig. ##FIG##1##2c##).</p>", "<p id=\"Par18\">To test more broadly whether hydrophilic moieties can recruit DDB1 we derivatized several degraders with hydroxy substituents or PEG groups, which led to effects ranging from a few-fold decrease to complete loss of activity across multiple R<sub>1</sub> scaffolds (Extended Data Fig. ##FIG##9##5b–f##, <bold>76</bold>–<bold>78</bold>). We also synthesized additional hybrid compounds by transplanting the hydrophilic gluing moiety of 21195 onto CR8 (DS61 (<bold>79</bold>)) or SR-4835 (DS62 (<bold>80</bold>)) scaffolds (Extended Data Fig. ##FIG##9##5g–i##) and saw that, while DS62 was incompatible with the DDB1–CDK12 interface, DS61 displayed molecular glue activity (EC<sub>50</sub> = 169 ± 7 nM) and its binding pose preserved the Asn907 interaction, albeit with a less optimal geometry (Extended Data Fig. ##FIG##9##5g–i##). These results demonstrate that kinase-engaging scaffolds with distinct exit vectors can act as efficient molecular glues, and that hydrophilicity of the gluing moiety does not preclude robust DDB1–CDK12 interactions despite expected desolvation penalties.</p>", "<title>Specific fingerprint defines minimal cyclin K degraders</title>", "<p id=\"Par19\">Having observed that CDK12 binders beyond CR8 derivatives can facilitate an analogous CDK12–DDB1 complex, we investigated more structurally dissimilar CDK12 inhibitors focusing on compound 919278 (<bold>81</bold>) (Fig. ##FIG##1##2d##). This inhibitor shows weak CDK12 binding affinity (5.6 µM) but pronounced downstream transcriptional effects<sup>##UREF##10##31##</sup>, which prompted us to hypothesize it may have gain-of-function activity. Strikingly, we found that despite its low molecular weight and lack of chemical similarity to CR8, SR-4835 or 21195, compound 919278 potently recruits DDB1 to CDK12–cyclin K in vitro (EC<sub>50</sub> = 38 ± 1 nM) (Fig. ##FIG##1##2d## and Extended Data Fig. ##FIG##9##5j##). Structural characterization demonstrated that notwithstanding its smaller size, the compound satisfies the key hinge contacts, shows a C<sub>Ar</sub>-H···O interaction with Glu814 akin to that of CR8, and interacts with CDK12 Tyr815 through hydrogen bonding (Fig. ##FIG##1##2d##). Crucially, its isoindolinone gluing moiety protrudes out into the interface engaging DDB1 Arg928 via π–cation interactions as seen for previous scaffolds (Fig. ##FIG##1##2d##). Hence, the diversity observed among DDB1–CDK12 glues extends beyond typical purine-based kinase inhibitor scaffolds.</p>", "<p id=\"Par20\">Interestingly, multiple other, small cyclin K degraders have recently been published<sup>##UREF##3##8##,##REF##34289372##10##,##REF##32804079##11##</sup>. Structural evaluation of HQ461 (<bold>82</bold>), Z11 (<bold>83</bold>), Z7 (<bold>84</bold>), dCeMM3 (<bold>85</bold>) and Z12 (<bold>86</bold>) (Fig. ##FIG##2##3## and Extended Data Fig. ##FIG##9##5j##) revealed that all promote the formation of an analogous ternary complex, and sustain the hinge hydrogen bonds and the π–cation interaction with DDB1 Arg928 (suboptimal for Z11 and dCeMM3; for HQ461 and Z11 we observe hydrogen bonding with the side chain instead), while also displaying interactions with additional residues (Fig. ##FIG##2##3a##). Those include CDK12 Tyr815 (hydrogen bonds for Z7 and Z11), Glu814 (C<sub>Ar</sub>-H···O interaction for Z7, Z11 and dCeMM3), Phe813 (halogen bonds for Z7 and dCeMM3) and Ile733 (hydrogen bond for HQ461) (Fig. ##FIG##2##3a##).</p>", "<p id=\"Par21\">DDB1–CDK12 complex formation and cyclin K degradation can thus be achieved with small, almost fragment-like compounds. Furthermore, our glue-bound DDB1–CDK12 structures, together with assessment of other reported glues (NCT02 (<bold>87</bold>), dCeMM2 (<bold>88</bold>) and dCeMM4 (<bold>89</bold>)), identify a minimal fingerprint for a cyclin K degrader leveraging a hinge-interacting acceptor–donor motif common to kinase inhibitors, and a gluing moiety bearing an aromatic system extending from the hydrogen bond donor (Fig. ##FIG##2##3b,c##). The structurally related inhibitor SNS032 (<bold>90</bold>) serves as a negative example, where a non-aromatic piperidine is expected to point towards DDB1 in the described CDK binding mode<sup>##REF##32502343##32##</sup>, consistent with SNS032 displaying no gain-of-function activity (Fig. ##FIG##2##3d##).</p>", "<title>Rearrangement triggered by dCeMM4 illustrates plasticity</title>", "<p id=\"Par22\">While all other compounds yielded highly similar ternary complexes (maximum RMSD 1.7 Å), the dCeMM4-induced complex was distinctive (RMSD 3.1 Å). The compound is positioned at the DDB1–CDK12 interface, with π–cation interaction of the furan ring with DDB1 Arg928, hydrogen bonding of the carbonyl with CDK12 Tyr815 and C<sub>Ar</sub>-H···O interaction with Glu814 (Fig. ##FIG##2##3e##). However, further inspection of the compound interface revealed that Arg882 of CDK12 is brought into the vicinity of the pocket and stabilized in position by interactions with Asp877. Such a conformational change is not feasible with other compounds due to steric hindrance, for example, with the aminobutanol moiety of CR8 (Fig. ##FIG##2##3e##). Remarkably, this local change leads to a rearrangement of the kinase activation loop (a.a. 876–898) yielding a closed-loop CDK12 conformation, apparent in one of the three molecules in the asymmetric unit (chain H, but not B, E) (Fig. ##FIG##2##3f##). While evidently not strictly required for compound binding, the observed conformation illustrates the inherent plasticity along the extensive DDB1–CDK12 interface.</p>", "<title>Relationships between in vitro and cellular activity</title>", "<p id=\"Par23\">A fundamental question in the molecular glue degrader field has been the relationship between ternary complex formation and cellular degradation. On the basis of previous examples, a step function-like relationship was postulated, whereby a few-fold difference in in vitro affinity toggles target degradation in cells<sup>##UREF##5##15##,##REF##30385546##33##</sup>. To investigate this further, we evaluated our set of cyclin K degraders using a dual-color cyclin K–enhanced green fluorescent protein (eGFP) stability reporter in HEK293T cells as previously described<sup>##UREF##5##15##</sup> (Fig. ##FIG##3##4a##, Supplementary Table ##SUPPL##0##2## and Supplementary Fig. ##SUPPL##0##4##). We were able to distinguish potent degraders (for example, CR8 and 21195) from weaker (for example, 919278) or non-degrading (for example, dinaciclib) compounds (Fig. ##FIG##3##4b##). The ten best-performing degraders were DS73, DS71, DS72, DS17, DS18, SR-4835, WX3, CR8, 21195 and DS28, a list that overlaps remarkably well (8/10) with our in vitro data. We then examined the correlation of cyclin K reporter degradation (DC<sub>50</sub>) and in vitro ternary affinity (EC<sub>50(TR-FRET)</sub>) across the entire compound set, including only compounds with unambiguous cellular degradation activity (<italic>n</italic> = 42) (Fig. ##FIG##3##4c##). A linear correlation between logDC<sub>50</sub> and logEC<sub>50 (TR-FRET)</sub> (<italic>R</italic><sup>2</sup> = 0.6) (Fig. ##FIG##3##4c##) was observed, whereas non-log data could be described with a Hill-type equation (<italic>R</italic><sup>2</sup> = 0.7) (Extended Data Fig. ##FIG##10##6a–c##).</p>", "<p id=\"Par24\">The overall EC<sub>50(TR-FRET)</sub>–DC<sub>50</sub> correlation (Fig. ##FIG##3##4c## and Extended Data Fig. ##FIG##10##6a,b##) finds in vitro complex formation largely predictive of in-cell degradation. The sigmoidal relationship further illustrates the physical relationship by which small differences in in vitro affinity translate to larger discrepancies in cellular degradation<sup>##REF##30385546##33##</sup>. While TR-FRET allows us to establish a rank order of in vitro activities, affinities tighter than 50 nM are below the dynamic range of our assay, probably leading to EC<sub>50</sub> overestimation for the best compounds. Performing the assay at lower protein concentrations for selected compounds revealed subnanomolar dissociation constants for the top derivatives (for example, DS17) but presented experimental challenges with a limited assay window (Extended Data Fig. ##FIG##10##6b## and <xref rid=\"Sec15\" ref-type=\"sec\">Methods</xref>). While the correlation between binding and degradation is apparent, effective quantification of these subnanomolar affinities is expected to further improve the description of this relationship (Extended Data Fig. ##FIG##10##6b,c##).</p>", "<title>Cyclin K degrader diversity</title>", "<p id=\"Par25\">To gauge the extent of chemical diversity among our compound set, we explored the distribution of various physicochemical properties and we found that cyclin K degraders that display in vitro activity span molecular weights from 317 Da to 722 Da and clog<italic>P</italic> values between 0.4 and 5.1 (Extended Data Fig. ##FIG##10##6d##). While the compounds are highly diverse, most are conventionally drug-like, as expected for kinase inhibitor-derived or almost fragment-like compounds (Fig. ##FIG##2##3g##). We then computed the Tanimoto coefficients describing the similarity to CR8 for each compound. Notably, the compound’s Tanimoto similarity to CR8 and its in vitro activity show no clear correlation, with the ten best DDB1–CDK12 molecular glues (DS18, 21195, DS72, DS17, DS19, DS25, DS73, SR-4835, CR8 and DS16) ranging from CR8-like (1.0) to distinct (0.33) (Fig. ##FIG##2##3h##), further supporting that diverse chemistries facilitate the formation of this complex.</p>", "<p id=\"Par26\">We next investigated the differences in cellular activity among these diverse compounds by probing the ubiquitin ligase-dependent cytotoxicity of the degraders. For this, we measured the viability of HEK293T cells after 72 h of compound exposure with and without pretreatment with the neddylation inhibitor MLN4924 (Fig. ##FIG##3##4d##, Supplementary Table ##SUPPL##0##2## and Supplementary Fig. ##SUPPL##0##5##). While for some compounds cyclin K degradation appears to be the dominant contribution to cytotoxicity (for example, 919278), others (such as 21195) show less pronounced rescue and hence work partly by conventional kinase inhibition or other, potentially off-target mechanisms (Fig. ##FIG##3##4d##). We combined the results from multiple assays, logDC<sub>50</sub>, logEC<sub>50(TR-FRET)</sub>, logEC<sub>50(cell viability)</sub> and a descriptor of cytotoxicity rescue upon MLN4924 co-treatment (%<sub>MLNrescue</sub>), as inputs for principal component analysis (PCA). Distinct clusters of cyclin K molecular glue degraders emerged, with the top degraders found in multiple subgroups (Extended Data Fig. ##FIG##10##6e##), illustrating that our experimental set features compounds with considerable diversity in physicochemical properties (Fig. ##FIG##2##3g## and Extended Data Fig. ##FIG##10##6d##) but also a range of cellular activities.</p>", "<p id=\"Par27\">To better dissect the cellular responses, we examined the extent and depth of cellular CDK12, CDK13 and cyclin K degradation by mass spectrometry using quantitative label-free proteomics on MDA-MB-231 cells treated with representative compounds (Fig. ##FIG##4##5a,b## and Extended Data Fig. ##FIG##11##7a##). These experiments identified three of the six compounds tested (DS17, 21195 and SR-4835) to be more effective at depleting cyclin K than CR8 at 1 µM concentration (Fig. ##FIG##4##5a,b##). All compounds tested selectively degrade cyclin K and the extent of depletion correlates well with the cyclin K stability reporter and TR-FRET complex formation data (Extended Data Fig. ##FIG##11##7b##; <italic>R</italic><sup>2</sup> = 0.84). Interestingly, while CDK12 showed only a mild decrease of abundance with all compounds, CDK13 depletion was more pronounced and appeared to scale with that of cyclin K (Fig. ##FIG##4##5b##).</p>", "<title>Decoupling kinase inhibitory selectivity from glue activity</title>", "<p id=\"Par28\">As CR8 has dual CDK inhibitor/cyclin K degrader activity, we examined the CDK inhibitory activity of our compound set using Lanthascreen (Extended Data Fig. ##FIG##12##8a–f##), which monitors fluorescent tracer displacement from the active site of a Europium-labeled kinase (Extended Data Fig. ##FIG##12##8a##). The assays were performed with CDK12, as well as with CDK9 and CDK2, representative transcriptional and cell-cycle CDKs similar in sequence to the kinase domain of CDK12 (Extended Data Fig. ##FIG##12##8b##).</p>", "<p id=\"Par29\">SR-4835 is CDK12/13 selective while CR8 has been reported to inhibit CDK1/2/5/7/9/12 (ref. <sup>##REF##24317512##34##</sup>). To investigate how specificity is tuned by compound modifications, we first evaluated the CDK inhibitory activity of the CR8/SR-4835 hybrid compounds (DS17–22) (Fig. ##FIG##1##2b## and Extended Data Fig. ##FIG##12##8c##). SR-4835, DS17 and DS18 were CDK12 selective, while CR8 and DS19 were not, linking potent pleiotropic CDK inhibition to the co-existence of phenylpyridine and isopropyl substituents on the purine scaffold (Extended Data Fig. ##FIG##12##8c##). Hence, the modification of the gluing moiety from phenylpyridine to dichlorobenzimidazole (CR8 versus DS17, DS19 versus DS18) is sufficient to increase the gluing potency and reduce off-target CDK inhibitory effects of CR8 (Extended Data Fig. ##FIG##12##8c##).</p>", "<p id=\"Par30\">Small cyclin K degraders such as Z11 or HQ461 show less optimal engagement of the ATP pocket than CR8 derivatives (Fig. ##FIG##2##3a##). Accordingly, while CR8 displayed CDK IC<sub>50</sub> values of 40–200 nM, the smaller compounds show weaker CDK association (Extended Data Fig. ##FIG##12##8f##). None of those compounds appreciably bound CDK2, and while compound 919278 showed some inhibition of CDK9/12 (IC<sub>50(CDK9)</sub> 120 nM, IC<sub>50(CDK12)</sub> 1,335 nM), dCeMM2-4 and Z11-12 displayed only micromolar IC<sub>50</sub> values and HQ461 displayed no inhibition up to 10 µM (Extended Data Fig. ##FIG##12##8f## and Supplementary Fig. ##SUPPL##0##6##). Hence, cyclin K degraders do not require pronounced traditional kinase inhibitory properties for molecular glue activity, and kinase inhibitory selectivity can be partly decoupled and tuned separately from ternary complex affinity optimization.</p>", "<title>Cyclin K degraders show distinct transcriptional signatures</title>", "<p id=\"Par31\">Finally, we asked whether cyclin K degraders effect a different transcriptional response than CDK12 degraders or CDK12 inhibitors. For this, we performed RNA sequencing (RNA-seq) in MDA-MB-231 cells, choosing triple-negative breast cancer cells as the relevant therapeutic context for CDK12/13–cyclin K inactivation<sup>##UREF##6##16##,##REF##31668947##18##</sup>. While a CDK12 inhibitor (dinaciclib) and CDK12 degrader (PROTAC BSJ-4-116 (<bold>91</bold>) that does not degrade cyclin K (ref. <sup>##REF##33753926##35##</sup>; Extended Data Fig. ##FIG##13##9a##) clustered together following PCA analysis of RNA-seq data, both the potent (CR8) and the weak degrader (HQ461) clearly clustered separately (Fig. ##FIG##4##5c## and Extended Data Fig. ##FIG##13##9b##). Cyclin K degradation therefore results in a different transcriptional signature than degradation or inhibition of CDK12. Supporting this notion, messenger RNA sequencing of cells treated with a larger set of compounds followed by PCA revealed specific clusters relating to their mechanism of action, with the relative extent of cyclin K degradation (and the associated CDK12/13 depletion) versus sole CDK inhibition further differentiating the observed PCA clusters (Fig. ##FIG##4##5d##). Moreover, the analysis of related compounds (for example, CR8 versus DS17–19 and SR-4835) illustrates how subtle chemical modifications impacting both inhibitory selectivity and degrader potency further tune these signatures (Fig. ##FIG##4##5d##). We observed that co-treatment of cells with MLN4924 rescued the cyclin K degradation-related perturbation, resulting in a shift to a dimethyl sulfoxide (DMSO)-like transcriptional state for compounds with limited CDK12 inhibition (919278) or elsewhere for potent CDK12/13 inhibitors (SR-4835) (Fig. ##FIG##4##5d## and Extended Data Fig. ##FIG##13##9c##). Therefore, cyclin K degrader compounds range from multi-CDK inhibitors/cyclin K degraders (for example, CR8), to CDK12/13-selective inhibitors and cyclin K degraders (for example, SR-4835 and DS17), and degraders with little-to-no CDK inhibition (for example, HQ461), all of which differ in their cellular activity profiles, thereby offering distinct therapeutic opportunities.</p>" ]	[ "<title>Discussion</title>", "<p id=\"Par32\">In this study, we extensively surveyed the structure–activity relationship of cyclin K degraders and, in the process, identified multiple novel scaffolds that degrade cyclin K, including published kinase inhibitors. Over 90 chemically diverse compounds were evaluated, among which 40 were found to trigger CDK12–DDB1 complex formation with an affinity of <100 nM in vitro. Crystallographic dissection of 28 ternary complexes demonstrated that despite considerable diversity of the molecular glues (Fig. ##FIG##2##3h## and Extended Data Fig. ##FIG##10##6d##), the overall complex architecture is highly similar.</p>", "<p id=\"Par33\">All the identified glues contact DDB1 Arg928, a residue we previously showed to be essential for complex formation<sup>##UREF##5##15##</sup>. Arginine residues are principally able to engage in polyvalent, low-selectivity ligand interactions and arene–arginine contacts have been shown to involve a mix of electrostatic and dispersion attractions<sup>##REF##32255135##36##–##REF##29719674##39##</sup>. Accordingly, we find that gluing moieties contact DDB1 preferentially through π–cation interactions (for example, DS08, Fig. ##FIG##0##1d##), which can support drug interactions over large distances (~6 Å) and variable geometries<sup>##REF##29719674##39##</sup>. Some compounds instead contact Arg928 via hydrogen bonding (for example, HQ461 and Z11; Fig. ##FIG##2##3a##) and hydrophobic interactions (for example, DS06; Fig. ##FIG##0##1c##). The low-affinity DDB1–CDK12 interaction primes the complex, while the ligand, through filling the kinase pocket and bridging over to DDB1, drives robust association, offering a rationale for the unusually broad chemical diversity observed.</p>", "<p id=\"Par34\">Other kinases beyond CDK12/13–cyclin K were not targeted in our studies (Fig. ##FIG##4##5a## and Extended Data Fig. ##FIG##11##7a##) and, notably, CDK13 degradation was more pronounced than that of CDK12 and appeared to scale with the loss of cyclin K (Fig. ##FIG##4##5b##). The specificity for the CDK12/13–DDB1 pairing therefore appears to be primed predominantly by the protein–protein interface (~2,100 Å<sup>2</sup>), featuring a CDK12/13-unique C-terminal tail<sup>##UREF##5##15##</sup>. This complementarity is underscored by a ~50 µM DDB1–CDK12–cyclin K binding affinity in the absence of compound<sup>##UREF##5##15##</sup>, yet no functional relevance of this interaction for endogenous kinase signaling is known<sup>##UREF##3##8##,##REF##34289372##10##,##REF##32804079##11##,##UREF##5##15##</sup>.</p>", "<p id=\"Par35\">Nonetheless, additional compound-mediated interactions are required not for specificity but for sufficient stabilization of the ternary complex for cyclin K ubiquitination and degradation. Notably, the diversity of cyclin K degraders stems not only from the many distinct ways by which the CDK12–DDB1 interface can be bridged by gluing moieties, but also from the many possibilities of how the feature-rich ATP pocket of CDK12 can be engaged by small molecules. This in turn gives rise to chemically diverse compounds with a varying relative extent of inhibitory and gain-of-function characteristics, where the inhibitory versus degradative properties can be directly tuned and largely decoupled. This is most evident for smaller compounds (for example, HQ461), which provide starting points for developing de facto interface stabilizers with no inhibitory activity (Fig. ##FIG##2##3a##). The data presented herein reveal design principles for small molecules that robustly inactivate CDK12/13–cyclin K and have properties that differ from traditional kinase inhibitor scaffolds. We also present additional advantageous starting scaffolds for medicinal chemistry optimization of clinically relevant cyclin K degraders, including those with more potent cyclin K degradation and better kinase inhibitory selectivity profiles than CR8 (for example, DS17). As cyclin K degraders phenotypically differ from CDK12 degraders or inhibitors (Fig. ##FIG##4##5c##), the compounds discussed herein offer unique therapeutic opportunities for the therapeutic pursuit of CDK12/13–cyclin K as emerging targets in oncology<sup>##REF##32958547##17##,##REF##31668947##18##</sup>.</p>", "<p id=\"Par36\">Our results yield principal learnings that can be applied to other molecular glue classes. We illustrate that small differences in ternary complex affinity translate to larger disparities in cellular degradation, which builds on an earlier concept of an affinity threshold (Fig. ##FIG##3##4c## and Extended Data Fig. ##FIG##10##6a–c##)<sup>##UREF##5##15##,##REF##30385546##33##</sup>. The correlation between cellular degradation and in vitro complex formation observed among a large compound set suggests that biochemical ternary affinity is predictive of in-cell degradation. Our data also demonstrate that cellular degrader screening for cell viability ± MLN4924 (Fig. ##FIG##3##4d##) is feasible and informative for degraders and is akin to compound screening in wild-type versus hyponeddylated cellular models<sup>##UREF##3##8##,##UREF##5##15##</sup>.</p>", "<p id=\"Par37\">More broadly, our results show that low-affinity interactions can be effectively strengthened by chemical matter. The more extensive and complementary the interface and the larger the interfacial cavity, the more solutions will exist to achieve gain-of-function glue activity with small molecules. Hence, low-affinity interfaces that encompass a defined ligand-binding pocket offer preferential starting points for molecular glue development. Furthermore, we propose that the absolute size of the protein–protein interface, as well as the compound’s relative contribution to the interface drives both the SAR and substrate specificity behavior. For thalidomide analogues and CRBN, the compound contributes <italic>~</italic>40% of the small interface area and therefore drives both specificity and affinity with tightly defined SAR<sup>##REF##33930325##14##,##REF##32865967##40##,##UREF##11##41##</sup>. In contrast, for DDB1–CDK12, the extensive protein–protein interface with <italic>~</italic>20% contributed by the compound allows for much greater variability in protein–ligand interactions, yielding a tolerant SAR but limiting the compound’s influence on neosubstrate specificity<sup>##REF##33930325##14##</sup>.</p>" ]	[]	[ "<p id=\"Par1\">Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin K to the DDB1–CUL4–RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure–activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.</p>", "<p id=\"Par2\">\n\n</p>", "<p id=\"Par3\">Detailed analysis of the structure–activity relationship for cyclin K degraders reveals diverse compounds that acquire glue activity through simultaneous binding to the CDK12 kinase pocket and engagement of several key DDB1 interfacial residues.</p>", "<title>Subject terms</title>" ]	[ "<title>Main</title>", "<p id=\"Par4\">The modulation of protein–protein interactions has become an important avenue of therapeutic intervention<sup>##REF##25173701##1##,##REF##27050677##2##</sup>. Recent advances in targeted protein degradation illustrate that compound-induced proximity between a ubiquitin ligase and a target protein can lead to target ubiquitination and degradation<sup>##REF##35042991##3##–##REF##33737725##5##</sup>. Of particular interest are molecular glue degraders, which are drug-like compounds that leverage complementary protein–protein interfaces to induce cooperative ligase–target interactions leading to target depletion<sup>##UREF##1##6##</sup>. Despite the clinical success of thalidomide derivatives and several recent, largely serendipitous discoveries of other molecular glue degraders<sup>##UREF##2##7##–##REF##35723413##13##</sup>, the rules that govern their discovery, design and rational optimization remain poorly defined<sup>##REF##33930325##14##</sup>.</p>", "<p id=\"Par5\">We recently reported that CR8 (<bold>1</bold>), a preclinical cyclin-dependent kinase (CDK) inhibitor, is a molecular glue degrader that binds CDK12–cyclin K and recruits the DDB1–CUL4–RBX1 E3 ligase core to ubiquitinate cyclin K (ref. <sup>##UREF##5##15##</sup>). Structural studies revealed that CR8 binds the ATP pocket of CDK12, leaving a phenylpyridine moiety exposed on the kinase surface to induce complex formation with the ligase adaptor DDB1. This places the CDK12-associated cyclin K in a position normally adopted by CRL4 substrates. CR8 therefore hijacks DDB1 in a manner that bypasses the requirement of a canonical substrate receptor (DCAF) typical for CUL4-based E3 ligases. The extensive (~2,100 Å<sup>2</sup>) DDB1–CDK12 interface is highly complementary and reveals a helical motif in the CDK12 C-terminal extension that engages DDB1 in a DCAF-like manner. While a basal affinity of ~50 µM was measured between DDB1 and CDK12–cyclin K in the absence of a compound, CR8 enhanced this affinity into the low nanomolar range, triggering polyubiquitination and degradation of cyclin K (ref. <sup>##UREF##5##15##</sup>). CR8 therefore shows dual activity, promiscuous CDK inhibition and selective cyclin K degradation, which leads to robust inactivation of CDK12, an emerging therapeutic target in oncology and beyond<sup>##UREF##6##16##–##REF##32350131##19##</sup>. Recently, chemically distinct compounds have been found to degrade cyclin K (refs. <sup>##UREF##3##8##,##REF##34289372##10##,##REF##32804079##11##,##REF##28128514##20##,##REF##36145262##21##</sup>), but as several lack any obvious chemical similarity to CR8 (refs. <sup>##UREF##3##8##,##REF##34289372##10##,##REF##32804079##11##</sup>), their precise mode of action remained unknown.</p>", "<p id=\"Par6\">In this Article, we perform a systematic dissection of the cyclin K degrader structure–activity relationship (SAR), investigate the in vitro and cellular activity of the compounds and present crystal structures of 28 glue-induced ternary complexes. Our findings inform on how target-binding compounds can acquire gain-of-function properties, yielding generalizable learnings for molecular glue degrader design.</p>", "<title>Online content</title>", "<p id=\"Par74\">Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41589-023-01409-z.</p>", "<title>Supplementary information</title>", "<p>\n\n\n\n\n\n\n</p>", "<title>Source data</title>", "<p>\n\n\n\n\n\n\n\n\n\n\n\n\n</p>" ]	[ "<title>Extended data</title>", "<p id=\"Par79\">\n\n</p>", "<p id=\"Par80\">\n\n</p>", "<p id=\"Par81\">\n\n</p>", "<p id=\"Par82\">\n\n</p>", "<p id=\"Par83\">\n\n</p>", "<p id=\"Par84\">\n\n</p>", "<p id=\"Par85\">\n\n</p>", "<p id=\"Par86\">\n\n</p>", "<p id=\"Par87\">\n\n</p>", "<title>Extended data</title>", "<p id=\"Par75\">is available for this paper at 10.1038/s41589-023-01409-z.</p>", "<title>Supplementary information</title>", "<p id=\"Par76\">The online version contains supplementary material available at 10.1038/s41589-023-01409-z.</p>", "<title>Acknowledgements</title>", "<p>We acknowledge the Paul Scherrer Institute for provision of synchrotron radiation beam time at beamline PXII of the Swiss Light Source. We thank M. McConkey for help with in vivo experiments. We are grateful to E. Cudré-Mauroux and J. Zagar for their help with recording all nuclear magnetic resonance data, as well as their assistance in spectra interpretation. We thank M. Schütz for laboratory management and organization. We are grateful to all Thomä and Ebert lab members, L. Meijer, S. Romero-Lopez, U. Hassiepen and G. Roth for discussions. This work was supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Program grant agreement no. 666068, European Research Council (ERC) under the European Union’s H2020 research program (NucEM, no. 884331), SNF 31003A_179541 and 310030_301206, from Krebsforschung (KFS 4980-02-2020), the Gebert Rüf Stiftung (GRS-057/14) and Novartis Research Foundation to N.H.T.; funding from the Swiss National Science Foundation for Sinergia grant no. CRSII5_186230 to D.G. and N.H.T.; the NIH (R01HL082945, P01CA108631 and P50CA206963), the Howard Hughes Medical Institute, the Edward P. Evans Foundation, and the Leukaemia and Lymphoma Society to B.L.E., as well as NIH grants NCI R01CA214608 and R01CA218278 to E.S.F. Z.K. was supported by a European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 765445. M.S. received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 702642. M.J. and J.L.S.-B. were supported by the grant DFG EXC2151–390873048.</p>", "<title>Author contributions</title>", "<p>Z.K. designed and carried out structural, biochemical and biophysical studies with the help of V.F. and G.P.; D.J.S. performed chemical synthesis and analysis with the help of D.H. and supervised by D.G.; M.S. and C.D.G. designed and performed cellular assays with the help of C.Z. and S.C.; K.A.D. performed mass spectrometry experiments and analysis supervised by E.S.F.; M.J. performed RNA-seq analysis with the help of M.S. and supervised by J.L.S.-B.; Z.K., G.K. and G.P. performed structure refinement; M.C. and C.M.-R. identified and validated Z7, Z11 and Z12 supervised by G.E.W.; B.L.E. and N.H.T. supervised the project; Z.K. and N.H.T. wrote the manuscript with input from all authors.</p>", "<title>Peer review</title>", "<title>Peer review information</title>", "<p id=\"Par77\"><italic>Nature Chemical Biology</italic> thanks Philip Chamberlain, Nathanael Gray, Frank Sicheri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.</p>", "<title>Data Availability</title>", "<p>Structural data have been deposited in the PDB under the accession codes <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BU1/pdb\">8BU1</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BU2/pdb\">8BU2</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BU3/pdb\">8BU3</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BU4/pdb\">8BU4</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BU5/pdb\">8BU5</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BU6/pdb\">8BU6</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BU7/pdb\">8BU7</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BU9/pdb\">8BU9</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUA/pdb\">8BUA</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUB/pdb\">8BUB</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUC/pdb\">8BUC</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUD/pdb\">8BUD</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUE/pdb\">8BUE</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUF/pdb\">8BUF</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUG/pdb\">8BUG</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUH/pdb\">8BUH</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUI/pdb\">8BUI</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUJ/pdb\">8BUJ</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUK/pdb\">8BUK</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUL/pdb\">8BUL</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUM/pdb\">8BUM</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUN/pdb\">8BUN</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUO/pdb\">8BUO</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUP/pdb\">8BUP</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUQ/pdb\">8BUQ</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUR/pdb\">8BUR</ext-link>, <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUS/pdb\">8BUS</ext-link> and <ext-link ext-link-type=\"uri\" xlink:href=\"https://doi.org/10.2210/pdb8BUT/pdb\">8BUT</ext-link>. Proteome quantification data are available in the PRIDE repository (<ext-link ext-link-type=\"uri\" xlink:href=\"http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041836\">PXD041836</ext-link>) or at <ext-link ext-link-type=\"uri\" xlink:href=\"https://github.com/fischerlab/\">https://github.com/fischerlab/</ext-link>. The protein-coding sequences employed can be identified through the following Uniprot entry IDs: human wild-type and mutant versions of DDB1 (Uniprot entry <ext-link ext-link-type=\"uri\" xlink:href=\"https://www.uniprot.org/uniprot/Q16531\">Q16531</ext-link>), CDK12 (<ext-link ext-link-type=\"uri\" xlink:href=\"https://www.uniprot.org/uniprot/Q9NYV4\">Q9NYV4</ext-link>, K965R) and CCNK (<ext-link ext-link-type=\"uri\" xlink:href=\"https://www.uniprot.org/uniprot/O75909\">O75909</ext-link>). <xref ref-type=\"sec\" rid=\"Sec44\">Source data</xref> are provided with this paper.</p>", "<title>Code availability</title>", "<p>Code necessary to reproduce statistical analysis is included as Supplementary Code ##SUPPL##3##1##.</p>", "<title>Competing interests</title>", "<p id=\"Par78\">N.H.T. receives funding from the Novartis Research Foundation and is a scientific advisory board (SAB) member of Monte Rosa Therapeutics and an advisor to Zenith Therapeutics and Ridgeline. B.L.E. has received research funding from Celgene, Deerfield, Novartis and Calico. He has received consulting fees from GRAIL, and he serves on the SABs for and holds equity in Neomorph, TenSixteen Bio, Skyhawk Therapeutics and Exo Therapeutics. E.S.F. is a founder, SAB member and equity holder of Civetta Therapeutics, Lighthorse Therapeutics, Proximity Therapeutics and Neomorph, Inc. (board member). E.S.F. is an equity holder and SAB member for Avilar Therapeutics, Ajax Therapeutics and Photys Therapeutics and a consultant to Novartis, Sanofi, EcoR1 Capital, Odyssey, Astellas and Deerfield. The Fischer lab receives or has received research funding from Novartis, Ajax, Voronoi, Interline, Deerfield and Astellas. D.G. is an SAB member of FoRx therapeutics. The C.M.-R. lab receives research funding from Almirall and Aelin Tx, and C.M.-R. is an SAB member of Nostrum Biodiscovery. G.E.W. is scientific founder and shareholder of Proxygen and Solgate, the Winter laboratory receives research funding from Pfizer. M.S. has received research funding from Calico Life Sciences LLC. G.P. is now an employee of Monte Rosa Therapeutics. C.D.G. is now an employee of VantAI. The remaining authors declare no competing interests.</p>" ]	[ "<fig id=\"Fig1\"><label>Fig. 1</label><caption><title>Modifications of the CR8 scaffold preserve its molecular glue activity.</title><p><bold>a</bold>, Crystal structure of the DDB1–CR8–CDK12–cyclin K complex (PDB: 6TD3) (ref. <sup>##UREF##5##15##</sup>). The zoomed panel depicts the binding mode of CR8, with the phenylpyridine moiety (gluing moiety; pale red) engaging DDB1 (surface representation). <bold>b</bold>, Chemical structure of the 2,6,9-trisubstituted purine core. The R<sub>1</sub> group is referred to as the gluing moiety and shown in red throughout. <bold>c</bold>, Chemical structures of CR8, DS16, DS11, roscovitine, DS06, DS23 and ternary complex crystal structures of the DDB1–CDK12 interfaces induced by those compounds, listed from best to worst binder, and their associated TR-FRET EC<sub>50</sub> values. Corresponding TR-FRET curves can be found in Extended Data Fig. ##FIG##5##1e##. <bold>d</bold>, Chemical structures of DS08 and DS15 and ternary complex crystal structures of interfaces induced by those compounds. Corresponding TR-FRET curves can be found in Extended Data Fig. ##FIG##5##1i##. <bold>e</bold>, Overlay of ternary complex structures from <bold>c</bold> and <bold>d</bold>. In <bold>c</bold> and <bold>d</bold>, interactions are represented by dashed lines. Hydrogen bonds to the hinge region are shown in pink, other hydrogen bonds in yellow, aromatic H-bonds in gray, and π–cation interactions in green. Regions with no unambiguous <italic>F</italic><sub>o</sub>–<italic>F</italic><sub>c</sub> density at 1<italic>σ</italic> are displayed with a smaller stick radius. Density maps, omit maps and interaction distances can be found in Supplementary Figs. ##SUPPL##0##1##–##SUPPL##0##3##.</p></caption></fig>", "<fig id=\"Fig2\"><label>Fig. 2</label><caption><title>Published CDK inhibitors have cryptic molecular glue activity.</title><p><bold>a</bold>, Chemical structure of SR-4835 and ternary complex crystal structure of the DDB1–CDK12 interface induced by the compound. <bold>b</bold>, Chemical structures of CR8/SR-4835 hybrid compounds and ternary complex crystal structures of the DDB1–CDK12 interfaces induced by DS17, DS18, DS19 and DS22. <bold>c</bold>, Chemical structure of 21195 and ternary complex crystal structure of the DDB1–CDK12 interface induced by the compound. <bold>d</bold>, Chemical structure of 919278 and ternary complex crystal structure of the DDB1–CDK12 interface induced by the compound. In <bold>a</bold>–<bold>d</bold>, interactions are represented by dashed lines. Hinge hydrogen bonds are shown in pink, other hydrogen bonds in yellow, aromatic H-bonds in gray, π–cation interactions in green, π–π interactions in cyan and halogen bonds in purple. Density maps, omit maps and interaction distances can be found in Supplementary Figs. ##SUPPL##0##1##–##SUPPL##0##3##.</p></caption></fig>", "<fig id=\"Fig3\"><label>Fig. 3</label><caption><title>Low-molecular-weight cyclin K glues.</title><p><bold>a</bold>, Chemical structures of HQ461, Z11, Z7, dCeMM3 and Z12 and ternary complex crystal structures of the DDB1–CDK12 interfaces induced by each compound. HQ461 could in theory bind at the interface in two directions (see fingerprint in <bold>c</bold>), yet the density, while somewhat ambiguous, suggests the methylpyridine moiety points towards DDB1. <bold>b</bold>, Chemical structures of NCT02, dCeMM2 and dCeMM4, which are cyclin K degraders. <bold>c</bold>, The fingerprint of a cyclin K degrader. <bold>d</bold>, Chemical structure of SNS032, which is not a cyclin K degrader despite binding CDK12. <bold>e</bold>, Ternary complex crystal structure with dCeMM4 (top) and overlay of dCeMM4 and CR8 (bottom). <bold>f</bold>, DDB1–CDK12–cyclin K complex architecture, with a conformational change in a CDK12 activation loop (spheres) induced by dCeMM4. While a closed-loop kinase conformation is often associated with an inactive kinase state whereby the Asp–Phe–Gly (DFG) motif flips, here no DFG flip was observed. <bold>g</bold>, Diversity of cyclin K degraders illustrated through a plot of the compounds’ molecular weight and their ternary complex formation affinity. The ten compounds most active in vitro are shown in purple and the low-molecular-weight cyclin K degraders described above are colored green. <bold>h</bold>, As in <bold>g</bold> but showing the compounds’ Tanimoto similarity to CR8 and their ternary complex formation affinity. <bold>a</bold>,<bold>e</bold>, Interactions are represented by dashed lines. Hinge hydrogen bonds are shown in pink, other hydrogen bonds in yellow, aromatic H-bonds in gray, π–cation interactions in green and halogen bonds in purple. Regions with no unambiguous <italic>F</italic><sub>o</sub>–<italic>F</italic><sub>c</sub> density at 1<italic>σ</italic> are displayed with a smaller stick radius. Density maps, omit maps and interaction distances can be found in Supplementary Figs. ##SUPPL##0##1##–##SUPPL##0##3##.</p><p>##SUPPL##6##Source data##</p></caption></fig>", "<fig id=\"Fig4\"><label>Fig. 4</label><caption><title>Cellular evaluation of cyclin K molecular glue degraders.</title><p><bold>a</bold>, Schematic of the cyclin K dual-color reporter assay. <bold>b</bold>, HEK293T cycK<sub>eGFP</sub> reporter assay results for four example compounds. Individual replicates are shown (<italic>n</italic> = 2); n.d., not determined. Data for all compounds can be found in Supplementary Fig. ##SUPPL##0##4##. <bold>c</bold>, Correlation of in vitro complex formation affinity (logEC<sub>50</sub> TR-FRET) and cycK<sub>eGFP</sub> reporter results (logDC<sub>50</sub>) modeled with a linear regression (<italic>R</italic><sup>2</sup> = 0.60). The in vitro TR-FRET EC<sub>50</sub> values for the best compounds (bold) are overestimated, which negatively impacts the correlation. The equivalent plot in linear scale is shown in Extended Data Fig. ##FIG##10##6a##. <bold>d</bold>, Viability assay in HEK293T cells for four example compounds, with curves corresponding to treatment with the individual drug or additional pretreatment with 100 nM of the neddylation inhibitor MLN4924. Individual replicates are shown (<italic>n</italic> = 2). Data for all compounds can be found in Supplementary Fig. ##SUPPL##0##5##.</p><p>##SUPPL##7##Source data##</p></caption></fig>", "<fig id=\"Fig5\"><label>Fig. 5</label><caption><title>Diverse cyclin K molecular glue degraders give rise to unique cellular responses.</title><p><bold>a</bold>, MDA-MB-231 cells were exposed to 1 µM DS17, CR8 or DMSO for 5 h followed by whole proteome quantification using label-free mass spectrometry (mean log<sub>2</sub> fold change, <italic>P</italic> value calculated by a moderated <italic>t</italic>-test, <italic>n</italic> = 4 (DMSO), <italic>n</italic> = 2 (DS17 and CR8)). <bold>b</bold>, Representation of the average peptide counts of cyclin K (dark gray), CDK12 (yellow) and CDK13 (blue). Data represent the mean ± standard deviation (<italic>n</italic> = 4 for DMSO and <italic>n</italic> = 2 for each compound treatment). The corresponding volcano plots can be found in Extended Data Fig. ##FIG##11##7a##. <bold>c</bold>, PCA of the RNA-seq data for CR8, BSJ-4-116, dinaciclib, HQ461 and DMSO (<italic>n</italic> = 3). <bold>d</bold>, PCA analysis of the RNA-seq data for a larger selection of compounds (<italic>n</italic> = 3). For 919278 and SR-4835, two conditions were assessed: compound alone (circle) or compound + MLN4924 (triangle). Co-treatment with the neddylation inhibitor resulted in large shifts of the resulting points (dashed arrows). In <bold>c</bold> and <bold>d</bold>, the corresponding volcano plots can be found in Extended Data Fig. ##FIG##13##9##.</p><p>##SUPPL##8##Source data##</p></caption></fig>", "<fig id=\"Fig6\"><label>Extended Data Fig. 1</label><caption><title>Mapping of interfacial pocket dimensions and key interactions with CR8 derivative series.</title><p><bold>a</bold>, Fluorescent label positions chosen for the optimized TR-FRET assay. <bold>b</bold>, Schematic of the compound titration used for ternary complex formation assessment. <bold>c</bold>, Optimized in vitro TR-FRET complex formation assay for CR8 and roscovitine reveals a large difference in activity (much larger than previously reported<sup>##UREF##5##15##</sup>) between the two compounds in accordance with the lack of cyclin K degradation activity of roscovitine in cells<sup>##UREF##5##15##</sup>. The assay is therefore an appropriately sensitive readout for the evaluation of closely related compounds. <bold>d</bold>, CDK12 loop (a.a. 731-743) that encloses the active site, with the Ile733 sidechain oriented towards the compound. This loop is omitted from most figure panels for clarity. <bold>e</bold>, In vitro TR-FRET complex formation assay for compound shown in Fig. ##FIG##0##1c##. <bold>f</bold>, Chemical structures of a series of derivatives bearing aliphatic chains at the R<sub>1</sub> position listed from best to worst binder (left). In vitro TR-FRET complex formation assay for these compounds (right). <bold>g</bold>, Chemical structures of a series of derivatives bearing saturated rings at the R<sub>1</sub> position listed from best to worst binder (left). In vitro TR-FRET complex formation assay for these compounds (right). <bold>h</bold>, The impact of aromaticity on ternary complex formation. Chemical structures of two aromatic-aliphatic pairs and the associated in vitro TR-FRET compound titration results. <bold>i</bold>, In vitro TR-FRET complex formation assay for compounds shown in Fig. ##FIG##0##1d##. Crystal structures with compounds DS08 and DS15 are displayed in Fig. ##FIG##0##1e##. (<bold>c</bold>, <bold>e</bold>-<bold>i</bold>) Individual replicates are shown (n = 17 for CR8; n = 4 for DS06, DS08, roscovitine; n = 2 for others).</p><p>\n##SUPPL##9##Source data##\n</p></caption></fig>", "<fig id=\"Fig7\"><label>Extended Data Fig. 2</label><caption><title>Miscellaneous modifications of CR8-like scaffolds.</title><p><bold>a</bold>, Chemical structures of a series of derivatives bearing an alkyl phenyl R<sub>1</sub> group with the alkyl linker varying in length listed from best to worst binder (left). In vitro TR-FRET complex formation assay for the compounds shown (right). <bold>b</bold>, Chemical structures of several derivatives containing fused or multiple rings listed from best to worst binder (left). In vitro TR-FRET complex formation assay for the compounds shown (right). <bold>c</bold>, Chemical structures of various CR8 derivatives listed from best to worst binder (left). In vitro TR-FRET complex formation assay for these compounds (right). <bold>d</bold>, Ternary complex crystal structure with DS43. <bold>e</bold>, Chemical structures of derivatives bearing heterocyclic gluing moieties listed from best to worst binder. <bold>f</bold>, In vitro TR-FRET complex formation assay for compounds shown in (<bold>e</bold>). <bold>g</bold>, Chemical structures of several compounds derived from simple modifications of the simplified CR8-like scaffold DS11 listed from best to worst binder. <bold>h</bold>, In vitro TR-FRET complex formation assay for compounds shown in (<bold>g</bold>). <bold>i</bold>, Crystal structure of the ternary complex formed with DS30 (chemical structure in (<bold>g</bold>)) (left) and overlay of the binding mode of DS11 and DS30 (right). (<bold>a-c</bold>, <bold>f, h</bold>) Individual replicates are shown (n = 17 for CR8; n = 4 for DS08, DS30, DS66, roscovitine; n = 2 for others). (<bold>d, i</bold>) Interactions are represented by dashed lines. Hinge hydrogen bonds are shown in pink, aromatic H-bonds in grey, other hydrogen bonds in yellow, and π-cation interactions in green.</p><p>\n##SUPPL##10##Source data##\n</p></caption></fig>", "<fig id=\"Fig8\"><label>Extended Data Fig. 3</label><caption><title>Other modifications of R<sub>1</sub> and R<sub>2</sub> groups.</title><p><bold>a</bold>, Chemical structures of CR8 derivatives where the location of the phenylpyridine nitrogen is varied, listed from best to worst binder. <bold>b</bold>, In vitro TR-FRET complex formation assay for compounds shown in (<bold>a</bold>), DMSO, and CR8. <bold>c</bold>, Chemical structures of CR8 derivatives. TR-FRET curves can be found in Extended Data Fig. ##FIG##6##2c##. <bold>d</bold>, Structures of interfaces induced by WX3 and DS24. <bold>e</bold>, Chemical structures of derivatives with various R<sub>2</sub> substituents, for example inspired by SR-4835 (DS19), dinaciclib (DS70) or 21195 (DS48). <bold>f</bold>, In vitro TR-FRET complex formation assay for compounds shown in (<bold>e</bold>). <bold>g</bold>, Chemical structures of compounds obtained through R-group docking at the R<sub>2</sub> position, displayed from best to worst binder. <bold>h</bold>, In vitro TR-FRET complex formation assay for compounds shown in (<bold>g</bold>). <bold>i</bold>, Crystal structure of the ternary complex formed with DS59. Interactions are represented by dashed lines. Hinge hydrogen bonds are shown in pink, aromatic H-bonds in grey, and π-cation interactions in green. Possible π-cation interactions between the diazole and proximal CDK12 lysine residues (K756, K861) were omitted for clarity<bold>. j</bold>, Crystal structure of the ternary complex formed with DS50. The R<sub>1</sub> and R<sub>2</sub> substituents could not be unambiguously fit into the density and were set to zero occupancy and are displayed with a smaller stick radius. Two probable conformations are shown. (<bold>b, f, h</bold>) Individual replicates are shown (n = 17 for CR8; n = 4 for DS28, DS44, DS53, DS59; n = 2 for others).</p><p>\n##SUPPL##11##Source data##\n</p></caption></fig>", "<fig id=\"Fig9\"><label>Extended Data Fig. 4</label><caption><title>Evaluation of known compounds and their derivatives for cryptic molecular glue activity.</title><p><bold>a</bold>, In vitro TR-FRET complex formation assay for various CDK12 inhibitors. <bold>b</bold>, Crystal structure of the ternary complex formed with DRF053 and the chemical structure of DRF053. <bold>c</bold>, In vitro TR-FRET complex formation assay with other CDK inhibitors. <bold>d</bold>, In vitro TR-FRET complex formation assay for SR-4835 (structure in Fig. ##FIG##1##2a##). <bold>e</bold>, SR-4835 induces conformational changes in the N-lobe of CDK12 as compared to CR8. The CR8-bound structure is shown with 50% transparency. <bold>f</bold>, Multiple sequence alignment of human CDKs highlighting a unique tyrosine residue in CDK12/13 (CDK12 Tyr815). <bold>g</bold>, Chemical structures of SR-4835 derivatives, displayed from best to worst binder (left). In vitro TR-FRET complex formation assay for these compounds (right). <bold>h</bold>, Crystal structure of the ternary complex formed with DS55. <bold>i</bold>, In vitro TR-FRET complex formation assay for DS17-22 (structures in Fig. ##FIG##1##2d##). <bold>j</bold>, Chemical structures of compounds disclosed in patent WO2021116178<sup>##UREF##8##27##</sup> and derivative DS64 bearing a related gluing moiety, listed from best to worst binder. Purine scaffold hopping is emphasized with a green highlight. <bold>k</bold>, In vitro TR-FRET complex formation assay for compounds shown in (<bold>j</bold>). (<bold>a</bold>, <bold>c</bold>, <bold>d</bold>, <bold>g</bold>, <bold>i</bold>, <bold>k</bold>) Individual replicates are shown (n = 17 for CR8; n = 4 for SR-4835, DS17, DS18, DS72, DS74; n = 2 for others). (<bold>b</bold>, <bold>h</bold>) Regions with no unambiguous F<sub><bold>o</bold></sub>-F<sub><bold>c</bold></sub> density at 1σ are displayed with a smaller stick radius.</p><p>\n##SUPPL##12##Source data##\n</p></caption></fig>", "<fig id=\"Fig10\"><label>Extended Data Fig. 5</label><caption><title>Hydrophilic and small compounds highlight cyclin K degrader diversity.</title><p><bold>a</bold>, In vitro TR-FRET complex formation assay for 21195 (structure in Fig. ##FIG##1##2c##). <bold>(b-f)</bold> Examples of the impact of increasing the hydrophilicity of the gluing moiety on multiple scaffolds including the relevant chemical structures and the associated in vitro TR-FRET compound titration results. <bold>b</bold>, DS06 and DS13. <bold>c</bold>, DS11 and DS68. <bold>d</bold>, DS08 and DS14. <bold>e</bold>, DS09 and DS40. <bold>f</bold>, DS55 and DS54. <bold>g</bold>, Chemical structures of 21195 and compounds resulting from hybridization of CR8 and SR-4835 with this inhibitor, listed from best to worst binder. <bold>h</bold>, In vitro TR-FRET complex formation assay for compounds shown in (<bold>f</bold>). <bold>i</bold>, Crystal structure of the ternary complex formed with DS61 (left) and the overlay of complexes induced by DS61, 21195, and CR8 (right). Interactions are represented by dashed lines. Hinge hydrogen bonds are shown in pink, other hydrogen bonds in yellow, aromatic H-bonds in grey, and π-cation interactions in green. <bold>j</bold>, In vitro TR-FRET complex formation assay for compounds shown in Fig. ##FIG##1##2d## and Fig. ##FIG##2##3a-e##. (<bold>a-f</bold>, <bold>h</bold>, <bold>j</bold>) Individual replicates are shown (n = 17 for CR8; n = 4 for DS06, DS08, 21195, SR-4835, dCeMM2, dCeMM4, Z7, Z11, HQ461; n = 2 for other compounds).</p><p>\n##SUPPL##13##Source data##\n</p></caption></fig>", "<fig id=\"Fig11\"><label>Extended Data Fig. 6</label><caption><title>Further characterisation of molecular glue degrader compounds.</title><p><bold>a</bold>, Correlation of in vitro assay data (TR-FRET EC<sub>50</sub> [nM]) with cellular cyclin K<sub>eGFP</sub> reporter assay results (DC<sub>50</sub> [nM]), based only on compounds with unambiguous activity in the reporter assay (n = 42). The relationship can be described with a Hill equation (R squared = 0.70), with the equation used solely to describe the mathematical relationship between the two experimental datasets and not for its biological meaning. <bold>b</bold>, In vitro TR-FRET complex formation assay performed as a compound titration with 50 nM CDK12-cyclin K (left) or 10 nM CDK12-cyclin K (right) for several compounds (n = 1). Data were fitted with a quadratic equation appropriate for a case where the expected K<sub>d</sub> value is lower than the protein concentration used<sup>##REF##30417032##69##</sup>. Lowering the protein concentration resulted in a much smaller assay window but yielded K<sub>d</sub>* values in the sub-nanomolar range for the top compounds (DS17, DS73), while showing no difference for the weak recruiter roscovitine, indicating that the tightest glues lie below the limit of detection of the TR-FRET assay (this is also highlighted by the spurious fit observed for DS17). <bold>c</bold>, Correlation of in vitro complex formation affinity (logEC<sub>50</sub> TR-FRET) and cycK<sub>eGFP</sub> reporter results (logDC<sub>50</sub>) modelled with a linear regression (R squared = 0.60). The in vitro TR-FRET values for the best compounds (bold) are overestimated and the green cloud indicates how the data points would be predicted to shift upon accurate affinity quantification, further improving the observed correlation (<italic>c.f</italic>. panel <bold>b</bold>). <bold>d</bold>, Histograms displaying the molecular weight, clogP, polar surface area, and the number or rotatable bonds distributions across the cyclin K degrader compound set. <bold>e</bold>, PCA of the combined multi-assay data for cyclin K degraders.</p><p>\n##SUPPL##14##Source data##\n</p></caption></fig>", "<fig id=\"Fig12\"><label>Extended Data Fig. 7</label><caption><title>Proteomics reveal large differences in the extent of cyclin K depletion.</title><p><bold>a</bold>, Label-free proteomics. Mean log2 fold change, p value calculated by a moderated t-test; n = 4 (DMSO), n = 2 (21195, SR-4835, DS30, 919278, and HQ461). MDA-MB-231 cells were treated with 1 µM drug for 5 h. <bold>b</bold>, Correlation of the average cyclin K peptide count with the TR-FRET EC<sub>50</sub> (left) or with the cyclin K<sub>eGFP</sub> reporter DC<sub>50</sub> (right).</p><p>\n##SUPPL##15##Source data##\n</p></caption></fig>", "<fig id=\"Fig13\"><label>Extended Data Fig. 8</label><caption><title>Cyclin K degraders do not require traditional kinase inhibitory properties for activity.</title><p><bold>a</bold>, Commercial in vitro Lanthascreen assay. The binding of an Alexa<sub>647</sub>-conjugated tracer to a kinase is detected by addition of an Eu-labelled anti-tag antibody. Binding of the tracer and antibody to a kinase yields a high TR-FRET signal, while tracer displacement with a kinase inhibitor results in signal loss. <bold>b</bold>, Multiple sequence alignment of CDK12, CDK9, and CDK2, omitting the C-terminal extension of CDK12. <bold>c</bold>, Selectivity profiling of CR8/SR-4835 hybrid compounds across CDK2/9/12 using Lanthascreen. Representative TR-FRET curves (n = 2) (top) and a table listing average IC<sub>50</sub> values and total number (n) of measurements (bottom). <bold>d</bold>, Selectivity profiling results for compounds derived from a recent patent and related derivatives. <bold>e</bold>, Selectivity profiling of compound 21195. <bold>f</bold>, Representative TR-FRET curves (n = 2) (left) and a table listing average IC<sub>50</sub> values and total number (n) of measurements (right) for low molecular weight cyclin K degraders. <bold>g</bold>, Representative TR-FRET curves (n = 2) (left) and a table listing average IC<sub>50</sub> values and total number (n) of measurements (right) for CR8 and DS70, a hybrid of CR8 and dinaciclib bearing the hydroxyethyl piperidine functionality present in this potent CDK inhibitor. DS70 shows more pronounced pan-CDK engagement than CR8. (<bold>c-g</bold>) Additional replicates and further data can be found in Supplementary Fig. ##SUPPL##0##6##.</p><p>\n##SUPPL##16##Source data##\n</p></caption></fig>", "<fig id=\"Fig14\"><label>Extended Data Fig. 9</label><caption><title>RNA sequencing reveals distinct transcriptional signatures for CDK12 inhibition, CDK12 degradation, and cyclin K degradation.</title><p><bold>a</bold>, Cyclin K reporter degradation assay (n = 2) (top). In vitro TR-FRET complex formation assay (bottom) showing no cyclin K molecular glue degrader activity for the CDK12 PROTAC BSJ-4-116 (n = 2 for BSJ-4-116, n = 17 for CR8). <bold>b</bold>, Volcano plots depicting the RNAseq results for CR8 (cyclin K degrader), BSJ-4-116 (CDK12 degrader), and dinaciclib (CDK inhibitor) (n = 3). <bold>c</bold>, Volcano plots showing the RNAseq results for 919278 and SR-4835, either alone or in combination with the neddylation inhibitor MLN4924 (n = 3).</p><p>\n##SUPPL##17##Source data##\n</p></caption></fig>" ]	[]	[ "<disp-formula id=\"Equ1\"><label>1</label><alternatives><tex-math id=\"M1\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${y}={\\rm{Bottom}}+\\frac{\\left({{x}}^{{{\\mathrm{Hillslope}}}}\\right)\\times ({{\\mathrm{Top}}}-{{\\mathrm{Bottom}}})}{{{{\\mathrm{EC}}}}_{50}^{{{\\mathrm{Hillslope}}}}+\\,{{x}}^{{{\\mathrm{Hillslope}}}}\\,}$$\\end{document}</tex-math><mml:math id=\"M2\"><mml:mrow><mml:mi>y</mml:mi><mml:mo>=</mml:mo><mml:mi mathvariant=\"normal\">Bottom</mml:mi><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msup><mml:mrow><mml:mi>x</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">Hillslope</mml:mi></mml:mrow></mml:msup></mml:mrow></mml:mfenced><mml:mo>×</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi mathvariant=\"normal\">Top</mml:mi><mml:mo>−</mml:mo><mml:mi mathvariant=\"normal\">Bottom</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow><mml:mrow><mml:msubsup><mml:mrow><mml:mi mathvariant=\"normal\">EC</mml:mi></mml:mrow><mml:mrow><mml:mn>50</mml:mn></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">Hillslope</mml:mi></mml:mrow></mml:msubsup><mml:mo>+</mml:mo><mml:mspace width=\"0.25em\"/><mml:msup><mml:mrow><mml:mi>x</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">Hillslope</mml:mi></mml:mrow></mml:msup><mml:mspace width=\"0.25em\"/></mml:mrow></mml:mfrac></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ2\"><label>2</label><alternatives><tex-math id=\"M3\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${y}={\\rm{Bottom}}+({\\rm{Top}}-{\\rm{Bottom}})\\,\\left(\\frac{{K}_{{\\mathrm{d}}}+L+x-\\sqrt{({\\left({K}_{{\\mathrm{d}}}+L+x\\right)}^{2}-4{Lx})}}{2L}\\right)$$\\end{document}</tex-math><mml:math id=\"M4\"><mml:mrow><mml:mi>y</mml:mi><mml:mo>=</mml:mo><mml:mi mathvariant=\"normal\">Bottom</mml:mi><mml:mo>+</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi mathvariant=\"normal\">Top</mml:mi><mml:mo>−</mml:mo><mml:mi mathvariant=\"normal\">Bottom</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mspace width=\"0.25em\"/><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mi>K</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">d</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mi>L</mml:mi><mml:mo>+</mml:mo><mml:mi>x</mml:mi><mml:mo>−</mml:mo><mml:msqrt><mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mfenced close=\")\" open=\"(\"><mml:mrow><mml:msub><mml:mrow><mml:mi>K</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">d</mml:mi></mml:mrow></mml:msub><mml:mo>+</mml:mo><mml:mi>L</mml:mi><mml:mo>+</mml:mo><mml:mi>x</mml:mi></mml:mrow></mml:mfenced></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mo>−</mml:mo><mml:mn>4</mml:mn><mml:mi>L</mml:mi><mml:mi>x</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:msqrt></mml:mrow><mml:mrow><mml:mn>2</mml:mn><mml:mi>L</mml:mi></mml:mrow></mml:mfrac></mml:mrow></mml:mfenced></mml:mrow></mml:math></alternatives></disp-formula>", "<disp-formula id=\"Equ3\"><label>3</label><alternatives><tex-math id=\"M5\">\\documentclass[12pt]{minimal}\n\t\t\t\t\\usepackage{amsmath}\n\t\t\t\t\\usepackage{wasysym} \n\t\t\t\t\\usepackage{amsfonts} \n\t\t\t\t\\usepackage{amssymb} \n\t\t\t\t\\usepackage{amsbsy}\n\t\t\t\t\\usepackage{mathrsfs}\n\t\t\t\t\\usepackage{upgreek}\n\t\t\t\t\\setlength{\\oddsidemargin}{-69pt}\n\t\t\t\t\\begin{document}$${y}={\\rm{Bottom}}+\\frac{({{\\mathrm{Top}}}-{{\\mathrm{Bottom}}})}{1+\\,{\\frac{{{\\rm{IC}}}_{50}}{x}}^{{{\\mathrm{Hillslope}}}}\\,}$$\\end{document}</tex-math><mml:math id=\"M6\"><mml:mrow><mml:mi>y</mml:mi><mml:mo>=</mml:mo><mml:mi mathvariant=\"normal\">Bottom</mml:mi><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi mathvariant=\"normal\">Top</mml:mi><mml:mo>−</mml:mo><mml:mi mathvariant=\"normal\">Bottom</mml:mi></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow><mml:mrow><mml:mn>1</mml:mn><mml:mo>+</mml:mo><mml:mspace width=\"0.25em\"/><mml:msup><mml:mrow><mml:mfrac><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=\"normal\">IC</mml:mi></mml:mrow><mml:mrow><mml:mn>50</mml:mn></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:mi>x</mml:mi></mml:mrow></mml:mfrac></mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">Hillslope</mml:mi></mml:mrow></mml:msup><mml:mspace width=\"0.25em\"/></mml:mrow></mml:mfrac></mml:mrow></mml:math></alternatives></disp-formula>" ]	[]	[]	[]	[]	[ "<supplementary-material content-type=\"local-data\" id=\"MOESM1\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM2\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM3\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM4\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM5\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM6\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM7\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM8\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM9\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM10\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM11\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM12\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM13\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM14\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM15\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM16\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM17\"></supplementary-material>", "<supplementary-material content-type=\"local-data\" id=\"MOESM18\"></supplementary-material>" ]	[ "<fn-group><fn><p><bold>Publisher’s note</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group>" ]	[ "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Figa_HTML\" id=\"d32e455\"/>", "<graphic xlink:href=\"41589_2023_1409_Fig1_HTML\" id=\"d32e649\"/>", "<graphic xlink:href=\"41589_2023_1409_Fig2_HTML\" id=\"d32e1011\"/>", "<graphic xlink:href=\"41589_2023_1409_Fig3_HTML\" id=\"d32e1339\"/>", "<graphic xlink:href=\"41589_2023_1409_Fig4_HTML\" id=\"d32e1491\"/>", "<graphic xlink:href=\"41589_2023_1409_Fig5_HTML\" id=\"d32e1652\"/>", "<graphic xlink:href=\"41589_2023_1409_Article_Equ1.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"41589_2023_1409_Article_Equ2.gif\" position=\"anchor\"/>", "<graphic xlink:href=\"41589_2023_1409_Article_Equ3.gif\" position=\"anchor\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig6_ESM\" id=\"d32e2860\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig7_ESM\" id=\"d32e2925\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig8_ESM\" id=\"d32e3002\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig9_ESM\" id=\"d32e3100\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig10_ESM\" id=\"d32e3172\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig11_ESM\" id=\"d32e3231\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig12_ESM\" id=\"d32e3259\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig13_ESM\" id=\"d32e3312\"/>", "<graphic position=\"anchor\" xlink:href=\"41589_2023_1409_Fig14_ESM\" id=\"d32e3337\"/>" ]	[ "<media xlink:href=\"41589_2023_1409_MOESM1_ESM.pdf\"><label>Supplementary Information</label><caption><p>Supplementary Note, Tables 2 and 3 and Figs. 1–7.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM2_ESM.pdf\"><caption><p>Reporting Summary</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM3_ESM.xlsx\"><label>Supplementary Table 1</label><caption><p>X-ray data collection and refinement statistics.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM4_ESM.r\"><label>Supplementary Code 1</label><caption><p>Supplementary code sufficient to reproduce the results of RNA-seq analysis.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM5_ESM.xlsx\"><label>Supplementary Data 1</label><caption><p>Source data for Supplementary Fig. 4.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM6_ESM.xlsx\"><label>Supplementary Data 2</label><caption><p>Source data for Supplementary Fig. 5.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM7_ESM.xlsx\"><label>Source Data Fig. 3</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM8_ESM.xlsx\"><label>Source Data Fig. 4</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM9_ESM.xlsx\"><label>Source Data Fig. 5</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM10_ESM.xlsx\"><label>Source Data Extended Data Fig. 1</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM11_ESM.xlsx\"><label>Source Data Extended Data Fig. 2</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM12_ESM.xlsx\"><label>Source Data Extended Data Fig. 3</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM13_ESM.xlsx\"><label>Source Data Extended Data Fig. 4</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM14_ESM.xlsx\"><label>Source Data Extended Data Fig. 5</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM15_ESM.xlsx\"><label>Source Data Extended Data Fig. 6</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM16_ESM.xlsx\"><label>Source Data Extended Data Fig. 7</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM17_ESM.xlsx\"><label>Source Data Extended Data Fig. 8</label><caption><p>Statistical source data.</p></caption></media>", "<media xlink:href=\"41589_2023_1409_MOESM18_ESM.xlsx\"><label>Source Data Extended Data Fig. 9</label><caption><p>Statistical source data.</p></caption></media>" ]	[{"label": ["4."], "mixed-citation": ["Cowan, A. D. & Ciulli, A. Driving E3 ligase substrate specificity for targeted protein degradation: lessons from nature and the laboratory. "], "italic": ["Annu. Rev. Biochem"]}, {"label": ["6."], "surname": ["Geiger", "Sch\u00e4fer", "Dreizler", "Walz", "Hausch"], "given-names": ["TM", "SC", "JK", "M", "F"], "article-title": ["Clues to molecular glues"], "source": ["Curr. Res. Chem. Biol."], "year": ["2022"], "volume": ["2"], "fpage": ["100018"], "pub-id": ["10.1016/j.crchbi.2021.100018"]}, {"label": ["7."], "surname": ["Ma"], "given-names": ["X"], "article-title": ["Discovery and structural characterization of a VHL-mediated molecular glue degrader targeting cysteine dioxygenase"], "source": ["Acta Crystallogr. A"], "year": ["2021"], "volume": ["77"], "fpage": ["a245"], "lpage": ["a245"], "pub-id": ["10.1107/S0108767321097543"]}, {"label": ["8."], "mixed-citation": ["Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. "], "italic": ["Nat. Chem. Biol."]}, {"label": ["9."], "surname": ["Han"], "given-names": ["T"], "article-title": ["Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15"], "source": ["Science"], "year": ["2017"], "volume": ["356"], "fpage": ["3755"], "pub-id": ["10.1126/science.aal3755"]}, {"label": ["15."], "mixed-citation": ["S\u0142abicki, M. et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. "], "italic": ["Nature"]}, {"label": ["16."], "mixed-citation": ["Lei, P. et al. Current progress and novel strategies that target CDK12 for drug discovery. "], "italic": ["Eur. J. Med. Chem."]}, {"label": ["23."], "mixed-citation": ["Roush, W. R., Duckett, D. & Monastyrskyi, A. Small molecule inhibitors of CDK12/CDK13. Patent WO2019217421 (2019)."]}, {"label": ["27."], "mixed-citation": ["Thede, K. et al. Pyrazolotriazines. Patent WO2021116178 (2021)."]}, {"label": ["28."], "mixed-citation": ["Johannes, J. W. et al. Structure-based design of selective noncovalent CDK12 inhibitors. "], "italic": ["ChemMedChem"]}, {"label": ["31."], "surname": ["Henry"], "given-names": ["KL"], "article-title": ["CDK12-mediated transcriptional regulation of noncanonical NF-kB components is essential for signaling"], "source": ["Sci. Signal."], "year": ["2018"], "volume": ["11"], "fpage": ["eaam821"], "pub-id": ["10.1126/scisignal.aam8216"]}, {"label": ["41."], "mixed-citation": ["Leissing, T. M., Luh, L. M. & Cromm, P. M. Structure driven compound optimization in targeted protein degradation. "], "italic": ["Drug Discov. Today Technol."]}, {"label": ["42."], "surname": ["Oumata", "Ferandin", "Meijer", "Galons"], "given-names": ["N", "Y", "L", "H"], "article-title": ["Practical synthesis of roscovitine and CR8"], "source": ["Org. Process Res. Dev."], "year": ["2009"], "volume": ["13"], "fpage": ["641"], "lpage": ["644"], "pub-id": ["10.1021/op800284k"]}, {"label": ["44."], "surname": ["Larsen", "Ulven"], "given-names": ["AF", "T"], "article-title": ["Direct "], "italic": ["N"], "sup": ["9"], "source": ["Chem. Commun."], "year": ["2014"], "volume": ["50"], "fpage": ["4997"], "lpage": ["4999"], "pub-id": ["10.1039/C3CC48642G"]}, {"label": ["46."], "mixed-citation": ["Li, T., Pavletich, N. P., Schulman, B. A. & Zheng, N. High-level expression and purification of recombinant SCF ubiquitin ligases. "], "italic": ["Methods Enzymol."]}, {"label": ["52."], "mixed-citation": ["Tickle, I. J., et al. STARANISO. "], "italic": ["Global Phasing"], "ext-link": ["http://staraniso.globalphasing.org/cgi-bin/staraniso.cgi"]}, {"label": ["57."], "surname": ["Croll"], "given-names": ["TI"], "article-title": ["ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps"], "source": ["Acta Crystallogr. D"], "year": ["2018"], "volume": ["74"], "fpage": ["519"], "lpage": ["530"], "pub-id": ["10.1107/S2059798318002425"]}, {"label": ["65."], "mixed-citation": ["R Core Team. "], "italic": ["R: A Language and Environment for Statistical Computing"]}]	{ "acronym": [], "definition": [] }	69	CC BY	no	2024-01-13 23:35:09	Nat Chem Biol. 2024 Sep 7; 20(1):93-102	oa_package/13/96/PMC10746543.tar.gz
PMC10756883	38157072	[]	[]	[]	[]	[]	[]	[ "<p id=\"Par1\">\n<bold>Correction to: Environ Monit Assess (2023) 195:1260</bold>\n</p>", "<p id=\"Par2\">\n10.1007/s10661-023-11836-z\n</p>", "<p id=\"Par3\">The article Differing field methods and site conditions lead to varying bias in suspended sediment concentrations in the Lower Mississippi and Atchafalaya Rivers, written by J. Murphy, L. Schafer and S. Mize, was originally published Online First without Open Access. After publication in volume 195, issue 11, article ID 1260 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2023 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit <ext-link ext-link-type=\"uri\" xlink:href=\"http://creativecommons.org/licenses/by/4.0/\">http://creativecommons.org/licenses/by/4.0/</ext-link>.</p>", "<p id=\"Par4\">The original article has been corrected.</p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<fn-group><fn><p><bold>Publisher's Note</bold></p><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group>" ]	[]	[]	[]	{ "acronym": [], "definition": [] }	0	CC BY	no	2024-01-13 23:36:44	Environ Monit Assess. 2024 Dec 29; 196(1):100	oa_package/10/20/PMC10756883.tar.gz
PMC10757870	0	[]	[]	[]	[]	[]	[]	[ "<p>We would like to take this opportunity to thank you for the time and expertise that you generously contribute to reviewing articles submitted to the Annals and the Bulletin. We want to acknowledge your support during 2023, without which it would not be possible to preserve the high standards of our journals.</p>", "<p>\n<list list-type=\"simple\"><list-item><p>Abougamil, Ahmed</p></list-item><list-item><p>Achar, Priya</p></list-item><list-item><p>Acheson, Austin</p></list-item><list-item><p>Adcox, Max</p></list-item><list-item><p>Agu, Obiekezie</p></list-item><list-item><p>Ahmed, Ahmed</p></list-item><list-item><p>Al Saoudi, Tareq</p></list-item><list-item><p>Alanbuki, Ammar</p></list-item><list-item><p>Albani, Agustin</p></list-item><list-item><p>Alder, Louise</p></list-item><list-item><p>Ali, Stephen</p></list-item><list-item><p>Al-Lami, Ali</p></list-item><list-item><p>Allan, Anna</p></list-item><list-item><p>Allison, Callum</p></list-item><list-item><p>Almidani, Ammar</p></list-item><list-item><p>Ananth, Sankar</p></list-item><list-item><p>Anantharamakrishnan, Krishnan</p></list-item><list-item><p>Anderson, Iain</p></list-item><list-item><p>Aroori, Somaiah</p></list-item><list-item><p>Aruparayil, Noel</p></list-item><list-item><p>Ashton-Key, Margaret</p></list-item><list-item><p>Asif, Aqua</p></list-item><list-item><p>Attlmayr, Bernhard</p></list-item><list-item><p>Baker, Daryll</p></list-item><list-item><p>Baldwin, Alexander</p></list-item><list-item><p>Bance, Rujuta</p></list-item><list-item><p>Barnard, James</p></list-item><list-item><p>Barnes, Nicola</p></list-item><list-item><p>Basu, Narendra</p></list-item><list-item><p>Bater, Michael</p></list-item><list-item><p>Bath, Michael</p></list-item><list-item><p>Batten, Timothy</p></list-item><list-item><p>Battersby, Nick</p></list-item><list-item><p>Becker, Giles</p></list-item><list-item><p>Bedford, James</p></list-item><list-item><p>Beral, Dan</p></list-item><list-item><p>Berry, David</p></list-item><list-item><p>Bhardwaj, Rakesh</p></list-item><list-item><p>Bhutta, Mahmood</p></list-item><list-item><p>Biyani, C. Shekhar</p></list-item><list-item><p>Biyani, Shekhar</p></list-item><list-item><p>Blackburn, Julia</p></list-item><list-item><p>Body, Sam</p></list-item><list-item><p>Bolton, William</p></list-item><list-item><p>Booker, Simon</p></list-item><list-item><p>Boorman, Patricia</p></list-item><list-item><p>Bowley, Doug</p></list-item><list-item><p>Bowrey, David</p></list-item><list-item><p>Boyce, Tamsin</p></list-item><list-item><p>Branagan, Graham</p></list-item><list-item><p>Brearley, Stephen</p></list-item><list-item><p>Brewin, James</p></list-item><list-item><p>Britton, David</p></list-item><list-item><p>Brookes, Jocelyn</p></list-item><list-item><p>Brown, Chris</p></list-item><list-item><p>Brown, Peter</p></list-item><list-item><p>Brown, Steve</p></list-item><list-item><p>Buchanan, Gordon</p></list-item><list-item><p>Burke, Joshua</p></list-item><list-item><p>Busuttil, Andrew</p></list-item><list-item><p>Carey, John</p></list-item><list-item><p>Caruana, Edward</p></list-item><list-item><p>Cawrse, Nick</p></list-item><list-item><p>Cerovac, Sonja</p></list-item><list-item><p>Chambers, David</p></list-item><list-item><p>Chan, Anthony</p></list-item><list-item><p>Chan, David</p></list-item><list-item><p>Chan, Gareth</p></list-item><list-item><p>Chan, Katie</p></list-item><list-item><p>Chandler, Susan</p></list-item><list-item><p>Cheetham, Mark</p></list-item><list-item><p>Chinai, Natasha</p></list-item><list-item><p>Clifford, Rachael</p></list-item><list-item><p>Cook, Tim</p></list-item><list-item><p>Copson, Ellen</p></list-item><list-item><p>Cripps, Neil</p></list-item><list-item><p>Cubitt, Jonathan</p></list-item><list-item><p>Daniels, Ian</p></list-item><list-item><p>Danton, Mark</p></list-item><list-item><p>Davidson, Mike</p></list-item><list-item><p>Davies, Alun</p></list-item><list-item><p>Davies, Evan</p></list-item><list-item><p>Davies, Justin</p></list-item><list-item><p>Davies, Michael</p></list-item><list-item><p>Davies, Rhodri</p></list-item><list-item><p>Davis, Owen</p></list-item><list-item><p>Davis-Husband, Cameron</p></list-item><list-item><p>Day, Andrew</p></list-item><list-item><p>Dearing, J</p></list-item><list-item><p>Desai, Mital</p></list-item><list-item><p>Dhanda, Jagtar</p></list-item><list-item><p>Dhillon, Sukhrajbir Singh</p></list-item><list-item><p>Dick, Alastair</p></list-item><list-item><p>Dickson, Edward</p></list-item><list-item><p>Dilley, Christopher</p></list-item><list-item><p>Dimitriadis, Panos</p></list-item><list-item><p>Dimock, Richard</p></list-item><list-item><p>Dimou, Leonidas</p></list-item><list-item><p>Dobbs, Thomas</p></list-item><list-item><p>Donati-Bourne, Jack</p></list-item><list-item><p>Doran, Helen</p></list-item><list-item><p>Dubois, Richard</p></list-item><list-item><p>Duff, Sarah</p></list-item><list-item><p>Dunlop, Doug</p></list-item><list-item><p>Dyson, Peter</p></list-item><list-item><p>Eddama, Mohammad</p></list-item><list-item><p>El Boghdady, Michael</p></list-item><list-item><p>El-Gawad, Ahmed</p></list-item><list-item><p>Erete, Leanna</p></list-item><list-item><p>Evans, Jonathan</p></list-item><list-item><p>Fazal, Muhammad</p></list-item><list-item><p>Fearnhead, Nicola</p></list-item><list-item><p>Fischer, Jochen</p></list-item><list-item><p>Fleming, Myles</p></list-item><list-item><p>Fleming, Simon</p></list-item><list-item><p>Fligelstone, Louis</p></list-item><list-item><p>Frampton, Adam</p></list-item><list-item><p>Gambhir, Raghvinder</p></list-item><list-item><p>Ganau, Mario</p></list-item><list-item><p>Gandhi, Ashu</p></list-item><list-item><p>Gardiner, Matthew</p></list-item><list-item><p>Gaunt, Adam</p></list-item><list-item><p>Geh, Jenny</p></list-item><list-item><p>Gillespie, Patrick</p></list-item><list-item><p>Gilmour, Adam</p></list-item><list-item><p>Goddard, Jonathan Charles</p></list-item><list-item><p>Goldstraw, Miles</p></list-item><list-item><p>Grant, Stuart</p></list-item><list-item><p>Griffiths, Ben</p></list-item><list-item><p>Griffiths, Ewen</p></list-item><list-item><p>Gruber, Elizabeth</p></list-item><list-item><p>Guhan, Bala</p></list-item><list-item><p>Guy, Richard</p></list-item><list-item><p>Habib, Helai</p></list-item><list-item><p>Hamish, Maher</p></list-item><list-item><p>Hampton, Thomas</p></list-item><list-item><p>Hance, Julian</p></list-item><list-item><p>Hardie, John</p></list-item><list-item><p>Hardman, Gillian</p></list-item><list-item><p>Hargest, Rachel</p></list-item><list-item><p>Harries, Rhiannon</p></list-item><list-item><p>Harris, Guy</p></list-item><list-item><p>Harrison, Will</p></list-item><list-item><p>Hashmi, Faisal</p></list-item><list-item><p>Hau, Melinda</p></list-item><list-item><p>Hayter, Edward</p></list-item><list-item><p>Hendrickson, Susan</p></list-item><list-item><p>Heppell, Simon</p></list-item><list-item><p>Hill, Sue</p></list-item><list-item><p>Holcombe, Chris</p></list-item><list-item><p>Hone, Rob</p></list-item><list-item><p>Hu, Jennifer</p></list-item><list-item><p>Hugues, Adrian</p></list-item><list-item><p>Hussain, Amer</p></list-item><list-item><p>Hutton, Mike</p></list-item><list-item><p>Ibrahim, Lena</p></list-item><list-item><p>Inston, Nicholas</p></list-item><list-item><p>Irvine, Tracey</p></list-item><list-item><p>Jameson, Simon S.</p></list-item><list-item><p>Jiwani, Mateen</p></list-item><list-item><p>Jones, Alistair</p></list-item><list-item><p>Jones, Ceri</p></list-item><list-item><p>Jones, Oliver</p></list-item><list-item><p>Jones, Rhys</p></list-item><list-item><p>Joshi, Heman</p></list-item><list-item><p>Jowett, Billy</p></list-item><list-item><p>Kafai Golahmadi, Aida</p></list-item><list-item><p>Kannan, Ruben</p></list-item><list-item><p>Karaguannidis, Georgios</p></list-item><list-item><p>Kaushik, Robin</p></list-item><list-item><p>Kavia, Rajesh</p></list-item><list-item><p>Kenefick, Nick</p></list-item><list-item><p>Kenyon, Olivia</p></list-item><list-item><p>Kershaw, Steven</p></list-item><list-item><p>Khan, Mansoor</p></list-item><list-item><p>Khan, Tahir</p></list-item><list-item><p>Khong, Grace</p></list-item><list-item><p>Khorsandi, Maziar</p></list-item><list-item><p>King, Ian</p></list-item><list-item><p>Kinshuck, Andrew</p></list-item><list-item><p>Kirwan, Cliona</p></list-item><list-item><p>Knight, Hannah</p></list-item><list-item><p>Kokelaar, Rory</p></list-item><list-item><p>Kolocassides, Kyriacos</p></list-item><list-item><p>Koshy, Renol</p></list-item><list-item><p>Kothari, Prasad</p></list-item><list-item><p>Kudsk-Iversen, Soren</p></list-item><list-item><p>Kulkarni, Shrirang Vasant</p></list-item><list-item><p>Kumar, Nagappan</p></list-item><list-item><p>Lamb, J. N.</p></list-item><list-item><p>Lane, Ian</p></list-item><list-item><p>Lau, Andrew</p></list-item><list-item><p>Law, Tom</p></list-item><list-item><p>Lawes, Daniel</p></list-item><list-item><p>Leach, Paul</p></list-item><list-item><p>Leeder, Paul</p></list-item><list-item><p>Leinster, Samuel</p></list-item><list-item><p>Leslie, Ian</p></list-item><list-item><p>Lim, Chung</p></list-item><list-item><p>Loftus, Ian</p></list-item><list-item><p>Logghe, Heather</p></list-item><list-item><p>Loh, Christopher</p></list-item><list-item><p>Longman, Rob</p></list-item><list-item><p>Lovett, Bryony</p></list-item><list-item><p>Low, Willy</p></list-item><list-item><p>Luvhengo, Thifhelimbilu Emmanuel</p></list-item><list-item><p>Lyons, Marie</p></list-item><list-item><p>Machaal, Ali</p></list-item><list-item><p>Macklin, Chris</p></list-item><list-item><p>Magee, Conor</p></list-item><list-item><p>Mahendran, Hans</p></list-item><list-item><p>Malhas, Amar</p></list-item><list-item><p>Malik, Cat</p></list-item><list-item><p>Mallick, Sameer</p></list-item><list-item><p>Manfield, James</p></list-item><list-item><p>Mannion, Richard</p></list-item><list-item><p>Mannu, Gurdeep</p></list-item><list-item><p>Markham, Hannah</p></list-item><list-item><p>Massey, Lisa</p></list-item><list-item><p>Masters, Andrew</p></list-item><list-item><p>Maw, Andrew</p></list-item><list-item><p>Mazari, Fayyaz</p></list-item><list-item><p>McCarthy, Rebecca</p></list-item><list-item><p>McDermott, Frank</p></list-item><list-item><p>McIrvine, Andrew</p></list-item><list-item><p>McKinnon, Chris</p></list-item><list-item><p>Mehdian, Roshana</p></list-item><list-item><p>Miller, Peggy</p></list-item><list-item><p>Mirshekar-Syahkal, Bahar</p></list-item><list-item><p>Modi, Chet</p></list-item><list-item><p>Morgan, Jenna</p></list-item><list-item><p>Mount, Chloe</p></list-item><list-item><p>Mullan, Michelle</p></list-item><list-item><p>Mutimer, Jonathan</p></list-item><list-item><p>Nada, Hany</p></list-item><list-item><p>Nagala, Sidhartha</p></list-item><list-item><p>Nakas, Apostolos</p></list-item><list-item><p>Nash, Guy</p></list-item><list-item><p>Neal, Christopher P.</p></list-item><list-item><p>Nicol, Deborah</p></list-item><list-item><p>Nizam, Ikram</p></list-item><list-item><p>Nugent, Karen</p></list-item><list-item><p>Oddy, Mike</p></list-item><list-item><p>Odili, Joy</p></list-item><list-item><p>Oeppen, Rachel</p></list-item><list-item><p>Oliver, David</p></list-item><list-item><p>O'Leary, Fionnula</p></list-item><list-item><p>Paranathala, Menaka</p></list-item><list-item><p>Parsons, Simon</p></list-item><list-item><p>Patel, Anant</p></list-item><list-item><p>Patel, Kirtikbhai</p></list-item><list-item><p>Patel, Nimesh</p></list-item><list-item><p>Patel, Pranav</p></list-item><list-item><p>Patel, Rahul</p></list-item><list-item><p>Peckham-Cooper, Adam</p></list-item><list-item><p>Perrotta, Gerardo</p></list-item><list-item><p>Phillips, Alexander</p></list-item><list-item><p>Piper, Rory</p></list-item><list-item><p>Potter, Shelley</p></list-item><list-item><p>Poullis, Mike</p></list-item><list-item><p>Powell-Chandler, Anna</p></list-item><list-item><p>Price, Stephen</p></list-item><list-item><p>Pucher, Philip</p></list-item><list-item><p>Quinlan, John</p></list-item><list-item><p>Raghu, Ashley</p></list-item><list-item><p>Ramhamadany, Eamon</p></list-item><list-item><p>Rasheed, Ashraf</p></list-item><list-item><p>Rees, Rowland</p></list-item><list-item><p>Rehman, Syed</p></list-item><list-item><p>Rew, David</p></list-item><list-item><p>Richards, Toby</p></list-item><list-item><p>Robertson, Andrew</p></list-item><list-item><p>Robson, Andrew</p></list-item><list-item><p>Rockall, Tim</p></list-item><list-item><p>Ross, Alistair</p></list-item><list-item><p>Sagar, Peter M</p></list-item><list-item><p>Sarkar, Rupa</p></list-item><list-item><p>Sarma, Diwakar ryali</p></list-item><list-item><p>Saroglu, Azize</p></list-item><list-item><p>Saunders, Rick</p></list-item><list-item><p>See, Abbas</p></list-item><list-item><p>selvakumar, S</p></list-item><list-item><p>Shaaban, Abeer</p></list-item><list-item><p>Sharma, Anita</p></list-item><list-item><p>Sharpe, Ian</p></list-item><list-item><p>Shirley, Rebecca</p></list-item><list-item><p>Simpson, Gregory</p></list-item><list-item><p>Singh, Arvind</p></list-item><list-item><p>Skerritt, Clare</p></list-item><list-item><p>Slater, Michelle</p></list-item><list-item><p>Smith, C. D.</p></list-item><list-item><p>Smith, Frank</p></list-item><list-item><p>Smith, Katherine</p></list-item><list-item><p>Soliman, Faris</p></list-item><list-item><p>Stafford, G. H.</p></list-item><list-item><p>Stefanou, Demetrios</p></list-item><list-item><p>Stephens, Michael</p></list-item><list-item><p>Stephenson, Brian</p></list-item><list-item><p>Stevenson, Andrew</p></list-item><list-item><p>Stone, Chris</p></list-item><list-item><p>Sulaiman, Lutfi</p></list-item><list-item><p>Swarnkar, Keshav</p></list-item><list-item><p>Tatla, Taran</p></list-item><list-item><p>Taylor, Gregory</p></list-item><list-item><p>Tennyson, Charlene</p></list-item><list-item><p>Thornton, Michael</p></list-item><list-item><p>Torkington, Jared</p></list-item><list-item><p>Tozer, Phil</p></list-item><list-item><p>Travers, Hannah</p></list-item><list-item><p>Trickett, Ryan</p></list-item><list-item><p>Trompeter, Alex</p></list-item><list-item><p>Upile, Navdeep</p></list-item><list-item><p>Uppal, Harpal</p></list-item><list-item><p>van Laarhoven, Stijn</p></list-item><list-item><p>Vaughan, Casey</p></list-item><list-item><p>Vimalachandran, Dale</p></list-item><list-item><p>Viswanath, YKS</p></list-item><list-item><p>Vlastarakos, Petros</p></list-item><list-item><p>Voller, Tom</p></list-item><list-item><p>Wahba, Basim</p></list-item><list-item><p>Walijee, Hussein</p></list-item><list-item><p>Warren, Oliver</p></list-item><list-item><p>Warusavitarne, Janindra</p></list-item><list-item><p>Wassif, Hoda</p></list-item><list-item><p>Welchman, Sophie</p></list-item><list-item><p>Welsh, Fenella</p></list-item><list-item><p>Wheeler, James</p></list-item><list-item><p>Wijesinghe, Lasantha</p></list-item><list-item><p>Williams, Gethin</p></list-item><list-item><p>Williams, Nigel</p></list-item><list-item><p>Williamson, James</p></list-item><list-item><p>Williamson, Jeremy</p></list-item><list-item><p>Wood, Sandy</p></list-item><list-item><p>Yardley, Iain</p></list-item><list-item><p>Zaver, Vasudev</p></list-item><list-item><p>Zilidis, George</p></list-item></list></p>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[]	{ "acronym": [], "definition": [] }	0	CC BY	no	2024-01-13 23:40:14	Ann R Coll Surg Engl. 2024 Jan 1; 106(1):99-100	oa_package/e5/11/PMC10757870.tar.gz
PMC10757871	36622245	[ "<title>Background</title>", "<p>Tumours of the appendix are rare disorders that often present clinically as the mucocele. Surgeons will be familiar with the incidental finding on computed tomography (CT) scan of the appendix mucocele, but what is less known is the pathology that underpins appendix tumours and how to correctly manage these ensure the best outcome.<sup>##REF##29920919##1##</sup> This is a case report of a 58-year-old male diagnosed with a massive appendix mucocele who underwent two-stage cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC).</p>" ]	[]	[]	[ "<title>Discussion</title>", "<p>The appendix is identical in cross-sectional histology and colonic histology; however, tumours of the appendix often have fundamental differences in terms of their molecular biology and histopathology. A combination of Peritoneal Surface Oncology Group International (PSOGI) and World Health Organization (WHO)<sup>##REF##19966601##2##</sup> terminology categorises tumours of the appendix as benign polyps (hyperplastic and serrated), benign tumours, such as appendiceal mucinous neoplasms, and pseudomyxoma peritonei (PMP) and variations in malignancy that include adenocarcinoma, goblet cell tumours and neuroendocrine tumours. This case report focuses solely on PMP, the pathology of the condition and further management.</p>", "<p>These benign lesions cause a mucocele due to deposits of mucin accumulating in the obstructed appendix. They are diagnosed histologically and show a varying type of epithelial architecture, but all exhibit a lack of infiltration consistent with their benign nature. These mucinous neoplasms are categorised into two forms based on the level of atypia in the specimen. Those showing mild cytological atypia and are classified as LAMN and those with high-grade atypia and increased mitotic figures as high-grade appendiceal neoplasms (HAMN). HAMN lesions are considered to have higher rates of malignant conversion. Around 94% have KRAS mutations and in around 40% of cases, p53 protein was overexpressed, which is associated with transformation to PMP and poor prognosis. LAMNs tend to be Microsatellite instability (MSI) stable but more studies are required to fully characterise the genetics.<sup>##REF##28746986##3##</sup></p>", "<p>PMP is a clinical descriptor and classed as ‘borderline malignant’ although is histologically benign. This condition is characterised by an accumulation of peritoneal mucus due to disseminated peritoneal mucinous neoplasia. The key step in progression from LAMN to PMP is the extravasation of mucin from the appendix into the peritoneum and this can exhibit a cellular component spreading along the peritoneum, or be acellular with mucinous ascites (LAMN 1 (pTis, pT3+) – no perforation; LAMN 2 (pT4a+) – perforated mucin into the peritoneal cavity). If no perforation occurs and the LAMN is pTis-pT3 then patients typically undergo a surveillance pathway consisting of CT scans at 6, 18 and 60 months, resulting in discharge if all normal. Patients with pT3 LAMN tumours are quoted a 2% lifetime risk of PMP development.<sup>##REF##33092969##4##</sup> Clinically, true PMP is a slowly progressing disease and PMP rarely spreads beyond the peritoneal cavity. The ‘malignant’ terminology comes from the mortality associated with intestinal obstruction due to peritoneal deposits on the small bowel, often the cause of death for most PMP patients. Review of the histological features of PMP has led to the various grading systems given in ##TAB##0##Table 1##.</p>", "<title>Cytoreductive surgery and HIPEC</title>", "<p>Cytoreductive surgery has been widely accepted as an effective method of treating peritoneal disease and is usually combined with the application of HIPEC. This involves removal of all macroscopic deposits in the form of visceral resection and peritoneal stripping. Often these are bowel resections (large and small), cholecystectomy, splenectomy, liver capsulectomy, omentectomy, bilateral salpingo-oophorectomy and peritonectomy in sites such as the hemidiaphragm. HIPEC is ineffective against nodules that are larger than 2.5mm, therefore all nodules ≥2.5mm must be resected for the treatment to be efficacious. The folds and reflections of the peritoneal cavity can harbour fluid effectively, which creates the need for opening/removing the lesser omentum and falciform ligament to ensure adequate flow of chemotherapy around the peritoneal cavity.<sup>##REF##33915487##5##</sup> The procedure is carried out by trained technicians who calculate the volumes required and set up the specialist equipment used in the administration, supervised by the overseeing surgeon. The dispensing equipment calculates the flow rate and four temperature probes placed intra-abdominally ensure that the chemotherapy is kept as close to 42°C as possible.<sup>##REF##33915487##5##</sup> The current regime of choice in the case of appendix tumours is mitomycin C.</p>" ]	[ "<title>Conclusions</title>", "<title>Key messages for managing the ‘unusual’ appendix</title>", "<p>When managing the unusual appendix in a local hospital, some key points will ensure the best outcome for these rare tumours.\n<list list-type=\"simple\"><list-item><label>1.</label><p>Early specialist centre referral is required if possible; appendix tumours are rare and should be managed long term in specialist centres that have a high case volumes.</p></list-item><list-item><label>2.</label><p>If a mucocele or suspected appendix tumour is found incidentally in the emergency department, then perform an appendectomy as normal. Avoid transecting obvious tumours and resect on the caecal pole if needed.</p></list-item><list-item><label>3.</label><p>If intra-abdominal mucin is present, either in the right iliac fossa or throughout the abdomen, sample this for histology. This will identify the appendix tumour and give an indication of the prognosis for the patient.</p></list-item><list-item><label>4.</label><p>Once the patient has recovered, they can be followed up by the specialist centre of choice because, if needed, completion right hemicolectomy is best performed in conjunction with cytoreductive surgery and HIPEC.</p></list-item></list></p>" ]	[ "<p>Tumours of the appendix are very rare tumours that can and often present with a mucocele. This is a case report highlighting the associated pathology of appendix tumours and the management of a large mucocele. Specifically, how a right hemicolectomy is very rarely needed in these cases regardless of size and local anatomical relationships and some important considerations for the practicing surgeon in the non-tertiary centre that encounters a case like this.</p>" ]	[ "<title>Case history</title>", "<p>We present a 58-year-old male with no medical history presenting with upper abdominal discomfort for 1 year. No other symptoms were reported. The patient underwent CT scanning of the abdomen and pelvis (##FIG##0##Figure 1##). The CT scan identified a massive mucocele of the appendix with mucin around the spleen. The multidisciplinary team (MDT) recommended cytoreductive surgery with or without HIPEC. Mucin was drained from the abdomen in all quadrants and the mass was found to be adherent to the spleen. The base of the appendix was normal, and the densely adherent splenic flexure was resected en-bloc (##FIG##0##Figure 1##). The patient’s peritoneal cancer index score was 30/39.</p>", "<p>A second operation to achieve complete cytoreduction was carried out following specialist MDT discussion highlighting the possible need for a two-stage procedure and confirmed owing to patient haemodynamic instability in the first procedure. Procedures included mass excision, subtotal colectomy, umbilectomy, anterolateral peritonectomies, splenectomy, cholecystectomy, greater and lesser omentectomy and ileorectal anastomosis. Histopathology showed a low-grade appendiceal neoplasm (LAMN, pT4a) arising from the appendix with acellular mucin.</p>" ]	[ "<title>Conflict of interest</title>", "<p>No competing interests declared.</p>", "<title>Funding</title>", "<p>No funding was received for this article.</p>", "<title>Ethical statement</title>", "<p>No ethical approval was required and full written consent was obtained and can be provided for all subjects involved.</p>", "<title>Author contributions</title>", "<p>All authors contributed to the concept, design and writing of the article with guarantor being Jonathan Wild.</p>" ]	[ "<fig position=\"float\" id=\"rcsann.2022.0068F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>(a,b) Computed tomography scans showing a fluid-filled left upper quadrant that displaces the stomach, whole of the small bowel, spleen and kidney (a). Multiseptated collection, representing a massive appendiceal mucocele (b) coronal section of the same CT scan highlighting displacement of the stomach, spleen small bowel and kidney. (c) Intraoperative image highlighting a normal appendix base despite massive size and pseudomyxoma peritonei indicating there is rarely any need for right hemicolectomy at the time of index surgery. (d) Resected specimen showing size and a bird’s-eye view highlighting the en-bloc colon (yellow) with the rest being mucocele.</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0068TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Comparison of the pathological classifications systems of peritoneal disease/PMP and the usual primary tumour causing each one</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">PSOGI CONSENSUS 2015</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">WHO 2020 (TNM8)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Usual primary tumour</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Acellular mucin</td><td rowspan=\"1\" colspan=\"1\">Not classified [M1a]</td><td rowspan=\"1\" colspan=\"1\">LAMN</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Low-grade mucinous carcinoma peritonei</td><td rowspan=\"1\" colspan=\"1\">MCP Grade 1 [M1b]</td><td rowspan=\"1\" colspan=\"1\">LAMN</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Intermediate-grade mucinous carcinoma peritonei</td><td rowspan=\"1\" colspan=\"1\">Not classified [M1b]</td><td rowspan=\"1\" colspan=\"1\">LAMN</td></tr><tr><td rowspan=\"4\" colspan=\"1\">High-grade mucinous carcinoma peritonei</td><td rowspan=\"4\" colspan=\"1\">MCP Grade 2 [M1b]</td><td rowspan=\"1\" colspan=\"1\">HAMN</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Non-mucinous AC</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mucinous AC</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Goblet cell AC</td></tr><tr><td rowspan=\"2\" colspan=\"1\">High-grade mucinous carcinoma peritonei with SRCs</td><td rowspan=\"2\" colspan=\"1\">MCP Grade 3 [M1b]</td><td rowspan=\"1\" colspan=\"1\">SRC AC</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Goblet cell AC</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>AC = appendix carcinoma; HAMN = high-grade appendix mucinous neoplasia; LAMN = low-grade appendix mucinous neoplasia; M1a = acellular mucin; M1b = intraperitoneal metastasis; M1c = extraperitoneal metastasis; MCP = mucinous carcinomatosis peritonei; PSOGI, Peritoneal Surface Oncology Group International; SRC = signet ring cells; WHO = World Health Organization.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"rcsann.2022.0068.01\" position=\"float\"/>" ]	[]	[]	{ "acronym": [], "definition": [] }	5	CC BY	no	2024-01-13 23:40:14	Ann R Coll Surg Engl. 2024 Jan 9; 106(1):93-95	oa_package/6d/32/PMC10757871.tar.gz
PMC10757872	36927113	[ "<title>Introduction</title>", "<p>The prevalence of ventral hernia disease is rising due to an increasingly obese and ageing population.<sup>##REF##21904861##1##,##REF##12496540##2##</sup> Over the past two decades there has been an increase in both clinical and academic activity attempting to lower postoperative hernia recurrence rates and reduce the burden of ventral hernia disease. To achieve this, abdominal wall reconstruction (AWR) is emerging as a subspecialty within general surgery, with increasing calls for specialised centres and specialised hernia surgeons.<sup>##REF##27324947##3##,##UREF##0##4##</sup> Indeed, in the UK, a group of abdominal wall surgeons under the auspices of the British Hernia Society published a ventral hernia triage algorithm in 2018 to facilitate sub-specialisation.<sup>##REF##28869388##5##</sup> More recently, a group of internationally renowned European abdominal wall surgeons published a landmark paper that outlines requirements and recommendations needed to establish an accredited abdominal wall centre.<sup>##REF##30671899##6##</sup> One of the many published criteria was for “A pre-operative multidisciplinary assessment of complex cases”, which was deemed as “<italic>mandatory</italic>”. In this publication, we outline the steps taken at Croydon University Hospital to establish an abdominal wall multidisciplinary team (MDT) meeting and report how this aids surgical decision making and improves patient care and outcomes.</p>" ]	[ "<title>Methods</title>", "<p>This is a prospective single-centre study, reporting a series of complex abdominal wall patients discussed in our abdominal wall MDT. Ethical permission for the study was obtained from our hospital’s research and development department. Data were collected from February 2020 to July 2022 inclusive. All consultants and trainees in our general surgery department were invited to attend our meetings and to refer patients for discussion. Additional specialists were invited to attend on an ad hoc basis. In accordance with current recommendations,<sup>##REF##30671899##6##–##REF##30138291##8##</sup> the meetings were consistently attended by an upper gastrointestinal (GI) surgeon (and abdominal wall lead), two lower GI surgeons, a GI radiologist and a plastic surgeon. All other members of the department were strongly encouraged to attend and submit cases for discussion. Our anaesthetists and chronic pain specialists were invited to attend if their expertise was required. A tertiary bariatrics centre was available for referral of morbidly obese patients; however, owing to delays in local weight-loss service provision, patients were encouraged to lose weight when required. In recent meetings, surgeons from several other hospitals have attended virtually and have been invited to discuss their own challenging cases as well as contribute their views towards managing our own patients.</p>", "<p>To acquire a detailed understanding, multiple datapoints were gathered for each case. All data were collected using a password-protected Excel spreadsheet (Microsoft Excel for Mac 2020, Version 16, Microsoft Corporation, Washington, US) and stored on a secure network server. Consequently, we collected each patient’s gender, age, body mass index (BMI) and smoking status. For hernia characteristics we recorded hernia type (primary, incisional, recurrent or parastomal), past surgical history, presence of a stoma or fistula, presence of a previous mesh (as well as mesh type and location) and formation of previous laparostomy. We collected the number of hernia defects and maximum width of the hernia defects. To assess morbidity, past medical history was collected with a particular focus on diabetes (latest glycated haemoglobin), cardiovascular disease and chronic obstructive pulmonary disease (COPD) because these have been shown to predispose to hernia recurrence.<sup>##UREF##2##9##</sup> Anticoagulant prescriptions were also recorded. Perioperative risk assessment was scored for each patient using the American Society of Anaesthesiologists (ASA) score,<sup>##UREF##3##10##</sup> the Portsmouth Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (P-POSSUM)<sup>##UREF##4##11##</sup> and the Carolinas Equation for Determining Associated Risks (CEDAR) score for postoperative wound events.<sup>##UREF##5##12##</sup></p>", "<p>The primary outcome of our MDT discussions was whether or not a patient was a candidate for surgical repair. If patients were recommended for an operation, we recorded whether preoperative Botulinum A toxin (Botox) was recommended, whether a component separation should be performed and if so whether an anterior component separation or a transversus abdominis release/posterior component separation was recommended. We recorded whether a mesh should be used and if so which and where it should be placed. We defined mesh location using the International Classification of Abdominal Wall Planes.<sup>##REF##31875954##13##</sup> Preoperative referral to a high-risk anaesthetic clinic, or to another specialty was documented. Where possible, anaesthetists with an interest in high-risk anaesthesia reviewed cases prior to attending the meeting. Patients considered inappropriate or unfit for surgery were reviewed in clinic and discharged with advice on conservative management. Postoperative patient outcomes were recorded prospectively, including systemic complications, local wound events, hernia recurrence, length of stay in the intensive care unit (ICU) and length of follow-up. To assess whether the AWR MDT aids surgical decision making we collected information on whether the patient had been discharged from the Croydon University Hospital general surgical department, irrespective of whether they had had an operation.</p>", "<p>Our AWR MDT meetings were held every six to eight weeks using the Microsoft Teams business communications platform (Microsoft Corporation, Washington, USA). Prior to each meeting, patients' details were populated onto our abdominal wall proforma and uploaded onto Croydon University Hospital’s electronic patient record system. Consequently, each patient’s details and clinical histories were readily available for each meeting.</p>" ]	[ "<title>Results</title>", "<title>Patient demographics and morbidity</title>", "<p>Eighteen meetings were held over a 30-month period. In total 156 patients were discussed. Demographics and patient comorbidities can be found in ##TAB##0##Table 1##. Ninety-eight (63%) patients were female and the median age of all patients was 58 years (26–86). Mean (sd) BMI was 34kg/mm<sup>2</sup> (±7.8). Twenty-five (16%) patients were current smokers, 13 (8%) were ex-smokers (who had quit tobacco use more than 1 month prior to surgery) and 118 (76%) were non-smokers. Thirty-six (23%) patients had no comorbidities, 40 (26%) had one comorbidity and 80 (51%) presented with two or more comorbidities. Previous abdominal surgery had been performed on 138 (88%) of our patients. With regards to comorbidities, 27 (17%) had diabetes, 32 (21%) had a history of cardiac disease, 19 (12%) had COPD and 24 (15%) were on anticoagulants. Preoperative risk scoring revealed a mean (sd) ASA score of 2.46 (±0.75), a mean (sd) P-POSSUM score for morbidity of 23.9% (±19.4, range 0.4% to 96%), a mean (sd) P-POSSUM for mortality of 1.7% (±3.6, range 0.01% to 28%), and a mean CEDAR score of 34.4% (±23.2, range 3% to 90%).</p>", "<title>Hernia characteristics</title>", "<p>##TAB##1##Table 2## describes the patients’ hernia characteristics. Thirty-one (20%) patients had a primary ventral hernia, 85 (54%) had an incisional hernia and 13 (8%) patients had a parastomal hernia. The remaining 27 (17%) patients presented with complex hernias: 7 (4%) had an inguinal hernia, 6 (4%) concurrent parastomal and incisional hernia, 6 (4%) concurrent divarication recti with primary umbilical hernia, 3 (2%) no hernia, 2 (1%) primary divarication recti, 1 (1%) spigelian, 1 (1%) concurrent incisional and inguinal hernia and 1 (1%) was a laparostomy healed by secondary intention. Forty-seven (30%) patients had previous mesh implants, 45 of these presented with recurrent hernia, 2 presented with chronic abdominal wall discomfort. Seven (54%) of the 13 parastomal hernias and 38 (45%) of the 85 incisional hernias were recurrent. The types of previous mesh implant are presented in ##TAB##2##Table 3##. Three (2%) patients had no hernia defect, 106 (68%) had one defect, 24 (15%) had two defects and 23 (15%) had more than two defects. Mean (sd) defect width was 7.9cm (±8.04). Twenty-one (13%) patients had a stoma present at the time of surgery and 10 (6%) had a fistula.</p>", "<title>MDT meeting outcomes</title>", "<p>Of the 156 patients discussed, 95 (61%) were recommended for surgery as detailed in ##TAB##3##Table 4##; 61 (39%) patients were advised against surgery. Seventy-eight (82%) of 95 patients were added straight to the waiting list, whereas 17 (18%) were asked to optimise modifiable risk factors prior to surgery: 3 (17%) were advised to stop smoking, 11 (65%) to lose weight and 3 (17%) to improve diabetic control. The reasons for advising against surgery were as follows: 18 (29%) patients had an excessively high risk for surgery, 15 (25%) cases were technically unfeasible, 10 (16%) patients had a tertiary referral for high-risk anaesthetic support, 8 (13%) patients had a plastic surgery referral at a different centre (prior to local involvement of a plastic surgeon at our centre), 6 (10%) were recommended to have further review in clinic and 4 (6%) were referrals to other specialities (2 [3%] pain team, 1 [2%] vascular and 1 [2%] bariatrics), see ##TAB##3##Table 4##.</p>", "<p>Of the 95 (61%) patients put forward for surgery, preoperative Botox injections were recommended for 34 (36%). The proposed procedures are described in ##TAB##3##Table 4##; 30 (31%) patients were advised to have a retrorectus mesh repair without adjuncts, 22 (23%) a retrorectus repair with either unilateral or bilateral transversus abdominis release, 8 (8%) a unilateral or bilateral anterior component separation with retrorectus mesh repair, 8 (8%) an open inguinal hernia repair, 7 (7%) an intraperitoneal onlay mesh repair and 4 (4%) a simple open hernia repair with preperitoneal mesh and abdominoplasty. A combination of endoscopic component separation, peritoneal flap repair, inter-oblique flap repair and simple suture repair were all advised for two (2%) patients, respectively. Eight (8%) patients were advised to have major complex surgery involving multiple procedures, including one (1%) laparostomy. Mesh type and location were also recommended. A summary of the MDT recommendations for mesh type and location can be found in ##TAB##4##Table 5##.</p>", "<title>Operative and nonoperative outcomes</title>", "<p>To date, 51 patients have had their operation with a mean (sd) follow-up of 358 days (±250, range 5–1,012). Twenty-four patients stayed on ICU, with a mean (SD) stay of 1.7 days (±3.5, range 1–7) and one outlier of 75 days. During the follow-up period, we recorded 16 (31%) postoperative complications and 2 (4%) mortalities. Both mortalities were due to causes unrelated to the indexed operation and occurred during the follow-up period. Six (38%) patients developed seromas (two [12%] infected), three (19%) wound infections, two (12%) hernia recurrences and one (6%) wound dehiscence. There was one (6%) case of intraoperative cardiac arrest during anaesthetic induction, one (6%) postoperative chest sepsis, one (6%) postoperative ileus and one (6%) bowel obstruction treated conservatively. Four (25%) patients required emergency wound exploration in theatre: two (12%) infected seromas, one (6%) flap necrosis and one (6%) wound dehiscence. At the time of writing, 92 (59%) of 156 patients discussed in our MDT have been discharged from Croydon University Hospital’s general surgery department. Thirty-seven (73%) postoperative patients have been discharged to primary care after hospital follow-up. Fifty-five (90%) patients considered unsuitable for surgery locally have been discharged back to primary care or referred elsewhere. These outcomes are summarised in ##TAB##5##Table 6##.</p>" ]	[ "<title>Discussion</title>", "<p>In this paper, we present our experience of managing a large series of complex abdominal wall patients discussed in our MDT. It is our belief that managing complex abdominal wall patients is increasingly challenging and a forum that allows clinicians to discuss their cases facilitates decision making, improves efficiency, optimises outcomes and reduces risk to both patients and clinicians. In our series, 92 of 156 patients were discharged from the general surgical department at Croydon University Hospital either with or without an operation. Consequently, we conclude that an MDT enables us to make the most critical decision, on whether or not to operate. Decisions can be difficult for clinicians regarding safe and appropriate care for patients requiring complex AWR and defaulting too readily to a conservative, non-interventional “watch and wait” approach without exploring definitive options may be seen. This approach has the potential to delay decision making and increase pre-existing morbidity associated with complex hernias while overburdening an already oversubscribed outpatients department. The appropriate discharge of patients to primary care if they are unsuitable for surgical intervention, following discussion in an AWR MDT, reduces unnecessary follow-up in secondary care, which will not alter their ultimate management. This, in turn, reduces cost and improves efficiency.</p>", "<p>AWR is a rapidly evolving subspecialty. Over the past 10 years, many new techniques have been published<sup>##REF##22607741##14##–##UREF##7##17##</sup> that claim to improve operative outcomes. Keeping up with the continual changes in operative technique,<sup>##REF##29502282##18##</sup> mesh composition,<sup>##REF##23592170##19##</sup> patient-reported outcomes<sup>##REF##22867715##20##</sup> and perioperative care is demanding, and an MDT forum can create educational opportunities allowing clinicians to stay up-to-date with the latest developments. This forum also promotes prospective data collection, allowing for the ongoing assessment of both patient characteristics and postoperative outcomes, which promotes learning and an improvement in the quality of care.</p>", "<p>During the past 2 years our AWR service has evolved. The AWR MDT started as a collaboration between general surgeons and gastrointestinal radiologists, but now includes a plastics surgeon (WA), a chronic pain specialist (RJ) and a high-risk anaesthetic consultant (RJ). Our preoperative Botox pathway has been established, in collaboration with our inpatient pharmacy. To date, our anaesthetic colleague (RJ) has administered preoperative Botox to 16 patients. Working with our orthotics department, we can now provide all our major AWR patients with postoperative abdominal wall binders. Although there is little current evidence that this improves operative outcomes,<sup>##REF##25201555##21##</sup> we believe this practice cannot be detrimental. To improve outcomes we have also adopted new operative reconstructive techniques such as the peritoneal flap repair,<sup>##REF##23568492##22##</sup> inter-oblique peritoneal flap repair,<sup>##REF##31813114##23##</sup> endoscopic component separation<sup>##UREF##8##24##</sup> and transversus abdominis release for parastomal hernia repairs.<sup>##REF##27023876##25##</sup> In the future, we aim to expand our research activity, improve our perioperative care pathways with pre-habilitation and weight loss programmes. Importantly, expanding into this new subspecialty requires energy from individual clinicians. Complex hernia surgery is a burgeoning and challenging subspecialty in its own right, yet widespread acceptance of it as such is yet to be seen. Consequently, it is likely that administrative and non-medical support staff, including MDT co-ordinators and specialist nurses, are not yet a common feature of many units undertaking this work. Currently, the MDT at Croydon University Hospital is almost entirely clinician led. Our hope is that administrative support will start to be provided for this emerging subspecialty within the foreseeable future.</p>", "<title>Study limitations</title>", "<p>Our current MDT programme is not without its limitations. First, our current prospective database does not collect contamination grade, regarded by some as a vital perioperative factor to affect outcomes. Going forward, we intend to incorporate both the Ventral Hernia Working Group grade and the Centre for Disease Control grade into our prospective database. Second, our programme has not developed a system whereby we can follow up our patients long term. This would enable us to understand how both our operative and nonoperative patients are progressing, and again allow us to improve the care we provide if late complications were to arise. Quality-of-life questionnaires<sup>##REF##22867715##20##,##REF##22527930##26##</sup> could also be used to further improve our understanding of how surgical repair affects our patients. We also look forward to broadening our retinue of meshes, to create bespoke management plans for our complex patients and assess their effects on longer-term outcomes. This includes a new biosynthetic mesh<sup>##UREF##9##27##</sup> and a hybrid mesh<sup>##REF##32970208##28##</sup> for clean-contaminated cases and parastomal hernia repairs, respectively. Furthermore, our regional weight-loss and bariatric surgical service is based at a nearby tertiary hospital. Ideally, we would refer obese patients for surgery with the view of repairing their hernia after their weight-loss procedure. However, our experience is that waiting times for completion of a formal weight-loss process is time consuming with the result that the hernias themselves increase overall morbidity during their time awaiting metabolic surgery. Coordinating our MDT with the weight-loss pathway and coordinating in-house follow-up for this length of time is a considerable challenge. We therefore encourage patients to lose weight themselves, which often seems unachievable. To improve our service, we need to establish an abdominal wall patient pathway with our local bariatrics unit.</p>", "<p>In conclusion, our AWR MDT has evolved over the past two years to become an integral part of the care we provide our patients. These are challenging cases that require collaboration between clinicians with discussions aimed at “trouble-shooting” and “problem-solving”. Consequently, our MDT platform prevents high-risk independent practice that could result in reckless surgery with poor postoperative outcomes. Consultants at Croydon University Hospital have found these meetings to be “helpful”, “informative”, “supportive” and “aid decision making, particularly on whether or not to operate”. For future work, we plan to improve our care by developing “the Croydon hernia bundle”. This “bundle” will provide preoperative and postoperative protocols designed to optimise patients prior to their surgery, hasten their discharge after surgery and improve long-term outcomes. These protocols will be evidence-based and we will continue to collect prospective data to see how they affect our outcomes.</p>" ]	[]	[ "<title>Introduction</title>", "<p>Abdominal wall reconstruction (AWR) is an emerging subspecialty within general surgery. The practice of multidisciplinary team (MDT) meetings to aid decision making and improve patient care has been demonstrated, with widespread acceptance. This study presents our initial experience of over 150 cases of complex hernia patients discussed in a newly established MDT setting.</p>", "<title>Methods</title>", "<p>From February 2020 to July 2022 (30-month period), abdominal wall MDTs were held bimonthly. Key stakeholders included upper and lower gastrointestinal surgeons, a gastrointestinal specialist radiologist, a plastic surgeon, a high-risk anaesthetist and two junior doctors integrated into the AWR clinical team. Meetings were held online, where patient history, past medical and surgical history, hernia characteristics and up-to-date computed tomography scans were discussed.</p>", "<title>Results</title>", "<p>Some 156 patients were discussed over 18 meetings within the above period. Ninety-five (61%) patients were recommended for surgery, and 61 (39%) patients were recommended for conservative management or referred elsewhere. Seventy-eight (82%) patients were directly waitlisted, whereas seventeen (18%) required preoperative optimisation: three (18%) for smoking cessation, eleven (65%) for weight-loss management and three (18%) for specialist diabetic assessment and management. In total, 92 (59%) patients (including operative and nonoperative management) have been discharged to primary care.</p>", "<title>Discussion</title>", "<p>A multidisciplinary forum for complex abdominal wall patients is a safe process that facilitates decision making, promotes education and improves patient care. As the AWR subspecialty evolves, our view is that the “complex hernia MDT” will become commonplace. We present our experience and share advice for others planning to establish an AWR centre.</p>" ]	[]	[]	[]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0167TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Patient demographics and comorbidities</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Patient demographic/morbidity</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">Frequency</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Female (%)</td><td rowspan=\"1\" colspan=\"1\">98 (63)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Median Age (range)</td><td rowspan=\"1\" colspan=\"1\">58 (26–86)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mean BMI (sd)</td><td rowspan=\"1\" colspan=\"1\">34 (7.8)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Smoking status (%)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Current</td><td rowspan=\"1\" colspan=\"1\">25 (16)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Ex-smoker</td><td rowspan=\"1\" colspan=\"1\">13 (8)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Non-smoker</td><td rowspan=\"1\" colspan=\"1\">118 (76)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Comorbidity (%)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> None</td><td rowspan=\"1\" colspan=\"1\">36 (23)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 1</td><td rowspan=\"1\" colspan=\"1\">40 (26)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> ≥2</td><td rowspan=\"1\" colspan=\"1\">80 (51)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Previous abdominal surgery (%)</td><td rowspan=\"1\" colspan=\"1\">138 (88)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Diabetic (%)</td><td rowspan=\"1\" colspan=\"1\">27 (17)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Cardiac disease (%)</td><td rowspan=\"1\" colspan=\"1\">32 (21)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">COPD (%)</td><td rowspan=\"1\" colspan=\"1\">19 (12)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">On anticoagulants (%)</td><td rowspan=\"1\" colspan=\"1\">24 (15)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mean ASA score (sd)</td><td rowspan=\"1\" colspan=\"1\">2.46 (0.75)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mean P-POSSUM morbidity (sd)</td><td rowspan=\"1\" colspan=\"1\">23.9 (19.4)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mean P-POSSUM mortality (sd)</td><td rowspan=\"1\" colspan=\"1\">1.7 (3.6)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mean CEDAR score (sd)</td><td rowspan=\"1\" colspan=\"1\">34.4 (23.2)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0167TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Hernia characteristics</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Characteristic</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Frequency</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Primary ventral hernia</td><td rowspan=\"1\" colspan=\"1\">31</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Incisional hernia</td><td rowspan=\"1\" colspan=\"1\">85</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Parastomal hernia</td><td rowspan=\"1\" colspan=\"1\">13</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Complex hernias</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>27</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Inguinal hernia</td><td rowspan=\"1\" colspan=\"1\">7</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Parastomal and incisional</td><td rowspan=\"1\" colspan=\"1\">6</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Divarication recti with umbilical</td><td rowspan=\"1\" colspan=\"1\">6</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Primary divarication recti</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Spigelian</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Incisional and inguinal hernia</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Laparostomy</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> No hernia</td><td rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Recurrent hernias</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>45</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Recurrent parastomal</td><td rowspan=\"1\" colspan=\"1\">7</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Recurrent incisional</td><td rowspan=\"1\" colspan=\"1\">38</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Hernia defects</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 0</td><td rowspan=\"1\" colspan=\"1\">3</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 1</td><td rowspan=\"1\" colspan=\"1\">106</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 2</td><td rowspan=\"1\" colspan=\"1\">24</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> >2</td><td rowspan=\"1\" colspan=\"1\">23</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Mean defect width in cm (sd)</td><td rowspan=\"1\" colspan=\"1\">7.9 (8.04)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Stoma present (%)</td><td rowspan=\"1\" colspan=\"1\">21 (13)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Fistula (%)</td><td rowspan=\"1\" colspan=\"1\">10 (6)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0167TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Frequency of previous implanted mesh type for recurrent hernia group</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Previous mesh type</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Frequency</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Prolene</td><td rowspan=\"1\" colspan=\"1\">26</td></tr><tr><td rowspan=\"1\" colspan=\"1\">No record</td><td rowspan=\"1\" colspan=\"1\">11</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Ventralex</td><td rowspan=\"1\" colspan=\"1\">5</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Cellis</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Ventralight</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Strattice</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Permacol</td><td rowspan=\"1\" colspan=\"1\">1</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0167TB4\"><label>Table 4<x xml:space=\"preserve\"> </x></label><caption><p>Outcomes of multidisciplinary team discussion</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Outcome (%)</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">Frequency</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">For surgery</td><td rowspan=\"1\" colspan=\"1\">95 (61)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Conservative management</td><td rowspan=\"1\" colspan=\"1\">61 (39)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>For surgery (%)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Added to waiting list</td><td rowspan=\"1\" colspan=\"1\">78 (82)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Optimise prior to surgery</td><td rowspan=\"1\" colspan=\"1\">17 (18)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Stop smoking</td><td rowspan=\"1\" colspan=\"1\">3 (17)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Weight loss</td><td rowspan=\"1\" colspan=\"1\">11 (65)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Diabetic control</td><td rowspan=\"1\" colspan=\"1\">3 (17)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Conservative management (%)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Too high risk</td><td rowspan=\"1\" colspan=\"1\">18 (29)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> No operation possible</td><td rowspan=\"1\" colspan=\"1\">15 (25)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Referred elsewhere for high-risk anaesthetic support</td><td rowspan=\"1\" colspan=\"1\">10 (16)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Referred to plastics</td><td rowspan=\"1\" colspan=\"1\">8 (13)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Review in clinic</td><td rowspan=\"1\" colspan=\"1\">6 (10)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Referred to another specialty (%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>4 (6)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Pain team</td><td rowspan=\"1\" colspan=\"1\">2 (3)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Vascular</td><td rowspan=\"1\" colspan=\"1\">1 (2)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Bariatrics</td><td rowspan=\"1\" colspan=\"1\">1 (2)</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Proposed procedures (%)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Preoperative Botulinum A</td><td rowspan=\"1\" colspan=\"1\">34 (36)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Retrorectus repair</td><td rowspan=\"1\" colspan=\"1\">30 (31)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Retrorectus repair +/− TAR</td><td rowspan=\"1\" colspan=\"1\">22 (23)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Retrorectus repair +/− ACS</td><td rowspan=\"1\" colspan=\"1\">8 (8)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Open inguinal repair</td><td rowspan=\"1\" colspan=\"1\">8 (8)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> IPOM</td><td rowspan=\"1\" colspan=\"1\">7 (7)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Hernia repair (preperitoneal mesh) and abdominoplasty</td><td rowspan=\"1\" colspan=\"1\">4 (4)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Endoscopic component separation</td><td rowspan=\"1\" colspan=\"1\">2 (2)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Peritoneal flap repair</td><td rowspan=\"1\" colspan=\"1\">2 (2)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Inter-oblique flap repair</td><td rowspan=\"1\" colspan=\"1\">2 (2)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Simple suture repair</td><td rowspan=\"1\" colspan=\"1\">2 (2)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Complex surgery/multiple procedures</td><td rowspan=\"1\" colspan=\"1\">8 (8)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0167TB5\"><label>Table 5<x xml:space=\"preserve\"> </x></label><caption><p>Proposed mesh type and location based on multidisciplinary team outcomes</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Location of mesh/Type (%)</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">Frequency</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Retrorectus prolene</td><td rowspan=\"1\" colspan=\"1\">38 (40)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Retromuscular prolene (incisional)</td><td rowspan=\"1\" colspan=\"1\">9 (10)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Retromuscular cellis (parastomal)</td><td rowspan=\"1\" colspan=\"1\">13 (14)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Intraperitoneal/IPOM</bold>\n</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\"> Cousin biotech</td><td rowspan=\"1\" colspan=\"1\">1 (1)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Ventralight</td><td rowspan=\"1\" colspan=\"1\">3 (3)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Ventralex</td><td rowspan=\"1\" colspan=\"1\">1 (1)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Inter-oblique/peritoneal flap sandwich prolene</td><td rowspan=\"1\" colspan=\"1\">4 (4)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Inguinal prolene</td><td rowspan=\"1\" colspan=\"1\">8 (8)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Intraoperative decision</td><td rowspan=\"1\" colspan=\"1\">18 (19)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0167TB6\"><label>Table 6<x xml:space=\"preserve\"> </x></label><caption><p>Operative and nonoperative patient outcomes</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Outcome</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">Frequency</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">No. of AWR procedures to date (%)</td><td rowspan=\"1\" colspan=\"1\">51 (54)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mean hospital follow-up, days (sd)</td><td rowspan=\"1\" colspan=\"1\">358 (250)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">No. patients on ICU</td><td rowspan=\"1\" colspan=\"1\">24</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mean stay of ICU, days (sd)</td><td rowspan=\"1\" colspan=\"1\">1.7 (3.5)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Complications (%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>16 (31)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Seromas</td><td rowspan=\"1\" colspan=\"1\">6 (38)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"><italic> </italic>Infected seromas</td><td rowspan=\"1\" colspan=\"1\">2 (12)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Wound infections</td><td rowspan=\"1\" colspan=\"1\">3 (19)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Hernia recurrence</td><td rowspan=\"1\" colspan=\"1\">2 (12)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Wound dehiscence</td><td rowspan=\"1\" colspan=\"1\">1 (6)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Intraoperative cardiac arrest</td><td rowspan=\"1\" colspan=\"1\">1 (6)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Chest infection</td><td rowspan=\"1\" colspan=\"1\">1 (6)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Ileus</td><td rowspan=\"1\" colspan=\"1\">1 (6)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Bowel obstruction</td><td rowspan=\"1\" colspan=\"1\">1 (6)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Wound exploration in theatre</td><td rowspan=\"1\" colspan=\"1\">4 (25)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Mortality*</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Nonoperative outcomes (%)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Discharged to primary care either postsurgery or for conservative management</td><td rowspan=\"1\" colspan=\"1\">92 (59)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Operative patients discharged</td><td rowspan=\"1\" colspan=\"1\">37 (73)</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Discharged patients for conservative management</td><td rowspan=\"1\" colspan=\"1\">55 (90)</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>ASA = American Society of Anaesthesiologists; BMI = body mass index; CEDAR = Carolinas Equation for Determining Associated Risks; COPD = chronic obstructive pulmonary disease; P-POSSUM = Portsmouth Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>ACS = anterior component separation; IPOM = intraperitoneal onlay mesh repair; TAR = transversus abdominis release</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>IPOM = intraperitoneal onlay mesh repair</p></fn><fn><p>Retromuscular: transversus abdominis release performed so mesh sits in the retrorectus and preperitoneal planes, defined as retromuscular by International Classification of Abdominal Wall Planes<sup>##REF##31875954##13##</sup></p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>AWR = abdominal wall reconstruction; ICU = intensive care unit</p></fn><fn><p>Occurred during follow-up period. Cause of death unrelated to indexed operation</p></fn></table-wrap-foot>" ]	[]	[]	[{"label": ["4."], "surname": ["K\u00f6ckerling", "Berger", "Jost"], "given-names": ["F", "D", "JO"], "article-title": ["What is a certified hernia center? The example of the German Hernia Society and German Society of General and Visceral Surgery"], "italic": ["Front Surg"], "year": ["2014"], "bold": ["1"], "fpage": ["1"], "lpage": ["4"]}, {"label": ["7."], "surname": ["Grove", "Kontovounisios", "Montgomery"], "given-names": ["TN", "C", "A"], "italic": ["et al.", "BJS Open"], "article-title": ["Perioperative optimization in complex abdominal wall hernias: Delphi consensus statement"], "year": ["2021"], "bold": ["6"], "fpage": ["zrab082"]}, {"label": ["9."], "surname": ["Parker", "Mallett", "Quinn"], "given-names": ["S", "S", "L"], "italic": ["et al.", "BJS Open"], "article-title": ["Identifying predictors of ventral hernia recurrence: systematic review and meta-analysis"], "year": ["2021"], "bold": ["5"], "fpage": ["1"], "lpage": ["9"]}, {"label": ["10."], "surname": ["Dripps"], "given-names": ["RD"], "article-title": ["New classification of physical status"], "italic": ["Anesthesiol"], "year": ["1963"], "bold": ["24"], "fpage": ["111"]}, {"label": ["11."], "surname": ["Prytherch", "Whiteley", "Higgins"], "given-names": ["DR", "MS", "B"], "italic": ["et al.", "BJS Open"], "article-title": ["POSSUM and Portsmouth POSSUM for predicting mortality"], "year": ["1998"], "bold": ["85"], "fpage": ["1217"], "lpage": ["1220"]}, {"label": ["12."], "surname": ["Heniford"], "given-names": ["BT"], "comment": ["CeDAR Mobile Application. Published by Carolinas Medical Center. Available on iTunes and Android app stores"]}, {"label": ["15."], "surname": ["G\u00f3mez-Menchero", "Guadalajara Jurado", "Su\u00e1rez Grau"], "given-names": ["J", "JF", "JM"], "italic": ["et al.", "Surg Endosc Other Interv Tech"], "article-title": ["Laparoscopic intracorporeal rectus aponeuroplasty (LIRA technique): a step forward in minimally invasive abdominal wall reconstruction for ventral hernia repair (LVHR)"], "year": ["2018"], "bold": ["32"], "fpage": ["3502"], "lpage": ["3508"]}, {"label": ["17."], "surname": ["K\u00f6hler", "Fischer", "Kaltenb\u00f6ck"], "given-names": ["G", "I", "R"], "italic": ["et al.", "J Laparoendosc Adv Surg Tech"], "article-title": ["Evolution of endoscopic anterior component separation to a precostal access with a new cylindrical balloon trocar"], "year": ["2017"], "bold": ["28"], "fpage": ["730"], "lpage": ["735"]}, {"label": ["24."], "surname": ["Jensen", "Henriksen", "Jorgensen"], "given-names": ["KK", "NA", "LN"], "article-title": ["Endoscopic component separation for ventral hernia causes fewer wound complications compared to open components separation: a systematic review and meta-analysis"], "italic": ["Surg Endosc Other Interventional Techniques"], "year": ["2014"], "bold": ["28"], "fpage": ["3046"], "lpage": ["3052"]}, {"label": ["27."], "surname": ["Scott", "Deeken", "Martindale", "Rosen"], "given-names": ["JR", "CR", "RG", "MJ"], "article-title": ["Evaluation of a fully absorbable poly-4-hydroxybutyrate/absorbable barrier composite mesh in a porcine model of ventral hernia repair"], "italic": ["Surgical Endoscopy and Other Interv Tech"], "year": ["2016"], "bold": ["30"], "fpage": ["3691"], "lpage": ["3701"]}]	{ "acronym": [], "definition": [] }	28	CC BY	no	2024-01-13 23:40:14	Ann R Coll Surg Engl. 2024 Jan 16; 106(1):29-35	oa_package/21/05/PMC10757872.tar.gz
PMC10757873	36263913	[ "<title>Introduction</title>", "<p>Flexible nasendoscopy (FNE) is the most commonly performed examination for the assessment of vocal cord movement. It is performed routinely on patients with voice complaints, and patient management is frequently based on the findings. FNE is the current gold standard for the evaluation of vocal cord motion, helping to distinguish between normal and reduced vocal cord movement. However, this subjective assessment can lead to inaccuracies and variability in diagnosis, especially in challenging cases. There is no reliable objective measure of categorising vocal cord movement from normal to complete paralysis. Furthermore, limited data exist on how consistent otolaryngologists are at rating vocal cord movement.<sup>##REF##27816357##1##,##REF##20564722##2##</sup></p>", "<p>The reliability of clinicians differentiating between binary categories of mobile and immobile vocal cords<sup>##REF##27816357##1##,##REF##20564722##2##</sup> and the presence or absence of paresis have been reported.<sup>##REF##28349567##3##</sup> Madden and Rosen<sup>##REF##27816357##1##</sup> and Roscow and Sulica<sup>##REF##20564722##2##</sup> reported 95% inter-rater reliability and 99% intra-rater agreement for binary vocal cord assessment, and Estes <italic>et al</italic><sup>##REF##28349567##3##</sup> an inter-rater reliability of 0.334 (Fleiss’s kappa). A three-category scale (paralysis, paresis, normal) has been used in reliability studies in paediatric patients.<sup>##REF##28802364##4##</sup> Liu <italic>et al</italic><sup>##REF##28802364##4##</sup> reported an inter-rater reliability (Cohen’s kappa) of 0.67 for the diagnosis of normal versus impaired movement, and a lower reliability of 0.49 when identifying the degree of movement (normal, paresis, paralysis). Intra-rater reliability ranged from 0.48 to 1 (Fleiss’s kappa). There is currently no reliable grading system for categorising vocal cord movement from normal to complete paralysis; e.g. similar to the House Brackman scale used to routinely grade facial nerve paralysis.</p>", "<p>The aim of this study was to determine whether experienced consultant head and neck surgeons were accurate and consistent in their assessment and grading of vocal cord movement.</p>" ]	[ "<title>Methods</title>", "<p>Thirty fibreoptic FNE videos of laryngeal movement were captured in a laryngology clinic. Cases ranged from normal vocal cord movement to complete laryngeal paralysis (nine normal; four palsies; three nodules; two each of cysts, functional dysphonia and inflammation; one each of Reinke’s oedema, presbyphonia, polyp, hypopharynx lesion, supraglottic lesion, crescentic defect of vocal cord, weakness and slower right vocal cord movement). The videos were pre-processed to reduce the effect of the honeycomb artefact caused by the fibreoptic endoscopes.<sup>##UREF##0##5##</sup> Six consultant head and neck surgeons (JM, RT, OH, MB, SR, KM) were asked to subjectively assess vocal cord motion by visual inspection of the laryngeal videos and to individually rate the movement of the left and right vocal cords independently on a scale of 0 to 4 (##TAB##0##Table 1##). No clinical history or sound was associated with the videos. This process was repeated with the same videos, in a different order, on three separate occasions with a minimum of two weeks between each rating session. Each consultant rated the videos three times giving a total of 180 individual ratings (2 [right and left cord] × 30 × 3 = 180) per consultant and 1,080 (180 × 6 consultants) ratings in total. The consultants were blinded to their previous scores and those of other raters. Ethical approval was not required for this study.</p>", "<title>Statistical analysis</title>", "<title>Agreement</title>", "<p>Agreement was computed using the ‘percentage agreement’ measure, which provides the percentage of cases in which two or more raters scored identically. To assess inter-rater agreement, two percentage agreement measures were computed: the overall agreement between raters for all categories combined (overall percentage agreement); and the agreement specific to a category (specific agreement). The purpose of ‘specific agreement’ is to objectively demonstrate whether clinicians are in better agreement when rating cases belonging to some categories than others (such as the fully mobile category as opposed to paresis). Intra-rater agreement (test–retest) was also computed for each consultant over the three sessions using overall percentage agreement.</p>", "<title>Reliability</title>", "<p>Inter- and intra-rater reliability were calculated using the generalised Fleiss’s kappa<sup>##REF##28802364##4##,##UREF##1##6##,##UREF##2##7##</sup> to compare with equivalent studies reported in the literature. The kappa statistic ranges from 0 to 1, where 0 depicts that raters are in agreement only by chance. Any value over 0 may be interpreted as representing: poor (<0.40), fair to good (0.40–0.75) and excellent (>0.75) agreement beyond chance. The rating scale was considered as an ordinal scale and an ordinal weighting scheme was used in the computation of Fleiss’s kappa.<sup>##REF##28802364##4##,##UREF##2##7##</sup></p>", "<p>For the intra-rater study, there were three sessions (replicates) per sample, which is appropriate<sup>##REF##11746313##8##,##UREF##3##9##</sup> because moderately high (>0.60) reliability was expected based on the trend in the literature.<sup>##REF##27816357##1##,##REF##28349567##3##,##REF##28802364##4##</sup> Because reliability was expected to be lower in the inter-rater study (as low as 0.33<sup>##REF##28349567##3##</sup>), six raters are appropriate.<sup>##REF##3629046##10##</sup></p>", "<title>Rating scales</title>", "<p>The study was conducted using a five-category scale (##TAB##0##Table 1##) to determine whether subtle differences in vocal cord motion can be visualised consistently between clinicians. It goes beyond the routine practice of describing motion as normal, paresis and paralysis, which is effectively a three-category scale. Hence a three-category scale was derived from the original five-category scale to determine the agreement/reliability using categories (normal/paresis/paralysis) that clinicians would normally use. This allows comparison between the three- and five-category scales. The re-categorisation from five to three categories was as follows: scores assigned to categories 0 and 1 were grouped together to form the ‘immobile’ category; scores assigned to categories 3 and 4 were grouped together to form the ‘fully mobile’ category; and category 2 remained effectively a ‘paresis’ category, resulting in the derived clinically relevant three-category scale. Inter- and intra-rater agreement and reliability measures were repeated using the derived scale.</p>", "<title>Ethical considerations</title>", "<p>United Kingdom research ethics committee advice was sought using the online tool from the NHS health research authority and Medical Research Council website and was not required.<sup>##UREF##4##11##</sup></p>" ]	[ "<title>Results</title>", "<p>All six consultants completed all the video assessments, giving a total of 1,080 individual vocal cord assessments. The results for the recorded five-category and derived three-category scales are reported.</p>", "<title>Agreement measures</title>", "<p>The exact agreement in scores between the consultants, averaged over the three sessions is provided in ##TAB##1##Table 2##. The overall percentage of observed inter-rater agreement, as shown in ##TAB##1##Table 2##, was consistent across sessions with a mean value of 67.7% with the five-category scale, increasing to 91.4% when the three-category scale was used.</p>", "<p>There was greater variability in the performance of the consultants in the five-category intra-rater study, with overall percentage agreement for a consultant between the three sessions ranging from 63.9% to 88.9%. Mean intra-rater agreement for the six consultants was 78.3% (sd 9.7%). With the three-category case, not only did the mean intra-rater agreement improve by 14.8% to give 93.1% agreement, but the variability in performance between consultants reduced, as shown by the threefold reduction in the standard deviation of the mean agreement measure.</p>", "<p>The specific agreement between consultants for each category, averaged over the three sessions, is provided in ##TAB##2##Table 3##.</p>", "<title>Reliability measures</title>", "<p>The consistency of discriminating vocal cord motion between the consultants (inter-rater) and between sessions for a given consultant (intra-rater) is provided in ##TAB##3##Table 4##. Kappa values were consistent across sessions and the reported inter-rater reliability is the mean reliability of all sessions. Discriminating vocal cord motion was less reliable using the five-category scale (<italic>κ </italic>= 0.52) than with the three-category scale (<italic>κ </italic>= 0.68).</p>", "<p>The intra-rater or test–retest reliability is the mean reliability of each consultant over the three sessions. With the five-category scale, intra-rater reliability ranged from 0.55 (fair) to 0.82 (excellent), with a mean of 0.69. Kappa values increased with the three-category scale and ranged from 0.64 to 0.87, with a mean of 0.75. Two of the six consultants had excellent reliability (0.78 and 0.82) with the five-category scale and three consultants had excellent reliability with the three-category scale (0.78, 0.87 and 0.87).</p>" ]	[ "<title>Discussion</title>", "<p>Correct diagnosis of a vocal cord movement abnormality is vital to help guide management of the patient, with potential medicolegal implications if misdiagnosed. There are many causes of abnormal movement, with movement ranging from fully mobile, to paresis to complete paralysis. Ideally, clinical assessment would result in a reliable five-category scale to allow use in a range of clinical situations such as reduction in movement in early invasive cancer or post thyroid surgery. Although the current gold standard for assessing the movement of a vocal cord is FNE, there are few published studies assessing consistency between different raters.</p>", "<title>Comparison between raters</title>", "<title>Agreement measures</title>", "<p>The six raters were asked to assess movement on a five-point scale, ranging from no movement to fully mobile. Inter-rater specific agreement was <60% for four of the five categories; immobile, slightly reduced movement, minimal residual mobility and paresis. The only category to have a high inter-rater specific agreement of 83.04%, was the fully mobile category. This may simply be because this is what clinicians see most commonly when performing FNE – a fully mobile vocal cord – with the high agreement being a reflection of pattern recognition. Furthermore, because the data set was formed from routine clinical cases, about 70% are of fully mobile vocal cords. Therefore, owing to the high prevalence, the positive predictive value of the clinicians for this score category would be high.<sup>##UREF##5##12##</sup> Furthermore, when assessing each individual rating in the five-point scale, the combined agreement measure in each category varied considerably, from only 16.6% for score 1 (minimal movement) to 83% for score 4 (fully mobile). This significant range in agreement highlights the difficulty in assessing vocal cord mobility. When the options are limited to three categories, there was improved inter-rater specific agreement, with fully mobile agreement at 96.11%, and no mobility at 75.11%.</p>", "<p>Analysis of specific agreement scores provides an insight into the categories for which the consultants were in greater agreement and the reason for the improvement in scores with the three-category scale. Clearly, much of the variability in scoring between clinicians is in categories 1 (minimal residual mobility), 2 (paresis) and 3 (slightly reduced mobility) in the five-category scale. The agreement in these categories for any session was <31%.</p>", "<title>Reliability measures</title>", "<p>Consistency in discriminating vocal cord motion between consultants was assessed. Discriminating vocal cord motion was less reliable using the five-category scale (<italic>κ </italic>= 0.52) compared with using the three-category scale (<italic>κ </italic>= 0.68), with both values falling in the fair to good grouping of reliability measures.<sup>##UREF##5##12##</sup> Liu <italic>et al</italic>, when assessing paediatric patients, reported a reliability of <italic>k</italic> = 0.49 for three categories.<sup>##REF##28802364##4##</sup> Assuming that nasendoscopy is more challenging in the paediatric population and that Liu <italic>et al</italic> also did not use audio, our results seem comparable. Madden and Rosen reported higher inter-rater reliability of 95%, but they used a binary scale, i.e. purposeful vocal fold motion or no purposeful vocal fold motion, and their video data included audio.<sup>##REF##27816357##1##</sup> Nevertheless, Rosow and Sulica, who also included audio and employed a binary scale, reported the reliability of identifying the presence or absence of volitional adduction as only <italic>k </italic>= 0.335.<sup>##REF##20564722##2##</sup> However, their assessment was based on stroboscopy making it difficult to draw any firm comparisons.</p>", "<title>Repeatability of assessment</title>", "<p>Consistency of re-examination affects clinical outcome and management decisions. When the five-point scale is used, it is clear that the intra-rater consistency is lower compared with the three-point score.</p>", "<p>The diagnosis of vocal cord paresis is felt to be more challenging than vocal cord paralysis.<sup>##REF##25394306##13##</sup> This is highlighted in this study with low inter-rater specific agreement for scores 1, 2 and 3 in the five-point scale, and score 1 in the three-point scale (##TAB##2##Table 3##), which demonstrates that clinicians disagree with what they are seeing when vocal cord paresis is present. Vocal cord movement is a continuum with paresis not as well recognised or studied as paralysis. Wu and Sulica highlighted that in laryngology practice in North America, the most common diagnostic tool for diagnosing paresis was stroboscopy, not FNE.<sup>##REF##25394306##13##</sup> Simpson <italic>et al</italic><sup>##REF##18329845##14##</sup> reported that in a large series of 739 patients presenting to a tertiary laryngology service with a chief complaint of dysphonia, of the 26.4% with paresis or paralysis on stroboscopy, only 1.8% of the patients had laryngeal electromyography (LEMG) confirmed vocal fold paresis. In stark comparison, Sataloff <italic>et al</italic><sup>##REF##22717495##15##</sup> demonstrated that in his series of 689 patients with suspected paresis or paralysis, that LEMG confirmed this diagnosis in 95.9% of the patients. This significant variation between diagnosis and confirmation on LEMG highlights that we are still not able to consistently differentiate between these diagnoses. Although LEMG is the only way to confirm definitively that a patient has a paralysis or paresis, it is not routinely performed in clinical practice.</p>", "<title>Limitations of the study</title>", "<p>This study aimed at assessing the consistency of clinicians evaluating movement of the vocal cord on a rating scale. Ideally, clinical assessment of voice should be multimodal and include voice recording, stroboscopic video analysis and electromyography recordings. These assessments should be used along with optical assessment in the form of FNE to ensure a full vocal assessment. ‘Worst-case scenario’ clinical situations were used, in which the clinician had no history from the patient and was unable to hear the patient’s voice when they assessed the video of vocal cord movement. Although not hearing voice quality is a limitation in the methodology of this study, this was necessary because it was the isolated subjective task of grading of vocal cord mobility without the distraction of hearing the effects of co-existent pathology that needed assessment. Because this is not representative of full clinical assessment, multimodal assessment of voice, taking account of the results of this study, should be considered in future studies. There was no extra information asked on the numerous other clinical findings that are seen in patients with vocal fold paralysis such as arytenoid prolapse, posterior gap, height and length mismatch.</p>", "<p>The wide variation in inter-rater scores for the five-point scale may be related to the fact that there was no accompanying clinical history or sound with the videos, making it an artificial situation. Madden and Rosen,<sup>##REF##27816357##1##</sup> when assessing consistency of vocal fold motion, included sound with their videos and demonstrated higher inter-rater reliability, suggesting that a ‘complete picture’ is required when assessing vocal cord movement. All the endoscopies performed were fibreoptic FNE, which rendered poorer video quality than newer generation distal chip views, possibly making the more subtle movement of the vocal cords more difficult to judge and categorise. However, the videos very much reflected the reality of seeing patients in clinics and wards.</p>" ]	[ "<title>Conclusion</title>", "<p>This study demonstrates quantitatively that it is challenging to accurately and consistently grade subtle differences in vocal cord movement, as proven by the reduced agreement and reliability when using a five-point scale instead of a three-point scale. Therefore, this study highlights the need to have an objective measure to improve the accuracy of assessment of vocal cord movement. Image processing of endoscopy videos could be employed for measurement of vocal cord movement symmetry to quantify the degree of vocal cord motion, thus providing a reliable measure to assist in diagnosis and evaluate post-treatment outcomes.</p>" ]	[ "<title>Introduction</title>", "<p>Flexible nasendoscopy (FNE) is the principal assessment method for vocal cord movement. Because the procedure is inherently subjective it may not be possible for clinicians to grade the degree of vocal cord movement reliably. The aim of this study was to assess the accuracy and consistency of grading vocal cord movement as viewed via FNE.</p>", "<title>Methods</title>", "<p>Thirty FNE videos, without sound or clinical information, were assessed by six consultant head and neck surgeons. The surgeons were asked to assess and grade right and left vocal cord movement independently, based on a five-category scale. This process was repeated three times on separate occasions. Agreement and reliability were assessed.</p>", "<title>Results</title>", "<p>Mean overall observed inter-rater agreement was 67.7% (sd 1.9) with the five-category scale, increasing to 91.4% (sd 1.9) when a three-category scale was derived. Mean overall observed intra-rater agreement was 78.3% (sd 9.7) for five categories, increasing to 93.1% (sd 3.3) for three categories. Discriminating vocal cord motion was less reliable using the five-category scale (<italic>k </italic>= 0.52) than with the three-category scale (<italic>k </italic>= 0.68).</p>", "<title>Conclusions</title>", "<p>This study demonstrates quantitatively that it is challenging to accurately and consistently grade subtle differences in vocal cord movement, as proven by the reduced agreement and reliability when using a five-point scale instead of a three-point scale. The study highlights the need for an objective measure to help in the assessment of vocal cord movement.</p>" ]	[ "<title>Conflicts of interest</title>", "<p>The authors declare no competing interests.</p>" ]	[]	[]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0091TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Rating scale used by the consultants</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Score</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Definition</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">No motion: The vocal cord is completely paralysed and shows no movement at all.</td></tr><tr><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">Almost no motion: The vocal cord is not completely paralysed, but shows only very slight movement.</td></tr><tr><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\">Half the range of motion: The vocal cord moves about half the range of motion of that of a healthy vocal cord.</td></tr><tr><td rowspan=\"1\" colspan=\"1\">3</td><td rowspan=\"1\" colspan=\"1\">Almost full motion: The vocal cord moves with almost full range of motion, but not completely.</td></tr><tr><td rowspan=\"1\" colspan=\"1\">4</td><td rowspan=\"1\" colspan=\"1\">Full range of motion: The vocal cord moves completely with full range of motion.</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0091TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Overall per cent agreement</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"2\" colspan=\"1\">Rating scale↓</th><th align=\"center\" colspan=\"2\" rowspan=\"1\">Inter-rater agreement (%)</th><th align=\"center\" colspan=\"2\" rowspan=\"1\">Intra-rater agreement (%)</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Mean</th><th rowspan=\"1\" colspan=\"1\">sd</th><th rowspan=\"1\" colspan=\"1\">Mean</th><th rowspan=\"1\" colspan=\"1\">sd</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Five categories</td><td rowspan=\"1\" colspan=\"1\">67.7</td><td rowspan=\"1\" colspan=\"1\">1.9</td><td rowspan=\"1\" colspan=\"1\">78.3</td><td rowspan=\"1\" colspan=\"1\">9.7</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Three categories</td><td rowspan=\"1\" colspan=\"1\">91.4</td><td rowspan=\"1\" colspan=\"1\">1.9</td><td rowspan=\"1\" colspan=\"1\">93.1</td><td rowspan=\"1\" colspan=\"1\">3.3</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0091TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Inter-rater specific agreement (%)</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Rating scale↓</th><th align=\"left\" colspan=\"5\" rowspan=\"1\">Inter-rater agreement (±sd)</th></tr></thead><tbody><tr><td rowspan=\"2\" colspan=\"1\">Five categories</td><td rowspan=\"1\" colspan=\"1\">Immobile</td><td rowspan=\"1\" colspan=\"1\">Minimum residual mobility</td><td rowspan=\"1\" colspan=\"1\">Paresis</td><td rowspan=\"1\" colspan=\"1\">Slightly reduced mobility</td><td rowspan=\"1\" colspan=\"1\">Fully mobile</td></tr><tr><td rowspan=\"1\" colspan=\"1\">58.6 (8.4)</td><td rowspan=\"1\" colspan=\"1\">16.7 (10.1)</td><td rowspan=\"1\" colspan=\"1\">23.9 (5.9)</td><td rowspan=\"1\" colspan=\"1\">22.8 (7.1)</td><td rowspan=\"1\" colspan=\"1\">83.1 (1.5)</td></tr><tr><td rowspan=\"2\" colspan=\"1\">Three categories</td><td colspan=\"2\" rowspan=\"1\">Immobile</td><td rowspan=\"1\" colspan=\"1\">Paresis</td><td colspan=\"2\" rowspan=\"1\">Fully mobile</td></tr><tr><td colspan=\"2\" rowspan=\"1\">75.1 (4.3)</td><td rowspan=\"1\" colspan=\"1\">23.9 (5.9)</td><td colspan=\"2\" rowspan=\"1\">96.1 (0.9)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0091TB4\"><label>Table 4<x xml:space=\"preserve\"> </x></label><caption><p>Reliability measures</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Rating scale↓</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">Inter-rater reliability: Fleiss’s kappa (±sd)</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">Intra-rater reliability: Fleiss’s kappa (±sd)</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Five categories</td><td rowspan=\"1\" colspan=\"1\">0.52 (0.03)</td><td rowspan=\"1\" colspan=\"1\">0.69 (0.11)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Three categories</td><td rowspan=\"1\" colspan=\"1\">0.68 (0.06)</td><td rowspan=\"1\" colspan=\"1\">0.75 (0.1)</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>Mean inter-rater agreement is the agreement between consultants in a given session, averaged over the three sessions. Mean intra-rater agreement is the agreement in the scores of a consultant between the three sessions, averaged over all consultants</p></fn><fn><p>sd = standard deviation above or below the mean</p></fn></table-wrap-foot>" ]	[]	[]	[{"label": ["5."], "surname": ["Menon R", "Soraghan", "Lakany"], "given-names": ["PL", "JJ", "H"], "italic": ["et al.", ".", "Presented at the 10th International Joint Conference on Biomedical Engineering Systems and Technologies"], "comment": ["Automatic quantification of vocal cord paralysis: An application of fibre-optic endoscopy video processing"], "year": ["2017"]}, {"label": ["6."], "surname": ["Girard"], "given-names": ["JM"], "italic": ["Master Inter-Observer Reliability"], "ext-link": ["http://mreliability.jmgirard.com"]}, {"label": ["7."], "surname": ["Gwent", "Gaithersburg"], "given-names": ["KL", "M."], "article-title": ["Handbook of inter-rater reliability: The definitive guide to measuring the extent of agreement among raters"], "italic": ["Advanced Analytics"], "edition": ["4th edn."], "publisher-loc": ["Gaithersburg, MD"], "publisher-name": ["Advanced Analytics, LLC"], "year": ["2014"]}, {"label": ["9."], "surname": ["Shoukri", "Asyali", "Donner"], "given-names": ["MM", "MH", "A"], "article-title": ["Sample size requirements for the design of reliability study: review and results"], "italic": ["Stat Methods Med Res"], "year": ["2004"], "bold": ["13"], "fpage": ["251"], "lpage": ["271"]}, {"label": ["11."], "collab": ["HRA"], "italic": ["HRA Decision Tool"], "ext-link": ["http://www.hra-decisiontools.org.uk/research"]}, {"label": ["12."], "surname": ["Fleiss"], "given-names": ["JL"], "article-title": ["Measuring nominal scale agreement among many raters"], "italic": ["Psychol Bull"], "year": ["1971"], "bold": ["76"], "fpage": ["378"], "lpage": ["382"]}]	{ "acronym": [], "definition": [] }	15	CC BY	no	2024-01-13 23:40:14	Ann R Coll Surg Engl. 2024 Jan 20; 106(1):36-40	oa_package/83/d1/PMC10757873.tar.gz
PMC10757874	36448937	[ "<title>Introduction</title>", "<p>Carpal tunnel syndrome (CTS) is one of the commonest compressive neuropathies, with a UK prevalence ranging from 7% to 16%.<sup>##REF##16421136##1##, ####REF##25378457##2##, ##UREF##0##3##, ##REF##30798784##4##, ##REF##17244422##5####17244422##5##</sup> Nerve conduction studies (NCS) can be used to obtain an electrophysiological diagnosis of the site of compression, e.g. when there is clinical doubt, alongside enabling stratification of severity of the nerve compression.<sup>##REF##25378457##2##,##REF##30039031##6##,##REF##17703044##7##</sup> Although NCS have been shown to have both high sensitivity and specificity, negative NCS findings do not necessary exclude potential CTS.<sup>##REF##8232399##8##</sup></p>", "<p>The precise role of NCS in diagnosing CTS remains debatable. The American Academy of Orthopaedic Surgeons (AAOS) 2016 guideline concludes limited evidence in the use of hand-held NCS in diagnosing CTS.<sup>##UREF##1##9##</sup> In the UK, regional clinical commissioning group (CCG) guidelines vary widely, with some regions requiring a positive NCS before the offer of carpal tunnel decompression (CTD), whereas others do not.<sup>##UREF##2##10##</sup> The National Institute for Health and Care Excellence (NICE) advocates that NCS are not necessary if typical symptoms are present, but should be considered if there is diagnostic uncertainty or if referral for surgical management is being undertaken.<sup>##UREF##3##11##</sup> Similarly, the British Orthopaedic Association (BOA) commissioning guide does not recommend NCS in primary care, but states that NCS should be used in secondary care where there is either diagnostic uncertainty, or in cases of persistent/recurrent CTS.<sup>##UREF##1##9##</sup></p>", "<p>The aim of this study was to assess secondary care practises in the initial diagnosis of new patients with suspected CTS, particularly with regard to the use of electrophysiology, and where this investigation fits into the overall assessment algorithm alongside other available tools such as history, examination findings and other modalities.</p>" ]	[ "<title>Methods</title>", "<p>A multicentre survey study was conducted across UK secondary care centres between February and April 2021. All collaborators were invited via a trainee-led collaborative research network, with surveys circulated via trainee networks and social media.</p>", "<title>Survey</title>", "<p>A survey was developed to assess current practices in the diagnosis and management of CTS. The objectives were to determine standard practise in managing new CTS referrals from primary care services, focusing on electrophysiology but also including the use of validated clinical questionnaires and imaging in diagnosis and severity stratification. To provide clinical context, four clinical were developed to investigate preferred management priority between non-operative measures (observation, splinting), steroid injection or CTD.\n<list list-type=\"simple\"><list-item><label>•</label><p>Scenario 1 (clinically and NCS positive): clear clinical features, persistent motor/sensory loss, confirmatory positive electrophysiology.</p></list-item><list-item><label>•</label><p>Scenario 2 (partially clinically and NCS positive): clear clinical features, no motor/sensory loss, confirmatory positive electrophysiology.</p></list-item><list-item><label>•</label><p>Scenario 3 (only clinically positive): clear clinical features, negative/unsupportive electrophysiology.</p></list-item><list-item><label>•</label><p>Scenario 4 (only NCS positive): unclear/intermittent/mild clinical features, positive electrophysiology (confirming median nerve compression).</p></list-item></list>The scenario questions were piloted with the first cohort of respondents to ensure reliability with the Cronbach alpha test. In total, the survey consisted of 14 questions, with mixed multiple choices and free text to allow adequate meaningful information collection without overburdening respondents (Appendix 1).</p>", "<title>Survey distribution</title>", "<p>Collaborators were recruited in different hospital sites to coordinate the local distribution of survey across clinical teams using either standardised paper or electronic forms. All secondary care healthcare professionals that review new referrals for suspected CTS were invited to participate, including senior orthopaedic and plastic surgeons (consultants, middle grade or specialty registrars) and advanced care practitioners (ACPs, including extended scope therapists and specialist nurse practitioners). Responses were collated centrally and anonymised. Respondents consented to the use of their responses for publication.</p>", "<title>Statistical analysis</title>", "<p>Results were analysed using IMB Statistical Product and Service Solutions (SPSS) Version 26 to produce baseline characteristics of demographic variables. Categorical variables were expressed as proportions or percentages. Free-text responses were classified under similar groups. No direct comparisons were made between regions. A chi-squared analysis, with a significance level of 0.05, was used to review the influence of clinical experience on the management of new CTS cases. The Cronbach alpha test was also performed to assess the reliability of the scenario questions.</p>" ]	[ "<title>Results</title>", "<title>Demographics</title>", "<p>In total, 137 survey responses were received (breakdown by Hospital Deaneries in Appendix 2). Of these 137, 72 (53%) were from teaching hospitals and 65 (47%) from district general hospitals; 107 (78%) respondents were from an orthopaedic background. The breakdown of responses according to clinical role is listed in ##TAB##0##Table 1##.</p>", "<title>Use of clinical questionnaires</title>", "<p>Validated questionnaires, including Kamath and Stothard, I-HaND Scale Version 2, Dash/Quick-Dash, Patient Evaluation Measure (PEM), EQ5D, Visual Analogue Scale (VAS), Michigan Hand Questionnaire and the Boston Questionnaire were used by only a minority of respondents (##FIG##0##Figure 1##). Of the cohort that routinely used questionnaires, four (31%) felt the findings might guide their management in the majority (>50%) of cases, whereas nine (69%) felt it was of less frequent benefit (two did not respond). Of the cohort that did not routinely use questionnaires, 67/122 (55%) felt a diagnosis should be made clinically, 22/122 (18%) preferred to rely on other modalities (mostly NCS) and the remainder cited other reasons, including lack of experience/incorporation into local practice/clear rationale, with some suggesting that screening questionnaires should ideally be performed by primary care teams before referral.</p>", "<title>Use of NCS</title>", "<p>Most respondents routinely utilised NCS in their practice to guide the diagnosis and management of newly suspected primary CTS (##FIG##1##Figure 2##). A total of 11 (8%) reported that their local referrals were always made with NCS already performed/requested, 88 (64%) reported this was sometimes the case, and 38 (28%) stated this was never the case. The rationale of clinicians that utilised NCS selectively or rarely is summarised in ##TAB##1##Table 2##.</p>", "<title>Severity stratification and case scenarios</title>", "<p>The importance of a basic history and examination in were emphasised in the approaches to stratifying CTS severity, summarised in ##TAB##2##Table 3##. The scenarios questions were piloted on the first 15 respondents (equal mix of clinical roles), with the Cronbach alpha reliability test concluding an acceptable reliability of 0.7. Findings are summarised in ##FIG##2##Figure 3## and ##TAB##3##Table 4##.</p>", "<title>Alternative investigations</title>", "<p>Of the 137 respondents, 81 (59%) utilise a diagnostic steroid injection when the diagnosis is unclear or atypical, for therapeutic management in selected cases or for prognostication, and 48 (35%) utilise imaging (USS or MRI) in either selected unclear cases, or when alternative or coexisting diagnosis are suspected (e.g. cervical radiculopathy, secondary causes of CTS such as tumour or following trauma).</p>" ]	[ "<title>Discussion</title>", "<p>This multicentre study highlights the wide variation in UK practice in the diagnosis and management of primary CTS.</p>", "<p>There remains uncertainty regarding the value of electrophysiology in guiding decision making in new cases of suspected primary CTS, consistent with the findings of other authors.<sup>##UREF##2##10##</sup> Although most (97%) respondents use NCS, rationale differed, although diagnostic uncertainty remained the primary reason (62%). Junior clinicians were more likely to use NCS, perhaps due to a lack of clinical experience resulting in a greater need for supportive diagnostic confirmation. In contrast, hand surgeons were more likely to use NCS selectively, placing greater emphasis on clinical history and examination for clinically straightforward cases.</p>", "<p>Questionnaires have been demonstrated to be valid and reliable tools for measuring functional deficits secondary to CTS (carpal tunnel questionnaire, CTQ), alongside having high (90%) positive predictive value—comparable with NCS (92%)—for predicting symptomatic improvement (Kamath and Stothard), albeit not diagnosis.<sup>##REF##32151499##12##,##REF##12954256##13##</sup> However, most respondents did not routinely use a questionnaire, with those that did suggesting it rarely changed their management.</p>", "<p>When faced with a clear clinical presentation and positive (supportive) NCS (alongside non-operative measures being exhausted before referral), most clinicians would opt for CTD as their first-line management. When the clinical presentation is inconsistent with NCS findings, most clinicians opt for more conservative management, with either a trial of splinting or steroid injection. It is important to note that patients with a clear clinical picture of CTS but negative electrophysiology still benefit from CTD, hence the absence of supportive NCS should not preclude CTD.<sup>##REF##31433719##14##</sup> Gunnarsson <italic>et al</italic> suggested that an adequate clinical examination has equivalent sensitivity and specificity (94% and 80%, respectively) to neurophysiological examination (85% and 87%, respectively).<sup>##UREF##4##15##</sup> Other available literature also advocates that provocative clinical tests have sufficient sensitivities and specificities, implying that NCS are unnecessary for straightforward cases and should be reserved for cases with diagnostic uncertainty, particularly given growing resource constraints.<sup>##REF##16079681##16##,##REF##12171229##17##</sup></p>", "<p>Although only 59% of our respondents reported using a steroid injection in the diagnosis of clinically uncertain CTS, as a low-cost combined diagnostic and therapeutic option, this could initially be utilised more frequently in place of NCS—particularly given the evidence that patients experiencing symptomatic relief of >3 months have better outcomes following subsequent CTD.<sup>##REF##26405432##18##,##REF##12671857##19##</sup> However, it is important to note that, in a direct comparison, CTD was shown to produce better outcomes than steroid injection alone in idiopathic CTS.<sup>##REF##15985575##20##</sup></p>", "<p>This study had several limitations. With most respondents being either non-consultant grade or non-specialist (hand surgeon), and with a limited dataset from only a proportion of England-based NHS Trusts, our data will not necessarily represent the breadth and gold standard of UK specialist practice. However, our results are therefore likely representative of ‘real-world’ differences in practice, with junior clinicians mirroring their supervising consultants, alongside their decision-making being influenced by a broader range of senior clinicians they have trained with across a larger number of rotational regional units. We also did not survey primary care clinicians, who increasingly manage CTS in community settings and who may adopt non-operative measures more frequently than their secondary care colleagues given the greater numbers of new presentations they encounter; this should form the basis of a future study, given the growing numbers managed in this setting.</p>" ]	[ "<title>Conclusion</title>", "<p>In summary, there is wide variation in diagnostic approaches to new cases of suspected CTS. Clear national evidence-based guidelines, influenced by the experience of relevant societies (including the British Society for Surgery of the Hand and BOA), are required to standardise management across the UK to improve patient care and optimise the use of increasingly constrained resources.</p>" ]	[ "<p>Collaborative authors: L Li, W Matthews (Cambridge University Hospital NHS Foundation Trust, UK), N Bua (Barnet General Hospital, UK), T Clark (Barnsley Hospital NHS Foundation Trust, UK), S Nisar (Bradford Teaching Hospital NHS Trust, UK), U Birole, B VijayKumar (Ealing Hospital, UK), R Wood, ML Popescu (Esneft-Ipswich Hospital, UK), R Dimock, Z Ali (Frimley Health NHS Foundation Trust, UK), S Sambhwani, A See (Kettering General Hospital, UK), D Patel (Leighton Hospital, Crewe, UK), A Griffiths, A Hilling (North Cumbria Hospitals NHS Trust, UK), A See (Northampton General Hospital, UK), F Arnaout, G Tamvakopoulos (Practice Plus Group Hospital - Shepton Mallet, UK), TA Edwards, J Taylor (Southmead Hospital, Bristol, UK), K Studnicka, L Thornton (Warrington and Halton Teaching Hospital, UK), R Cuthbert (Whittington Health NHS Trust, UK), N Picardo, P Tan (University Hospitals Birmingham NHS Foundation Trust, UK), L Athanatos, M Baguley (University Hospital of Leicester NHS Trust, UK), A Daoub, CT Ong, T Chester (Wye Valley NHS Trust, UK).</p>", "<title>Introduction</title>", "<p>The optimal role of nerve conduction studies (NCS) in management of carpal tunnel syndrome (CTS) is unclear, with no standardised guidance. This study aimed to identify variation in practice in the initial diagnosis of patients with suspected CTS, alongside evaluating how NCS findings influence clinical decision making.</p>", "<title>Methods</title>", "<p>A national multicentre collaborative survey was conducted in 2021. All centres providing surgery for CTS were invited to participate, primarily via social media. All middle–senior grade orthopaedic/plastic surgeons and advanced care practitioners that regularly manage new referrals for suspected CTS were eligible to respond. Local representatives at each participating site submitted their responses to a central team who collated and analysed the results.</p>", "<title>Results</title>", "<p>A total of 137 healthcare professionals responded from 18 UK NHS Trusts. Of these 137, 124 (91%) reported not employing any validated clinical questionnaires in their routine practice, preferring to rely on clinical diagnosis and/or NCS if available, whereas 84 (61%) utilised NCS to aid diagnosis, with significant differences among professionals with differing experience (<italic>p</italic> < 0.01). The most common methods for determining the severity of CTS were history, examination and NCS. In symptomatic CTS with confirmatory NCS, over 50% of clinicians would choose surgical decompression as their first-line intervention. In cases of either negative NCS or atypical presentation, 37% and 51%, respectively, would consider conservative management (e.g. splintage) or steroid injection first line.</p>", "<title>Conclusions</title>", "<p>With growing waiting lists for NCS and surgery, national consensus guidelines should be developed to support decision making, while maximising efficient utilisation of increasingly constrained resources.</p>" ]	[]	[]	[ "<fig position=\"float\" id=\"rcsann.2022.0087F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>Use of clinical questionnaires in the diagnosis of CTS. Most (89%) do not use validated clinical questionnaires. Only 11% routinely used clinical questionnaires and, of these, the frequency of use varied from <10% to >90% cases.</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2022.0087F2\" fig-type=\"figure\"><label>Figure 2<x xml:space=\"preserve\"> </x></label><caption><p>Use of NCS in the diagnosis of CTS. Most do use NCS for newly suspected CTS, but frequency of ordering CTS varies. Of those who routinely used NCS, 48 requested the study after clinic whereas 9 requested before first clinic. Chi-squared analysis found that specialty registrars and middle grade doctors were more likely to use NCS routinely, whereas hand surgeons (both plastics and orthopaedics) used NCS more selectively (<italic>p</italic> < 0.01).</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2022.0087F3\" fig-type=\"figure\"><label>Figure 3<x xml:space=\"preserve\"> </x></label><caption><p>Preferred management in four hypothetical clinical scenarios</p><p>In both scenarios 1 and 2 (clinically and NCS positive for primary CTS), most would advocate CTD first line. In scenarios 3 and 4 (clinical findings and NCS findings inconsistent), most propose more conservative initial management. No statistical correlation between clinical role/grade and management option of each scenario.</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0087TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Clinical role of respondents</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Clinical role</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Responses (<italic>n</italic>)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Percentage (%)</th></tr></thead><tbody><tr><td colspan=\"3\" rowspan=\"1\">Orthopaedic surgery</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Consultant (hand specialist)</td><td rowspan=\"1\" colspan=\"1\">36</td><td rowspan=\"1\" colspan=\"1\">26</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Consultant (non-hand specialist)</td><td rowspan=\"1\" colspan=\"1\">16</td><td rowspan=\"1\" colspan=\"1\">12</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Specialty registrar/middle grade</td><td rowspan=\"1\" colspan=\"1\">55</td><td rowspan=\"1\" colspan=\"1\">40</td></tr><tr><td colspan=\"3\" rowspan=\"1\">Plastic surgery</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Consultant (hand specialist)</td><td rowspan=\"1\" colspan=\"1\">11</td><td rowspan=\"1\" colspan=\"1\">8</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Consultant (non-hand specialist)</td><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Specialty registrar/middle grade</td><td rowspan=\"1\" colspan=\"1\">7</td><td rowspan=\"1\" colspan=\"1\">5</td></tr><tr><td colspan=\"3\" rowspan=\"1\">Advanced care practitioners</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Physio and occupational therapists</td><td rowspan=\"1\" colspan=\"1\">6</td><td rowspan=\"1\" colspan=\"1\">4</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Advanced nurse practitioners</td><td rowspan=\"1\" colspan=\"1\">4</td><td rowspan=\"1\" colspan=\"1\">3</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0087TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Rationale of selective or rare utilisation of NCS in newly suspected CTS</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Responses</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<italic>n</italic>\n</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Diagnostic uncertainty/atypical clinical presentation</td><td rowspan=\"1\" colspan=\"1\">55</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Severe Disease</td><td rowspan=\"1\" colspan=\"1\">14</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Diabetic/potential other neuropathy /possible secondary cause</td><td rowspan=\"1\" colspan=\"1\">15</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Medicolegal purposes</td><td rowspan=\"1\" colspan=\"1\">5</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0087TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Factors considered in severity stratification of newly diagnosed CTS</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Factor</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<italic>n</italic>\n</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">History</td><td rowspan=\"1\" colspan=\"1\">132</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Examination</td><td rowspan=\"1\" colspan=\"1\">133</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Questionnaire</td><td rowspan=\"1\" colspan=\"1\">5</td></tr><tr><td rowspan=\"1\" colspan=\"1\">NCS</td><td rowspan=\"1\" colspan=\"1\">115</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Imaging</td><td rowspan=\"1\" colspan=\"1\">7</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Others (e.g. quality of life, age)</td><td rowspan=\"1\" colspan=\"1\">4</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0087TB4\"><label>Table 4<x xml:space=\"preserve\"> </x></label><caption><p>Clinical scenarios: preferred management</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><tbody><tr><td colspan=\"5\" rowspan=\"1\">Scenario 1 (clinical and NCS positive): clear clinical features, persistent motor/sensory loss and confirmatory positive electrophysiology</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Management</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Conservative (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Steroid injection (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Surgery (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Other (<italic>n</italic>)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">1st choice</td><td rowspan=\"1\" colspan=\"1\">4</td><td rowspan=\"1\" colspan=\"1\">9</td><td rowspan=\"1\" colspan=\"1\">120</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">2nd choice</td><td rowspan=\"1\" colspan=\"1\">7</td><td rowspan=\"1\" colspan=\"1\">23</td><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td rowspan=\"1\" colspan=\"1\">3rd choice</td><td rowspan=\"1\" colspan=\"1\">11</td><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\">4</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td colspan=\"5\" rowspan=\"1\">Scenario 2 (partial clinical and NCS positive): clear clinical features, no motor/sensory loss and confirmatory positive electrophysiology</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Management</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Conservative (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Steroid injection (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Surgery (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Other (<italic>n</italic>)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">1st choice</td><td rowspan=\"1\" colspan=\"1\">22</td><td rowspan=\"1\" colspan=\"1\">38</td><td rowspan=\"1\" colspan=\"1\">71</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">2nd choice</td><td rowspan=\"1\" colspan=\"1\">11</td><td rowspan=\"1\" colspan=\"1\">22</td><td rowspan=\"1\" colspan=\"1\">21</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td rowspan=\"1\" colspan=\"1\">3rd choice</td><td rowspan=\"1\" colspan=\"1\">14</td><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">8</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td colspan=\"5\" rowspan=\"1\">Scenario 3 (only clinically positive): clear clinical features, but negative/ unsupportive/ lack of electrophysiology</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Management</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Conservative (n)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Steroid injection (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Surgery (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Other (<italic>n</italic>)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">1st choice</td><td rowspan=\"1\" colspan=\"1\">37</td><td rowspan=\"1\" colspan=\"1\">70</td><td rowspan=\"1\" colspan=\"1\">25</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">2nd choice</td><td rowspan=\"1\" colspan=\"1\">20</td><td rowspan=\"1\" colspan=\"1\">21</td><td rowspan=\"1\" colspan=\"1\">17</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td rowspan=\"1\" colspan=\"1\">3rd choice</td><td rowspan=\"1\" colspan=\"1\">7</td><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">20</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td colspan=\"5\" rowspan=\"1\">Scenario 4 (only NCS positive): unclear/intermittent/mild clinical features, but positive electrophysiology confirming median nerve compression</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Management</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Conservative (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Steroid injection (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Surgery (<italic>n</italic>)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Other (<italic>n</italic>)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">1st choice</td><td rowspan=\"1\" colspan=\"1\">57</td><td rowspan=\"1\" colspan=\"1\">51</td><td rowspan=\"1\" colspan=\"1\">18</td><td rowspan=\"1\" colspan=\"1\">6</td></tr><tr><td rowspan=\"1\" colspan=\"1\">2nd choice</td><td rowspan=\"1\" colspan=\"1\">13</td><td rowspan=\"1\" colspan=\"1\">23</td><td rowspan=\"1\" colspan=\"1\">15</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td rowspan=\"1\" colspan=\"1\">3rd choice</td><td rowspan=\"1\" colspan=\"1\">6</td><td rowspan=\"1\" colspan=\"1\">3</td><td rowspan=\"1\" colspan=\"1\">21</td><td rowspan=\"1\" colspan=\"1\">0</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><p>CTS = carpal tunnel syndrome; NCS = nerve conduction studies</p></table-wrap-foot>", "<table-wrap-foot><p>CTS = carpal tunnel syndrome; NCS = nerve conduction studies</p></table-wrap-foot>", "<table-wrap-foot><p>NCS = nerve conduction studies</p></table-wrap-foot>" ]	[ "<graphic xlink:href=\"rcsann.2022.0087.01\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2022.0087.02\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2022.0087.03\" position=\"float\"/>" ]	[]	[{"label": ["3."], "collab": ["British Orthopaedic Association"], "source": ["Commissioning guide: treatment of carpal tunnel syndrome"], "ext-link": ["https://www.boa.ac.uk/resources/carpal-tunnel-syndrome-guide-final--pdf.html"]}, {"label": ["9."], "collab": ["American Academy of Orthopaedic Surgeons (AAOS)"], "source": ["Management of carpal tunnel syndrome evidence-based clinical practice guideline"], "comment": ["Published online 2016.", "(cited December 2023)"], "ext-link": ["https://www.orthoguidelines.org/"]}, {"label": ["10."], "surname": ["Ryan", "Shaw", "Graham"], "given-names": ["D", "A", "S"], "italic": ["et al.", "Bulletin"], "article-title": ["Variation in CCG policies for the treatment of carpal tunnel syndrome"], "year": ["2017"], "bold": ["99"], "fpage": ["28"], "lpage": ["31"]}, {"label": ["11."], "comment": ["Assessment \| Diagnosis \| Carpal tunnel syndrome \| CKS \| NICE.", "(cited December 2023)"], "ext-link": ["https://cks.nice.org.uk/topics/carpal-tunnel-syndrome/diagnosis/assessment/"]}, {"label": ["15."], "surname": ["Gunnarsson", "Amilon", "Hellstrand"], "given-names": ["LG", "A", "P"], "italic": ["et al.", "J Hand Surg"], "article-title": ["The diagnosis of carpal tunnel syndrome: sensitivity and specificity of some clinical and electrophysiological tests"], "year": ["1997"], "bold": ["22"], "fpage": ["34"], "lpage": ["37"]}]	{ "acronym": [], "definition": [] }	20	CC BY	no	2024-01-13 23:40:14	Ann R Coll Surg Engl. 2024 Jan 30; 106(1):64-69	oa_package/28/c6/PMC10757874.tar.gz
PMC10757875	38160715	[]	[]	[]	[]	[]	[]	[ "<p>With the conclusion of 2023, the surgical profession continues to address numerous challenges, including inefficiencies of service, training difficulties, carbon footprint, the role of artificial intelligence and clinician burnout. All these issues are complex, multi-faceted, and evolving with no simple solutions, and they demand ongoing research and analysis. I am glad that the <italic>Annals</italic> now attracts a growing caseload of research on these ‘non-clinical’ topics that contributes to the body of evidence.</p>", "<p>Some may argue that ‘non-clinical’ topics such as those outlined above carry less academic weight or importance. As Editor-in-Chief<italic>,</italic> I disagree and consider such topics of equal value as pure clinical papers. Furthermore, as a pan-surgical journal, the <italic>Annals</italic> affords the optimal vehicle to publish and promote topics that more specialised journals would have difficulty accepting within their terms of reference. This is a significant strength of our journal, and we will continue to encourage authors to submit work on these topics in addition to traditional clinical research.</p>", "<p>Notwithstanding the above, and while the breadth of topics considered by our journal has increased since 1947, the rigour of peer review continues, and the methodological strength of any submitted research needs to be optimal. The journal welcomes well-planned projects with clearly stated aims and power analysis to afford statistical clarity. Opportunistic, retrospective post-hoc studies are rarely of a standard or value the wider readership expects and gains from.</p>", "<p>This ‘wider readership’ will likely become even wider, as this January 2024 edition marks the first fully gold open access issue for the <italic>Annals</italic> – providing immediate free access at first publication. This is a significant evolution for the journal that I am pleased to highlight. Open access facilitates faster and broader dissemination of research through a variety of digital media. The <italic>Annals</italic> will continue to publish high-quality surgical research that is relevant to the wider surgical profession and incorporates a wide breadth of topics. Specifics about our open access policy are available on the journal website.<sup>##UREF##0##1##</sup></p>", "<p>It is wholly unjust for me to accept any credit for the transition to open access, a process that has taken a year to complete. As with any significant change, the process has incorporated proposals, presentations, votes, meetings and wider discussions. Subsequently, implementing the changes on various digital platforms and amending agreements with publishers and online depositories has involved much time. The professional and dedicated work of Mandy Webb (Head of Publishing, RCS England) and Morgane Tixier (Publishing Coordinator, RCS England) are the principal reasons the journal can now evolve to open access. I am indebted to both.</p>", "<p>I am optimistic that 2024 will see the <italic>Annals</italic> continue to progress due to the wide and relevant research it promotes, the academic rigour of the peer review process and the faster availability of published work. The core of the journal, the standards it maintains, continue to be the wide body of reviewers. Reviews of depth and insight dictate the standard of articles the readers see, and most articles are forged into greater manuscripts through the comments and thoughts of the reviewers. In this edition, we publish a list, with great thanks, of colleagues who provide a quiet yet valued service to the <italic>Annals</italic>.</p>", "<p>We exist in a data-driven world – clinically, academically, financially and through publication media. Numerous metrics are now available for journals, for example, usage, citations, altmetrics, impact factor and subscription rates. Bill Walsh, the respected coach of the San Francisco 49ers American football team, famously titled his book “<italic>The Score Takes Care of Itself</italic>”<sup>##UREF##1##2##</sup> which I would recommend. Furthermore, I strive to ensure the <italic>Annals</italic> continues to focus on the people (authors, reviewers, editors, publishing team) and the process (peer review and publication) and let the metrics take care of themselves.</p>" ]	[]	[ "<fig position=\"float\" id=\"rcsann.2023.0113-F1\" fig-type=\"figure\"><caption><p><bold>Benedict Rogers,</bold> Editor-in-Chief <italic>Annals</italic> of the Royal College of Surgeons of England</p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"rcsann.2023.0113.01\" position=\"float\"/>" ]	[]	[{"label": ["1."], "collab": ["Royal College of Surgeons of England"], "ext-link": ["https://publishing.rcseng.ac.uk/open-access"]}, {"label": ["2."], "surname": ["Walsh"], "given-names": ["B"], "source": ["The Score Takes Care of Itself. My Philosophy of Leadership."], "publisher-loc": ["London"], "publisher-name": ["Penguin Publishing Group"], "year": ["2009"]}]	{ "acronym": [], "definition": [] }	2	CC BY	no	2024-01-13 23:48:00	Ann R Coll Surg Engl. 2024 Jan 1; 106(1):1	oa_package/90/b3/PMC10757875.tar.gz
PMC10757876	36374299	[ "<title>Introduction</title>", "<p>Recent years have seen an increasing interest in the development of specialised abdominal wall reconstruction (AWR) units and for such surgery to become recognised as a subspecialty in its own right.<sup>##REF##27324947##1##,##REF##28378225##2##</sup> The proponents of such changes cite the increasing complexity of the techniques involved and our enhanced understanding of the requirements and implications of abdominal wall surgery.<sup>##REF##28378225##2##–##UREF##0##4##</sup> Several papers have been published that serve as blueprints for those seeking to establish dedicated AWR services, but little has been written about how to go about training the future generations of AWR specialists that would be required to run them.<sup>##UREF##0##4##–##REF##33599900##7##</sup> In this article we discuss the issues surrounding specialised AWR training and outline how such training programmes could be designed for maximum educational value.</p>" ]	[]	[]	[]	[ "<title>Conclusion</title>", "<p>In this paper we have outlined the reasons why AWR is worthy of specialist training and what some of the potential barriers to this training may be. The authors believe that while the goals and format of any such training will be inherently controversial, the clinical need for AWR specialisation is sufficiently great for solutions to these barriers to be sought. It is the authors’ hopes that this paper will prompt discussion in the surgical community regarding the establishment of recognised specialist clinical units and that this paper will serve as a blueprint for the formation of further subspecialist training opportunities.</p>" ]	[ "<p>Complex abdominal wall reconstruction is an emerging subspecialty yet, despite the abundance of abdominal wall hernias requiring treatment and the increasing complexity of this type of surgery, there are few opportunities for surgeons to gain subspecialist training in this field. In this paper we discuss the need for focused training in complex abdominal wall reconstruction, outline some of the problems that may be hindering the availability of such opportunities and propose potential solutions to these issues.</p>" ]	[ "<title>Why do we need AWR subspecialists?</title>", "<p>Recent estimates suggest that roughly 500,000 ventral hernia repairs are performed annually in both the US and Europe, so it would appear that there are plenty of cases with which budding AWR specialists can expand their operative volume and experience.<sup>##REF##29754613##8##</sup> However, with such a high caseload there are simply too many ventral hernias requiring surgery for it <italic>not</italic> to remain a procedure within the domain of the generalist. Even the most staunch proponent of sub-specialisation would have to agree that the sheer demand for this type of surgery would necessitate only the most complex cases being managed by a dedicated AWR team.<sup>##REF##27324947##1##,##UREF##0##4##,##REF##29754615##5##</sup></p>", "<p>The centre of excellence model has been successfully applied across a wide range of clinical fields; however, given the undeniable need for the majority of hernia repairs still to be done by generalists some have argued that a line of distinction needs to be drawn between the terms ‘hernia programme’ and ‘centre of excellence’.<sup>##REF##29754615##5##</sup> The former can be thought of as a more inclusive version of the latter with its focus being on teamwork and collaboration with non-specialists for the betterment of clinical outcomes globally as opposed to only those outcomes from within the specialist unit itself.<sup>##REF##29754615##5##</sup></p>", "<p>Patients with complex hernias are liable to be best managed in specialist centres; however, how one defines complexity can vary thus making the identification of referral criteria difficult. Complexity may refer to the hernia itself, the patient, both or simply the likelihood of recurrence or a surgical site occurrence. A useful starting point would be the consensus definition previously described by Slater <italic>et al</italic> in which 22 patient and hernia variables were divided into four separate categories – hernia size and location, contamination/soft tissue condition, patient history/risk factors and clinical scenario – from which three classes of complexity (minor, moderate and severe) were described (##FIG##0##Figure 1##).<sup>##REF##24150721##9##</sup> For the majority of patients, in whom few or no risk factors for a ‘complex’ hernia repair are present treatment by a non-specialist is likely to yield comparable outcomes to those of a specialist and thus it would not be justifiable to centralise their care.<sup>##REF##27324947##1##,##REF##24150721##9##</sup> Conversely, in those patients with risk factors for complexity the evidence suggests that their management by specialist AWR teams would be advantageous both clinically and financially.<sup>##REF##25118644##10##–##REF##29234938##12##</sup> To aid clinicians in identifying those patients most likely to benefit from referral to a high-volume tertiary centre guidelines have been proposed that advocate for careful patient selection and a multidisciplinary approach to ventral hernia management at the highest tier of complexity.<sup>##REF##28869388##13##</sup> With regard to training, the mere existence of fellowship programmes has been shown to improve the perioperative outcomes of the units in question.<sup>##REF##27815743##14##,##REF##25666098##15##</sup></p>", "<p>In addition to providing clinical care to the high-risk subgroup of hernia patients, some have argued that specialist AWR teams should also provide a supportive role to the wider surgical community by coordinating research studies and hernia registries and by offering educational opportunities and mentorship.<sup>##REF##27324947##1##,##REF##28378225##2##,##UREF##0##4##,##REF##29754615##5##</sup> Such services would address the issues resulting from the decline in operative exposure to hernia repair and AWR that is seen in trainees entering independent practice and ideally would also reduce the number of recurrences ultimately requiring referral to a tertiary centre by enabling less experienced surgeons to optimise their outcomes in line with the national Getting It Right First Time programme.<sup>##REF##31754953##3##,##UREF##1##16##</sup></p>", "<title>Why are there so few fellowship programmes in AWR?</title>", "<p>General surgical trainees typically experience sub-optimal experience in inguinal hernia repair, but this deficiency has been shown to be rectifiable during fellowship.<sup>##REF##31754953##3##,##REF##33908142##17##</sup> This is particularly true for the laparoscopic approaches in those undertaking minimally invasive surgery (MIS) programmes.<sup>##UREF##2##18##</sup> In contrast to the amount of data regarding inguinal hernia repair there is comparatively little regarding exposure to AWR during either residency or fellowship. Although MIS fellowships provide invaluable experience in many operations around 70% of AWR patients will possess one or more criterion for complexity making the MIS approaches less favourable.<sup>##REF##24150721##9##</sup> Hence, while there clearly are fellows gaining experience in AWR, they may not be doing so in all the techniques and patient populations required to achieve robust expertise in the field. With roughly 80% of general surgeons in the US and UK undertaking a fellowship after their training we must consider why so few opportunities for AWR-specific training exist.<sup>##REF##31754953##3##</sup> It is likely that there are multiple underlying reasons:</p>", "<p>\n<list list-type=\"simple\"><list-item><label>–</label><p>Part of the reason for the paucity of fellowship-level training in AWR could result from the fledgling nature of the specialty. If there are few AWR centres at which fellows can obtain high-volume experience, then there are also few places for these fellows to go on to after their training. If there are few opportunities to subspecialise after fellowship, then this may deter candidates from pursuing an AWR-based practice. A lack of candidates could be perceived as a lack of interest, which could in turn lead some to question whether establishing post-residency training in AWR would be viable. Additionally, if the majority of patients are still going to need to have their surgery performed by non-specialists, then this may lead some to believe that focused AWR training is unnecessary.<sup>##REF##27815743##14##,##REF##25666098##15##</sup> This catch-22 situation makes the creation of an AWR service, and by extension an AWR fellowship, significantly more challenging.</p></list-item><list-item><label>–</label><p>A second factor could be that AWR is an interface specialty in which both general surgeons and plastic surgeons may play a central role.<sup>##REF##28187028##19##</sup> An interface specialty is one in which two or more surgical disciplines overlap to share a common area of clinical practice.<sup>##UREF##3##20##,##UREF##4##21##</sup> While the majority of ventral hernia repairs are managed by general surgeons, fellowship-level training in AWR would need to focus on those patients who require more complex repairs for whom a collaborative approach is more appropriate.<sup>##REF##28187028##19##</sup> Mastery of an interface specialty ideally requires an interface fellowship format.<sup>##UREF##3##20##,##UREF##4##21##</sup> The key aspect of such programmes is that fellows receive training in each of the surgical fields involved thereby expanding the fellow’s knowledge base and operative arsenal beyond that of their original specialty.<sup>##UREF##4##21##</sup> Designing such fellowships is challenging since host departments need to be able to provide a trainee-centred educational experience.</p></list-item><list-item><label>–</label><p>A third contributory factor is funding. In healthcare systems where fee-for-service is standard, specifically in North America, many fellowships are funded from accounts set up to support specific programmes. Fellows bill for their services as surgical assistants with that money going directly into these accounts. The money is then used to pay the fellow a set salary and for the running of the programme – administration, research and academic expenses, etc. Using this model any programme is self-perpetuating so long as the fellows bill for more than their salary and expenses since no external funding is required. In other healthcare systems, such as that of the UK, fellows are an additional expense to the employer, which therefore places the onus on the programmes to prove that the fellowship provides value for money. This in turn incentivises service provision to be favoured over training. Compounding the funding issue is that, despite the long term monetary advantages to improving AWR outcomes, very few grants are available to support clinical development in this area.<sup>##REF##21904861##22##</sup></p></list-item></list></p>", "<title>What are the key objectives for a successful AWR fellowship programme?</title>", "<p>The Accreditation Council for Graduate Medical Education (ACGME) defines a fellowship as ‘a period of advanced graduate medical education beyond a core residency programme for physicians who desire to enter more specialised practice’.<sup>##UREF##5##23##</sup> The most obvious primary objective therefore would be that successful fellows will have acquired both operative and non-operative expertise in the key aspects of AWR beyond that of core training by the time they have completed the programme. A secondary objective would be for both the fellow and the host institution to contribute to AWR-related academic activities such as research and education.</p>", "<p>These two goals tie in with the standards required by the European Hernia Society (EHS) for a hernia centre to achieve accreditation.<sup>##REF##30671899##24##</sup> This provides us with a good starting point from which we can determine the type of facility that could realistically support a fellowship:</p>", "<p>\n<list list-type=\"simple\"><list-item><label>–</label><p>With clinical excellence being the primary objective, any host institution would have to be a high-enough volume centre to be able to sustainably deliver sufficient clinical experience for its fellows to achieve the desired standards in a variety of techniques by its completion.</p></list-item><list-item><label>–</label><p>Secondly, the host institution would need to possess the infrastructure to be able to coordinate hernia registries, research trials, educational opportunities and the like so that the academic and supportive roles of a hernia programme can be fulfilled.</p></list-item><list-item><label>–</label><p>Finally, as discussed earlier, the programme should ideally be conducted as a joint venture between general surgery and plastic surgery departments, ideally using an interface fellowship model so that the full range of techniques applicable to AWR can be taught by surgeons from the appropriate specialty.<sup>##REF##28187028##19##</sup></p></list-item></list></p>", "<title>How should an AWR fellowship be structured?</title>", "<p>This is an area which will be heavily influenced by the model of funding in use and the existing practices and culture of the host facility. In a modular approach the year is split into multiple short-term blocks during which trainees are expected to focus on achieving a specific set of goals before moving on. This is ideal when trying to teach a wide range of subjects and skills which require exposure to a diverse spectrum of clinical experiences. Modular training has been suggested to be more effective than the traditional format of longer periods of service provision and apprenticeship typically seen in Europe.<sup>##REF##25731946##25##</sup> One major difficulty in adopting a modular design is that it requires centres to seamlessly continue providing the same standard of patient care despite trainees frequently changing blocks and periodically being off service. This is most easily achieved by fellows being supernumerary; however, this would be unappealing for funding bodies looking for consistent returns on their investment.</p>", "<p>Regardless of whether a modular or apprenticeship model is adopted, a second consideration is how to provide the high-volume, flexible, trainee-centred educational experience previously discussed. This is where being an interface specialty is advantageous. Few centres will have sufficient volume to provide fellows with five full days worth of AWR experience each week, but by taking a hybridised approach and devoting part of the weekly timetable to gaining experience in an allied surgical discipline then fellows would become more versatile and skilled and, importantly, more employable on their completion. Trauma, MIS, colorectal, bariatrics, surgical oncology – there are numerous fields with significant overlap capable of providing suitable complementary experiences.</p>", "<p>A hybridised, modular structure also creates the potential for programmes to become rotational, possibly utilising multiple healthcare facilities in a geographical area. A local syllabus could be bolstered by remote learning with prearranged and agreed exposure to other units. Such remote attendance at other units might not only benefit the fellow but could conceivably be of value to their host unit by cross fertilisation of ideas and practices and by facilitating academic collaboration.</p>", "<title>What should be part of an AWR fellowship syllabus?</title>", "<p>When devising a syllabus for subspecialty training, one must assume that the appropriate levels of ability have already been achieved in those areas common to all surgical disciplines and generic in a trainee’s background specialty. Additionally, one must accept that any list of educational goals is liable to be controversial. Similarly, it is impossible for such lists to be comprehensive without being impractically long. These discrepancies are due to a variety of influences such as clinical background, local practices, career intentions, health service culture, accessibility of services and patient expectations (##FIG##1##Figure 2##).</p>", "<p>It should be emphasised that the horizontal alignments of the procedures shown in ##FIG##2##Figure 3## should not be seen as exclusive, as this would be contrary to the ethos of an interface fellowship. If, for example, a fellow from a general surgery background has the motivation and opportunity to become proficient in panniculectomy and abdominoplasty, then this should be facilitated. The distinctions between the three vertical tiers are somewhat arbitrary, but broadly speaking for anything mandatory a fellow would be expected to be nearing or beyond the end of their learning curve by the completion of their fellowship. Those in the desirable category are procedures in which competence may be advantageous from a future scope-of-practice point of view but they are not necessarily fundamental to be considered an expert in AWR.</p>", "<p>As with ##FIG##2##Figure 3##, the list of essential topics to be learnt during an AWR fellowship (##FIG##3##Figure 4##) is inevitably going to be contentious. The desired standard of knowledge or understanding of the topics shown should be greater than that expected of a generalist such that one would be able to provide advice or clarification if requested. This ties in with the supportive and mentorship roles of a hernia programme as discussed previously.</p>", "<p>Active participation in regular AWR multidisciplinary team (MDT) meetings should be encouraged to familiarise fellows with the decision-making processes underlying the management of those patients whose clinical situations fall into the scenarios shown on the right of ##FIG##3##Figure 4##.</p>", "<title>How could programmes confirm that standards are being met?</title>", "<p>Fellowship training can be thought of as a period in which clinicians make the transition from the supervision and active observation of residency to simply doing the job. It provides an opportunity to ascend from conscious competence to unconscious competence at the apex of Miller’s triangle (##FIG##4##Figure 5##).<sup>##REF##2400509##26##</sup></p>", "<p>The learning curves for laparoscopic and open inguinal hernia repairs range between 50–100 and 40–64 respectively, numbers which should be easily surpassable during a single year of fellowship.<sup>##REF##30324107##11##,##REF##33908142##17##,##REF##28718887##27##–##REF##31758277##29##</sup> For the majority of the operations in ##FIG##2##Figure 3## the learning curves have not been investigated. Data from the National Consultant Information Programme (NCIP) show that the median number of incisional hernia repairs between October 2018 and September 2021 inclusive was 5 per general surgeon with the 95<sup>th</sup> centile being only 26.<sup>##UREF##6##30##</sup> Over the same time period the median number of such operations per hospital is roughly 120.<sup>##UREF##6##30##</sup> By concentrating complex AWR in a smaller number of high-volume centres the learning curves for the necessary techniques could easily be studied and subsequently used to guide future training requirements at the specialist registrar level. However, although increased operative volume has been repeatedly shown to result in improved outcomes, it would be remiss of a training programme to rely solely on logbook numbers and fellowship duration to assess competence.<sup>##REF##30094752##31##,##REF##33835325##32##</sup> Several validated, objective means of assessing operative ability are available. Formative use of such assessment tools should be encouraged at pre-determined intervals throughout fellowship in order to identify areas on which to focus ongoing training needs.</p>", "<p>The assessment of knowledge at fellowship level is more problematic, and little has been written on this topic. Although advanced abdominal wall surgery examinations do exist, such as the Fellow of the European Board of Surgery Abdominal Wall Section (FEBS AWS), they are primarily aimed at surgeons with established practices.<sup>##UREF##7##33##,##UREF##8##34##</sup> The syllabus for such exams certainly have merit in terms of guiding fellowship education, and achievement of the required standard should be feasible for the majority of post-FRCS fellows.<sup>##UREF##8##34##</sup> However, it could be argued that unless appointment into a substantiative post becomes reliant on the possession of post-FRCS qualifications, then to mandate an additional formal test of knowledge might deter applicants who would otherwise be interested in pursuing an AWR fellowship. Although imperfect, determining whether or not a fellow has acquired an acceptable degree of specialist knowledge will therefore likely remain a subjective judgement call for the foreseeable future.</p>", "<title>Conflicts of interest/Competing interests</title>", "<p>The authors confirm that they have no conflicting or competing interests that may inappropriately bias this work. STA and CW have nothing to declare. MS has received consulting fees from Allergan Aesthetics and Bard, honoraria for lectures from Bard and support for attending meetings from Bard. CJW has received honoraria for lectures and support for attending meetings from Gore and Cook and has accepted a gift of an AWR textbook on behalf of the Department of Surgery at Wirral University Teaching Hospitals NHS Foundation Trust.</p>" ]	[]	[ "<fig position=\"float\" id=\"rcsann.2022.0058F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>Criteria for complex abdominal wall hernia as defined by Slater <italic>et al</italic><sup>##REF##24150721##9##</sup></p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2022.0058F2\" fig-type=\"figure\"><label>Figure 2<x xml:space=\"preserve\"> </x></label><caption><p>Global objectives of an abdominal wall reconstruction (AWR) fellowship</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2022.0058F3\" fig-type=\"figure\"><label>Figure 3<x xml:space=\"preserve\"> </x></label><caption><p>Suggested procedures to be included on abdominal wall reconstruction (AWR) fellowship syllabus. Techniques more relevant to general surgery are positioned on the left whereas those more associated with plastic surgery are positioned on the right; the central area represents the common ground between the two specialties.</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2022.0058F4\" fig-type=\"figure\"><label>Figure 4<x xml:space=\"preserve\"> </x></label><caption><p>Essential topics in abdominal wall reconstruction (AWR)</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2022.0058F5\" fig-type=\"figure\"><label>Figure 5<x xml:space=\"preserve\"> </x></label><caption><p>Miller’s triangle<sup>##REF##2400509##26##</sup></p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"rcsann.2022.0058.01\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2022.0058.02\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2022.0058.03\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2022.0058.04\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2022.0058.05\" position=\"float\"/>" ]	[]	[{"label": ["4."], "surname": ["Shao", "Elhage", "Deerenberg"], "given-names": ["J", "S", "E"], "italic": ["et al.", "Plast Aesthet Res"], "article-title": ["Establishing a center of excellence in abdominal wall reconstruction"], "year": ["2020"], "bold": ["7"], "fpage": ["1"], "lpage": ["10"]}, {"label": ["16."], "collab": ["Getting It Right First Time"], "ext-link": ["https://www.gettingitrightfirsttime.co.uk/"], "comment": ["(cited December 2023)."]}, {"label": ["18."], "surname": ["Cox", "Pearl", "Parreno"], "given-names": ["TC", "JP", "D"], "italic": ["et al.", "Fellowship Training Eliminates the Learning Curve for Laparoscopic Inguinal Hernia Repair"], "publisher-loc": ["San Antonio, TX, USA"], "publisher-name": ["Sages"], "year": ["2011"]}, {"label": ["20."], "surname": ["Giblin", "Wright", "Henley"], "given-names": ["A", "T", "M"], "italic": ["et al.", "BMJ"], "article-title": ["Reconstructive trauma surgery interface fellowship"], "year": ["2012"], "bold": ["345"], "fpage": ["e7258"]}, {"label": ["21."], "surname": ["Lees", "Henley", "Sandhu"], "given-names": ["V", "M", "D"], "article-title": ["Interface specialty training in the UK"], "italic": ["Ann R Coll Surg Eng"], "year": ["2010"], "bold": ["92"], "fpage": ["126"], "lpage": ["128"]}, {"label": ["23."], "collab": ["ACGME Common Program Requirements (Fellowship)"], "year": ["2021"], "ext-link": ["https://www.acgme.org/globalassets/pfassets/programrequirements/cprfellowship_2022v3.pdf"], "comment": ["(cited December 2023)"]}, {"label": ["30."], "collab": ["NCIP: About the National Consultant Information Programme"], "ext-link": ["https://www.gettingitrightfirsttime.co.uk/ncip/"], "comment": ["(cited December 2023)"]}, {"label": ["33."], "surname": ["East"], "given-names": ["B"], "comment": ["Become an UEMS certified AWR surgeon (FEBS AWS)", "(cited December 2023)"], "ext-link": ["https://europeanherniasociety.eu/uems/"]}, {"label": ["34."], "collab": ["UEMS Section of Surgery"], "comment": ["Abdominal Wall Surgery Syllabus: European Union of Medical Specialists - Section of Surgery and European Board of Surgery; 2022", "(cited December 2023)"], "ext-link": ["https://uemssurg.org/working-groups/abdominal-wall-surgery/syllabus/"]}]	{ "acronym": [], "definition": [] }	34	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 14; 106(1):2-8	oa_package/f5/1a/PMC10757876.tar.gz
PMC10757877	37051769	[ "<title>Introduction</title>", "<p>Cauda equina syndrome (CES) is an emergency spinal pathology that commonly presents to doctors in the emergency department. If a prompt diagnosis of CES is not achieved, there can be severe, irreversible loss of bladder, bowel and sexual function, which often has a devastating impact on the patient and can lead to expensive litigation.<sup>##REF##19336488##1##</sup></p>", "<p>There is no single symptom or clinical sign that predicts CES, and even combinations of symptoms and signs have a high predictive value only when CES is advanced and frequently irreversible.<sup>##REF##17453789##2##–##UREF##0##6##</sup> Portable bladder ultrasonography (BUS) is available in most emergency departments and is increasingly used in the diagnosis of CES as well as in determining when potential CES patients should be referred for magnetic resonance imaging (MRI).<sup>##REF##31479434##7##,##REF##32475252##8##</sup> This systematic review considered the role of BUS in the emergency assessment of potential CES patients, the implications of urinary volumes and other clinical findings in the diagnosis of CES, and whether/when MRI should be performed.</p>" ]	[ "<title>Methods</title>", "<p>A literature search was performed on the PubMed<sup>®</sup> and MEDLINE<sup>®</sup> databases, in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines,<sup>##REF##19621072##9##</sup> employing the search terms “cauda equina syndrome” AND “bladder ultrasound”.</p>" ]	[ "<title>Results</title>", "<p>The literature search returned 46 abstracts. Seven full papers were selected for review. The remaining 39 abstracts did not report useful clinical information. The 7 full papers reviewed yielded a further 11 papers and so 18 papers were reviewed in total.</p>", "<p>The absence of physical signs can exclude CES. In a single centre review of 142 suspected CES (sCES) cases, normal perianal sensation (PAS), anal tone (AT) and bulbocavernosus reflex (BCR) were associated with negative MRI (MRI−) in 100% of cases.<sup>##REF##32935582##10##</sup></p>", "<p>Deyo <italic>et al</italic> found that urinary retention (volume not specified) had a 90% sensitivity and a 99% specificity for positive MRI (MRI+).<sup>##REF##1386391##11##</sup> Furthermore, the absence of urinary retention excluded CES in 99.9% of cases.</p>", "<p>Domen <italic>et al</italic> retrospectively reviewed 58 patients undergoing urgent lumbar MRI for sCES.<sup>##REF##19490073##12##</sup> Eight were MRI+ and all eight had emergency surgery within 24 hours (mean: 13.2 hours, standard deviation: 4.7 hours). Preoperative post-micturition ultrasonography was performed in six cases and all had a post-void residual urinary volume (PVR) of >500ml. There was reduced sensation of micturition in 25%, clinical urinary retention in 87.5%, urinary incontinence in 37.5% and faecal incontinence also in 37.5% of cases. Objective signs included reduced PAS and reduced anal sphincter (AS) reflex in 37.5% (each) and reduced AT in 25% of cases. The odds ratio for MRI+ was 4.0 where PVR was >500ml, 15.5 with a PVR of >1,000ml, and 48 with a PVR of >500ml and two of three clinical features (bilateral sciatica, urinary retention or faecal incontinence).</p>", "<p>Hoeritzauer <italic>et al</italic> retrospectively reviewed 276 patients with sCES.<sup>##REF##30298195##5##</sup> Over a quarter (78/276, 28%) were MRI+ and of these, 86% (67/78) had disc prolapses. PVRs were measured in 65 cases. Among the MRI+ cases, the PVR was <100ml in 33%, 100–500ml in 47% and >500ml in 20% of patients. For a PVR of >100ml, the sensitivity of a positive MRI was 67% (i.e. 67% of the MRIs were normal) with a specificity of 52% (i.e. 52% of the MRIs were positive).</p>", "<p>Venkatesan <italic>et al</italic> retrospectively reviewed 92 patients with sCES.<sup>##REF##31479434##7##</sup> The pre and post-void BUS results for all cases were 470ml and 248ml respectively; for MRI+ (17/92, 18%), they were 672ml and 466ml, and for MRI− (75/92, 82%), they were 424ml and 199ml. The odds ratio for a positive MRI was 20.7 with PVR ≥200ml. The clinical signs in MRI+ cases were reduced PAS (82%), reduced/absent AT (53%) and absent voluntary anal contraction (VAC) (29%). In MRI− cases, reduced PAS on examination was present in 56% and reduced/absent AT was present in 37% of patients. A PVR of ≥200ml had a probability of MRI+ of 43% (sensitivity 94%, specificity 72%). Venkatesan <italic>et al</italic> concluded that if there was normal PAS and a PVR of <200ml, then MRI could be deferred until the next day. One (6%) of the 17 patients with positive MRI had bilaterally reduced PAS with a PVR of <200ml.</p>", "<p>Katzouraki <italic>et al</italic> performed a prospective study of 260 patients with sCES.<sup>##REF##32475252##8##</sup> MRI+ was found in 34 (13%), all of whom underwent emergency surgery. The average degree of canal occlusion in the MRI+ cases was 76% (95% confidence interval: 72–81%). The clinical features were urinary incontinence (97%), saddle anaesthesia (73%), reduced PAS (63%) and reduced/absent AT (33%). The PVR was ≥200ml in 94% of MRI+ cases (with 6% ≤200ml). Of the four cases with a PVR of <200ml, two had normal PAS and AT, two had unilateral reduction of PAS, one had reduced AT and in one, AT was normal; all four underwent emergency surgery. PVR >200ml had 94% sensitivity in predicting MRI+ (specificity 67%, positive predictive value 30%, negative predictive value 99%). Katzouraki <italic>et al</italic> concluded that urgent MRI is not needed if the PVR is <200ml and there is normal PAS and VAC. MRI can therefore be deferred to normal working hours or be performed on a routine basis. None of the 34 cases (13%) where the MRI was deferred had positive MRI and none developed CES.</p>", "<p>Kalidindi <italic>et al</italic> assessed 249 sCES cases, with formal urodynamic studies (UDS) being performed in the majority.<sup>##REF##31907657##13##</sup> All patients had low back pain, unilateral or bilateral radiculopathy, bladder symptoms or signs of CES and were MRI+. There was urinary frequency or urgency in 115 (46%), urinary retention in 87 (35%) and incontinence in 47 (19%). Uroflowmetry (UFM) and PVR were performed. In 34 cases (14%), they were normal and CES was excluded. Of the remaining 215 patients, 211 agreed to undergo invasive UDS. Thirty-three (16%) of the 211 patients had a contractile bladder and CES was excluded. Eighty-five (40%) had a hypocontractile bladder; there was reduced PAS, VAC or BCR in 66 (78%) of these and CES was diagnosed. Of the 19 cases with normal PAS, VAC and BCR, the most common causes of abnormal UFM/PVR were pain and medication. Ten patients were treated conservatively and none deteriorated. Of the 66 patients with hypocontractile bladders with reduced PAS, VAC and/or BCR, 54 (82%) had a high PVR and all underwent emergency surgery. In the 12 individuals with hypocontractile bladders and normal PAS, VAC and/or BCR, 9 had surgery for other reasons. Among the three cases treated conservatively, one patient developed abnormal signs and underwent surgery. Ninety-three (44%) of the 211 patients who agreed to UDS had an acontractile bladder. Of these, 86 (92%) had abnormal signs and underwent surgery. Seven (8%) had pain or drug induced bladder problems. (Of four treated conservatively, none deteriorated.) Overall, only 141 (58%) of the 245 patients in the study by Kalidindi <italic>et al</italic> (excluding 4 drop-outs) had neurogenic bladder symptoms from CES and underwent emergency surgery. Sixty-seven patients (27%) had non-neurological causes of bladder symptoms (including prostatic hypertrophy, drugs, pain, detrusor overactivity or stress incontinence) and were treated conservatively. High PVRs can be found in hypocontractile bladders of non-neurogenic origin and low PVRs can be found in neurogenic bladders if the patient passes urine with abdominal straining. Kalidindi <italic>et al</italic> concluded that PVR alone was not a sensitive test for CES.</p>" ]	[ "<title>Discussion</title>", "<p>CES is a constellation of symptoms and signs; not all will be present at the time of diagnosis. Typically, there is low back pain, often severe. There can be unilateral or bilateral radicular pain. There may also be lower limb numbness, paraesthesia and/or weakness. There is usually bladder, bowel and/or sexual dysfunction as well as subjective alteration of PAS. Objective signs are generally present as well as symptoms. The clinical symptoms and signs of CES do not reliably correlate with cauda equina compression on MRI and clinical assessment alone cannot reliably diagnose or exclude MRI-proven cauda equina compression.<sup>##REF##17453789##2##–##UREF##0##6##</sup> Symptoms suggestive of CES are very common in MRI− cases: bladder symptoms are present in 67% and bilateral sciatica in 20%.<sup>##REF##30298195##5##</sup> Up to 70% of MRI− cases will have reduced PAS and up to 51% will have reduced AT on physical examination.<sup>##REF##33177221##14##</sup></p>", "<p>Failure to diagnose CES is frequently associated with long-term, severe neurological and functional disability, and there is often litigation. In order to avoid a misdiagnosis of CES, large numbers of MRI scans are performed that are negative and typically, less than 20% of MRI scans are positive.<sup>##REF##31479434##7##,##REF##32475252##8##,##REF##29607679##15##</sup> In the emergency department, two signs are usually assessed: PAS and AT. The clinical assessment of AT is inaccurate;<sup>##REF##8409694##16##</sup> in a model simulating AT, only 64% of AT assessments were correct.<sup>##REF##25811266##17##</sup> PAS and AT are not the most sensitive signs of sacral nerve root injury. The assessment of anal squeeze (AS) may be more accurate than AT.<sup>##REF##25811266##17##</sup></p>", "<p>BCR is rarely tested in CES but an absent BCR has a high correlation with MRI+.<sup>##REF##19621072##9##</sup> The reflex is tested by squeezing the glans penis or clitoris (or tugging on a bladder catheter) and observing contraction of the anal sphincter, which is the normal response. No anal sphincter contraction is evidence of sacral nerve root injury. BCR is currently not used widely and it is a difficult examination in women in the lateral position. The high correlation of a lack of BCR and MRI+ may be due to an absent BCR being more likely in severe CES. Assessment of BCR is controversial and is unlikely to be widely adopted. Some argue that because no single sign predicts MRI+ accurately in sCES cases, BCR examination cannot be relied on. However, the accuracy of clinical diagnosis of CES increases if several signs of sacral nerve root injury are assessed.<sup>##UREF##1##18##</sup></p>", "<p>Portable BUS is now commonly used to assess patients with sCES. A probe is placed over the suprapubic area of the abdomen with the patient prone, and bladder images are recorded in sagittal and transverse planes. The ultrasonography machine automatically calculates urinary volumes.</p>", "<p>BUS is unsuitable for patients with severe abdominal scars, uterine prolapse, pregnancy or abdominal ascites and the technique is operator-dependant.<sup>##REF##463603##19##</sup> BUS can tell us about pre and post-void bladder volumes. Pre-void BUS quantifies the degree of bladder distention/retention. Post-void imaging tells us about the extent to which the bladder is emptying to completion. If there is urinary retention, the patient should be asked whether they have a normal sensation of bladder fullness. Painless retention of a large urinary volume suggests an insensate bladder, which is commonly found in CES. Nevertheless, in non-CES cases of lumbar disc disease, there is reduced bladder sensation in 50% of cases, of whom 25% strain to void.<sup>##REF##23108280##20##</sup> In patients with severe CES, some sensation of bladder fullness can be found in over 95% of patients<sup>##REF##35285345##21##</sup> although the sensation of bladder fullness is not normal. Patients should be asked whether they have a normal sensation of bladder fullness rather than whether there is a complete absence of sensation.</p>", "<p>The PVR is the residual volume of urine in the bladder post-micturition. In young adults, a PVR of <50ml is deemed normal while in the older population, 50–100ml is considered normal.<sup>##REF##35182176##22##,##REF##34404563##23##</sup> A high PVR is evidence of incomplete bladder emptying but not all of these patients have neurogenic bladder dysfunction.<sup>##REF##31907657##13##</sup> When detailed urological assessment (UFM, PVR and UDS) was performed in patients with positive symptoms and signs of CES and MRI+, 16% had a normal contractile bladder on UDS, 40% had a hypocontractile bladder (with 22% of these having no objective neurological deficit [i.e. there was no neurological cause for the hypocontractile bladder]) and 44% had an acontractile bladder (with 7.5% of these having no neurological cause for bladder dysfunction).<sup>##REF##31907657##13##</sup></p>", "<p>The higher the PVR, the greater the probability of the patient being CES+ (i.e. having both clinical and radiological evidence of CES requiring emergency surgery).<sup>##REF##30298195##5##,##REF##31479434##7##,##REF##32475252##8##</sup> The Nottingham spinal unit has suggested a cut-off PVR of 200ml<sup>##REF##31479434##7##,##REF##32475252##8##</sup> and as long as there are no abnormal neurological signs (normal PAS and VAC), emergency MRI is not required and the imaging can be deferred. It is important to note the qualification of normal PAS and VAC. A PVR of <200ml does not exclude symptomatic CES and can be found in up to 20% of CES+ cases.<sup>##REF##1386391##11##</sup> However, provided PAS and VAC are normal, a PVR of <200ml indicates that the risk of CES is minimal.<sup>##REF##32475252##8##</sup></p>", "<p>In the two largest studies on CES, 3 (6%) of the 51 patients who were MRI+ had a PVR of <200ml (with positive signs).<sup>##REF##31479434##7##,##REF##32475252##8##</sup> A recent study of 50 medicolegal cases found that in MRI+ patients, 50% had a PVR of <200ml.<sup>##REF##35182176##22##</sup> The author is aware of a number of clinical and medicolegal cases where doctors have assumed that a PVR of <200ml means that there is no risk of CES despite the presence of positive physical signs, which were ignored.<sup>##REF##35182176##22##</sup> It is probably sensible to regard the PVR as a continuous variable. A PVR of <200ml indicates a low probability of the patient being MRI+ whereas a PVR of >200ml has a probability of 43%.<sup>##REF##31479434##7##</sup> The PVR should be considered in conjunction with physical signs. The greatest probability of CES+ is found in patients with a higher PVR and positive signs of CES.<sup>##REF##31479434##7##,##REF##32475252##8##,##REF##19490073##12##</sup></p>", "<p>The subclassification of CES has recently been reconsidered and expanded.<sup>##REF##34862914##24##</sup> The new subclassification is set out in ##TAB##0##Table 1## and it is hoped that this will increase the recognition of early CES, where good outcomes are likely to be achieved. Most patients who are capable of passing urine (to achieve a PVR) are incomplete CES (CESI) patients; there will be a small number of exceptions where patients pass urine by straining.<sup>##REF##31907657##13##</sup> CESI patients are in a favourable group for which outcomes are typically better than for patients with CES with neurogenic retention of urine (CESR). Patients with a very high PVR (typically >1,000ml) will most commonly have CESR.</p>", "<p>MRI is a finite resource, particularly in district general hospitals, where the primary diagnosis of CES is usually made. It is good practice to minimise out-of-hours MRI, provided this has no or minimal effect on patient safety. The ideal, of course, is to perform MRI for all patients who will be MRI+ and for the lowest possible number of MRI− patients but significant rates of negative MRIs are the price of minimising false negative CES. The presence or absence of objective signs of CES and the PVR can be used to determine the urgency of MRI in the emergency department.<sup>##REF##34404563##23##</sup> Symptom-only CES is uncommon. These are patients who have symptoms strongly suggesting CES but no abnormal signs. The probability of such a patient having a positive MRI is low. Such cases should be discussed with the local spinal service.</p>" ]	[ "<title>Conclusions</title>", "<p>In the emergency department, standard practice should be to take a history of potential symptoms of CES, and then to perform a detailed neurological examination including PAS, AT and AS followed by BUS to determine the PVR. In the author’s opinion, if all four are normal, the patient can be discharged with a cauda equina warning card.</p>", "<p>Conversely, if there is any positive sign (PAS, AT or AS), then CES cannot be excluded even if the PVR is <200ml and emergency MRI is required. If the PVR is >200ml, emergency MRI is required regardless of signs (although most MRI+ cases will have signs). If there are no signs but the PVR is not normal (i.e. 50–200ml), there will be a few CES+ cases and MRI should ideally be performed within 24 hours. PVR is insensitive as a stand-alone test of bladder function.<sup>##REF##31907657##13##</sup> There are non-neurological causes of abnormal PVR and for cases with a high PVR but no signs of CES, there should be formal UDS as soon as practicable.</p>" ]	[ "<p>For cauda equina syndrome (CES), current clinical assessment in the emergency department usually involves perianal sensation (PAS) and anal tone (AT). Neither reliably predict magnetic resonance imaging (MRI) demonstrating a large central disc prolapse (MRI+). Other clinical examination findings increase the probability of MRI+. Other tests of sacral nerve root function include anal squeeze (AS) and the bulbocavernosus reflex (BCR). If BCR, PAS and AT, and AS are combined and they are all normal, CES can be excluded in almost all cases. Portable bladder ultrasonography is now commonly used to assess bladder function, particularly in measuring the post-void residual urinary volume (PVR). PVR is deemed normal at <50ml. If the PVR is <200ml and there are no objective signs, MRI+ is rare. If the PVR is >200ml, MRI+ is found in 43% of cases.</p>", "<p>The combined assessment of PAS, AT and AS (and BCR in selected cases) and PVR increases the specificity and sensitivity of a clinical diagnosis of CES (i.e. maximising MRI+ and minimising MRI−). Recommendations for when to perform MRI are made.</p>" ]	[]	[]	[]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0168TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Subclassification of cauda equina syndrome (CES)<sup>##REF##34862914##24##</sup></p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><tbody><tr><td rowspan=\"1\" colspan=\"1\">CESS (CES suspected or suspicious)</td><td rowspan=\"1\" colspan=\"1\">Bilateral radiculopathy, no CES, increased risk of CES</td></tr><tr><td rowspan=\"1\" colspan=\"1\">CESE (CES early)</td><td rowspan=\"1\" colspan=\"1\">Symptom-only CES, symptoms of perineal sensory impairment and/or a change in bladder function, often no objective signs</td></tr><tr><td rowspan=\"1\" colspan=\"1\">CESI (CES incomplete)</td><td rowspan=\"1\" colspan=\"1\">Symptoms and objective signs of CES with voluntary control of micturition (executive bladder control)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">CESR (CES with neurogenic retention of urine)</td><td rowspan=\"1\" colspan=\"1\">Paralysed insensate bladder with overflow incontinence (loss of executive bladder control)</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[]	[{"label": ["6."], "surname": ["Dionne", "Adefolarin", "Kunzelman"], "given-names": ["N", "A", "D"], "italic": ["et al.", "Muscuoskelet Sci Pract"], "article-title": ["What is the diagnostic accuracy of red flags related to cauda equina syndrome (CES), when compared to magnetic resonance imaging (MRI)? A systematic review"], "year": ["2019"], "bold": ["42"], "fpage": ["125"], "lpage": ["133"]}, {"label": ["18."], "surname": ["Ballstaedt", "Woodbury"], "given-names": ["L", "B."], "article-title": ["Bladder Post Void Residual Volume"], "publisher-loc": ["Treasure Island", "FL"], "publisher-name": ["StatPearls"], "year": ["2021"]}]	{ "acronym": [], "definition": [] }	24	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 13; 106(1):9-12	oa_package/32/b9/PMC10757877.tar.gz
PMC10757878	36748787	[ "<title>Introduction</title>", "<p>Colorectal cancer survivors suffer many problems affecting quality of life (QOL), ranging from psychological distress to urological, bowel and sexual dysfunction.<sup>##UREF##0##1##</sup> Follow-up programmes focus mainly on the detection of recurrence rather than QOL assessment.</p>", "<p>There is a move to rebalance this to assess QOL robustly. The purpose is threefold: first, to provide patients with necessary support; second, to collate a body of evidence such that patients incorporate QOL in decisions regarding management strategies; and third, evidence is emerging that use of patient-reported outcome measures (PROMS) may improve survival in cancer patients.<sup>##REF##28586821##2##</sup> The National Institute of Health and Care Excellence now recommends PROMS be used as secondary endpoints in future clinical trials.<sup>##UREF##1##3##</sup></p>", "<p>There has been much work in identifying the best tools to assess QOL in colorectal cancer, much of it focusing on PROMS.<sup>##REF##28384684##4##</sup> There is, however, significant heterogeneity. Mcnair reported 53 different PROMs tools from 104 different papers.<sup>##UREF##2##5##</sup> At present no consensus on a set of PROMs to assess QOL in survivors of colorectal cancer exists.</p>", "<p>This paper reports PROMs from patients who have undergone laparoscopic surgery for rectal cancer at a single institution, utilising two validated instruments for QOL assessment. Both have been agreed on by a recent international collaborative aiming to incorporate PROMS in follow-up regimens.<sup>##REF##28384684##4##</sup></p>" ]	[ "<title>Methods</title>", "<p>A database of patients who have undergone surgical treatment for rectal cancer is kept at the Royal Surrey County Hospital. All patients treated from 2005 to 2015 were identified.</p>", "<p>Information includes date of operation, operation type, complications, utilisation of chemotherapy or radiotherapy and date of last follow-up.</p>", "<p>All patients were provided with a survey composed of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CR29 and QLQ-C30 questionnaires. These PROMS tools were identified by the International Consortium for Health Outcomes Measurement’s Delphi exercise regarding patient-centred outcomes for colorectal cancer.<sup>##REF##28384684##4##</sup> This exercise was conducted over a period of 8 months culminating in February 2016.</p>", "<p>The EORTC QLQ-C30 is a validated tool for measuring overall QOL in cancer patients. It is a combination of functional, symptom and global QOL scales. The QLQ-CR29 is a disease-specific module for colorectal cancer, created by the EORTC to supplement the QLQ-CR30. It comprises scales concerning bowel function, sexual function and gastrointestinal symptoms, and contains a stoma-specific component.</p>", "<p>Comparisons were made between the following cohorts:\n<list list-type=\"simple\"><list-item><label>• </label><p>above and below 36 and 60 months’ follow-up;</p></list-item><list-item><label>• </label><p>the presence or not of a stoma;</p></list-item><list-item><label>• </label><p>whether the patient had undergone radiotherapy;</p></list-item><list-item><label>• </label><p>whether the patient had undergone chemotherapy;</p></list-item><list-item><label>• </label><p>whether the patient had suffered a complication;</p></list-item><list-item><label>• </label><p>above and below the median age;</p></list-item><list-item><label>• </label><p>whether the patient had undergone anterior resection (AR) or abdominoperineal excision of the rectum (APR).</p></list-item></list></p>", "<title>Data analysis</title>", "<p>Patients were initially contacted by post. Those who did not respond were then contacted by telephone and offered a repeat postal questionnaire or the opportunity to complete the survey by telephone. Results were tabulated electronically and data transformed as per the EORTC QLQ-C30 scoring manual. The same formulae were used and applied to QLQ-CR29, which has no formal scoring manual.</p>", "<title>Statistical analysis</title>", "<p>For each variable, independent <italic>t</italic>-tests were performed to compare the means between groups; for example, APR vs AR. Levene’s test for homogeneity of variance was then performed. Statistical significance for both the homogeneity of variance and equality of means <italic>t</italic>-test was defined as <italic>p</italic><0.05. For continuous variables such as age, the median value of the data set was taken as the cut-off point. All data were analysed using IBM SPSS version 23. For scale data, no composite values were used such as repeat values or means. If data were unavailable or missing they were excluded from the analysis.</p>" ]	[ "<title>Results</title>", "<p>Some 141 patients were identified: 12 patients died and 11 were lost to follow-up; 118 (83.7%) responded, of whom 17 refused to take part and 101 completed the questionnaires (71.6%). Sixty-nine respondents answered by post and 32 by telephone.</p>", "<p>The mean age was 67 (47–88) years; the median follow-up 58 (21–162) months. There were 34 female and 67 male participants. Thirty-three patients had a tumour height below 5cm, 33 had a tumour height between 5 and 10cm, and 32 had a tumour height between 10 and 15cm. Tumour height was unknown for three participants.</p>", "<p>Thirty patients underwent laparoscopic APR and 71 underwent a laparoscopic AR. Of the patients undergoing AR, 52 had a covering ileostomy formed, 50 of which were successfully reversed. One patient required formation of an end colostomy after reversal owing to an anastomotic leak. A second was given a colostomy 5 months postoperatively for rectal prolapse. No patients undergoing AR required end colostomy at their initial operation. Details regarding treatment modalities are shown in ##TAB##0##Table 1##.</p>", "<p>Complications occurred in 18 patients (18.8%). A list of complications is provided in ##TAB##1##Table 2##.</p>", "<title>EORTC QLQ-C30</title>", "<p>All respondents answered all 30 questions. This questionnaire consists of five functional scales (physical, cognitive, role, emotional and social), three symptom scales (fatigue, pain, nausea and vomiting) and six individual items (dyspnoea, insomnia, loss of appetite, diarrhoea, constipation and financial difficulties), giving a total of 14 domains. Each of the scales comprises between two and five component questions. Functional scale scores are produced as a percentage, with a higher value denoting a better functional outcome. Symptom scales, again as a percentage, denote worse symptomatology. The symptom scales are reversed when calculating the global health score to allow for this difference, resulting in a higher score correlating with an improved global status or satisfaction.</p>", "<p>There are two further questions assessing overall health and QOL, termed ‘Global’ questions. Detailed analysis of QOL score by treatment modality can be found in Appendix 1 (available online) but are summarised below. For other factors such as age, time from follow-up and complications, detailed QOL analysis is shown in Appendix 2 (available online).</p>", "<title>Overall health</title>", "<p>Question 29 asks patients to rate their overall quality of health and question 30 their overall QOL. Patients respond on a scale of 1–7, with 1 pertaining to worse health and 7 to perfect health. The modal score for both questions was 6. Some 48% of responders answered question 29 with a score of 6 or 7 and 61% of patients answered question 30 with a score of 6 or 7.</p>", "<title>AR vs APR</title>", "<p>APR patients reported better scores for diarrhoeal symptoms, this being the only statistically significant difference. Patients undergoing APR reported better functional and symptom scores in nearly all categories, fairing slightly worse in terms of loss of appetite and pain. They also reported better overall health and QOL scores. The results did not reach statistical significance.</p>", "<title>Chemotherapy</title>", "<p>Patients who had undergone chemotherapy reported better global (overall health and overall QOL) scores, reaching statistical significance (<italic>p</italic> < 0.05). They also tended to report better functional scores in each of the five domains. Chemotherapy patients reported worse symptom-related scores, except for nausea, vomiting and constipation, and reported more problems with financial difficulties. These results were not statistically significant.</p>", "<title>Radiotherapy</title>", "<p>Patients who had undergone radiotherapy reported better scores in terms of physical function, role function and cognitive function. Worse scores were reported for emotional and social function. Radiotherapy patients reported worse scores for most symptom areas, except for nausea and vomiting, dyspnoea and constipation. Global scores were higher in the radiotherapy group. No results in this comparison achieved statistical significance.</p>", "<title>Stomata</title>", "<p>Thirty-seven patients had a stoma at the time of data collection; 64 did not. There were no statistically significant differences found between patients with or without stomata. Excluding fatigue and pain, stoma patients reported better scores across all categories, and reported a positive overall QOL. Some 5% of patients graded QOL below the middle value of 4, and 65% assigned QOL a score of 6 or 7.</p>", "<title>Length of follow-up</title>", "<p>At the time of data collection, 87 patients were more than 36 months from their operation and 14 patients were less than 36 months from their operation. No statistically significant differences were seen between both groups. There was a trend towards improved QOL scores in patients who were less than 36 months from their operation. This cohort almost uniformly reported better functional, symptom and global QOL scores. The exception was for shortness of breath.</p>", "<p>Sixty-three patients were more than 60 months from their operation and 38 patients less than 60 months from their operation. No results reached statistical significance when comparing both groups. Patients more than 60 months from their operation reported better functional scores, except for emotional function. Symptom scores were split almost equally between the groups. Global scores tended to be higher in patients who were less than 60 months from their operation.</p>", "<title>Other factors</title>", "<p>Patients who suffered complications did not routinely report worse functional, symptom or global scores. When compared with patients who did not suffer a complication, there were no statistically significant results.</p>", "<p>In terms of age, patients above and below the mean age answered similarly. The older group did, however, report more positive scores that were statistically significant for physical, emotional and cognitive function.</p>", "<title>EORTC QLQ-CR29</title>", "<p>The EORTC QLQ-CR29 is a disease-specific module designed to be used in conjunction with EORTC QLQ-CR30. It contains 29 questions. There are 4 functional and 18 symptom scales. Four scales comprise two questions, the remainder comprise one question.</p>", "<p>Of the 101 returned questionnaires, 25 patients did not populate the survey completely. Of these, the majority did not answer one or both questions regarding sexual function. Given these symptom scales involved a maximum of two data points, accounting for them in data analysis would result in significant potential for bias. These 25 patients were therefore been excluded from the analysis.</p>", "<title>AR vs APR</title>", "<p>Fifty-four patients underwent AR and 22 patients APR. APR patients reported higher scores for sexual interest. AR patients reported higher scores for sexual difficulties. Both results were statistically significant. There were no other statistically significant results, and there was an even spread of reported outcomes between groups.</p>", "<title>Chemotherapy</title>", "<p>Forty-four patients underwent chemotherapy and 32 patients did not. Chemotherapy patients reported worse scores for dysuria, problems with taste and sore skin, all results being statistically significant. There were no other statistically significant results. Chemotherapy patients reported worse scores in 13 of 21 domains.</p>", "<title>Radiotherapy</title>", "<p>Twenty-eight patients underwent radiotherapy and 48 did not. Radiotherapy patients reported worse scores for faecal incontinence: this was statistically significant. No other results were statistically significant. Patients who had undergone radiotherapy reported worse scores in 16 of 21 domains.</p>", "<title>Stomata</title>", "<p>Twenty-nine patients had a stoma at the time of data collection, whereas 47 did not. Patients with a stoma reported higher scores for sexual interest. This was the only statistically significant result. Patients without a stoma reported worse scores in 12 of 20 domains. The question regarding stoma difficulties was excluded from this analysis because it was not comparable.</p>", "<title>Length of follow-up</title>", "<p>At the time of data collection, 66 patients were more than 36 months from their operation, whereas 10 patients were less than 36 months from their operation. Patients who were less than 36 months from their operation reported greater scores for anxiety and worries about weight. They also reported higher scores for sexual interest. These were all statistically significant results.</p>", "<p>Forty-five patients were more than 60 months from their operation, whereas 31 patients were less than 60 months from their operation. There were three statistically significant differences. Patients less than 60 months from their operation reported more worries about weight, and patients who were more than 60 months from their operation reported worse symptoms with regards to bloating and abdominal pain.</p>", "<p>Although not reaching statistical significance, patients more than 36 months from their operation reported worse scores in 14 of 21 domains. Patients more than 60 months from their operation reported worse scores in 13 of 21 domains.</p>", "<title>Other factors</title>", "<p>Fifteen patients suffered complications, whereas 61 did not. Patients with complications reported significantly worse scores for hair loss and mouth dryness. No other results were significant. Patients above and below the mean age reported similar scores.</p>" ]	[ "<title>Discussion</title>", "<p>This study has assessed PROMs for QOL following surgery for rectal cancer in a large cohort. The study population is heterogenous, including participants with permanent and temporary stomata, those who have had restoration of intestinal continuity, and those who have undergone chemotherapy and radiotherapy. Patients have been compared who have undergone different treatment modalities and vary widely in terms of age and stage of recovery. PROMs have been assessed using validated measurements for their condition.</p>", "<p>The questionnaires cover 59 symptom- and function-related areas. Considering this large number and broad range of questions, statistically significant differences between groups are few. They are summarised in ##TAB##2##Table 3##. The relatively low number of statistically significant differences between comparative groups is in line with several published papers on the subject.</p>", "<p>Several areas showed a trend towards significance, which may have been more marked given a larger sample size. A baseline questionnaire would have been beneficial in this instance, because many symptoms may have predated surgery in this elderly cohort. This should be a necessary line of enquiry for future prospective studies.</p>", "<p>One striking finding is that patients with a permanent stoma report similar QOL to those who have had intestinal continuity restored. Questions regarding sexual functioning were better in permanent stoma patients in particular, in contrast to several other papers.<sup>##UREF##3##6##, ####REF##12894013##7##, ##REF##16180267##8####16180267##8##</sup> Although they reported different sets of problems <bold>–</bold> for example, AR patients reported worse symptoms regarding diarrhoea, and APR patients regarding embarrassment – overall QOL scores were similar.</p>", "<p>Although data exist to suggest that a stoma has an appreciably negative impact on quality of health,<sup>##REF##12894013##7##,##UREF##4##9##,##REF##20602501##10##</sup> there is contrasting evidence consistent with our cohort’s results. Camilleri-Brennan <italic>et al</italic> arrived at similar conclusions in their prospective, case-matched comparison of APR and AR patients,<sup>##UREF##3##6##</sup> as did Gosselink.<sup>##UREF##4##9##</sup> A Cochrane review published in 2012 also concluded that QOL in both groups of patients is similar.<sup>##UREF##5##11##</sup> This is perhaps a reflection of the quality of support for stoma patients, and may also be an example of ‘reframing’, where acceptance of certain consequences of treatment leads to an improved perception of QOL.<sup>##REF##11206224##12##,##UREF##6##13##</sup> Stoma patients have consistently reported better scores for symptoms relating to diarrhoea and gastrointestinal function in a number of studies.<sup>##REF##16180267##8##,##REF##19571701##14##,##REF##20127342##15##</sup></p>", "<p>Higher overall scores for older patients in physical, emotional and cognitive function may also be an example of reframing. This matches the findings of Arndt <italic>et al</italic>, who reasoned they may accept worse function as part of increasing age, both in the context of having undergone multimodal cancer therapy and in comparing overall health with peers. Furthermore, younger patients may not have access to the same resources that can help as coping strategies.<sup>##REF##16829069##16##</sup></p>", "<p>The effect of adjuvant therapy was not as marked as expected, although patients who had undergone radiotherapy in particular tended to report worse scores, reaching statistical significance for diarrhoea. Chemotherapy patients reported better overall QOL, but they reported worse symptom-related scores. Although not statistically significant in the majority of cases, one can infer from the trends that adjuvant therapy negatively impacts patients far more than the modality of surgery. Much other data support this.<sup>##REF##16180267##8##,##UREF##7##17##, ####UREF##8##18##, ##UREF##9##19####9##19##</sup></p>", "<p>In terms of overall quality of health and life, our cohort compare well with other rectal cancer patients. This can, however, be difficult to compare directly because few papers use the same combination of questionnaires. Some 48% and 61% of responders in our study replied with a score of 6 or 7 to questions 29 and 30 in the EORTC QLQ-C30 questionnaire, respectively; corresponding to good or perfect health and QOL. A UK Department of Health report in 2015 that included over 6,000 rectal cancer patients described that 29% reported perfect health, compared with 40% of the general population.<sup>##UREF##0##1##</sup></p>", "<p>This paper is subject to various limitations. The data were limited to patients who chose to respond. This may mean those with potentially significantly different experiences were not assessed. Patients answered either by post or by telephone; it is possible that two different methods of populating the questionnaire influenced the responses given. Patients who had filled out EORTC QLQ-CR29 incompletely were excluded from the analysis, which may also have exerted bias. The study was not designed or powered to assess for one clinical or statistical endpoint. The paper did not consider concurrent medical illness, or level of anastomosis, both which have shown to adversely affect QOL.<sup>##REF##15752893##20##, ####REF##12394435##21##, ##REF##11176118##22##, ##REF##15019011##23####15019011##23##</sup></p>", "<p>The study does not contain a comparator for pretreatment QOL. Although we have shown that overall QOL is good post treatment, we have not illustrated how it has changed as a result of the various therapies employed. Similarly, we have assessed QOL at one time point postoperatively, with all participants responding at various lengths of time post treatment. A series of assessments of QOL would have been beneficial in this respect with questionnaires at predefined intervals: for example, at baseline, 3, 6 and 12 months postoperatively, and yearly thereafter. Patients with early tumours managed with endoluminal approaches have also not been assessed because the primary focus of the paper was to assess the impact of resectional surgery. This is an area of increasing importance and such approaches may have a significantly lower impact on QOL. These limitations are being addressed by a prospective study (the CiTRus trial) currently underway at the Royal Surrey County and Clatterbridge hospitals (ClinicalTrials.gov Identifier: NCT04697394).</p>", "<p>Although these limitations should qualify interpretation of the data, the authors feel, after assessment of other studies, that the sample size and methodology mean that important conclusions can be drawn.</p>", "<p>QOL and PROMs are increasingly being incorporated in colorectal cancer management and follow-up programmes. Work is currently underway to assess whether patient- rather than clinician-led follow-up may have an impact on clinical outcomes.<sup>##UREF##10##24##</sup></p>" ]	[ "<title>Conclusions</title>", "<p>Our paper has shown that overall QOL is high after surgical treatment for rectal cancer, but specific factors may influence different symptoms. More work that uses standardised PROM and QOL assessment measures is required, such that patients can be better informed regarding functional and symptomatic issues that may occur following treatment. This is particularly important in early-stage disease, where a variety of organ-preserving strategies are now available. Ultimately, this will guide better patient-centred decision-making in rectal cancer and assist in identifying and delivering tailored solutions to QOL issues in the postoperative setting.</p>" ]	[ "<title>Introduction</title>", "<p>Colorectal cancer survivors have many problems affecting their quality of life (QOL). Traditional follow-up focuses on the detection of recurrence rather than QOL. Efforts are being made to assess patient-reported outcomes (PROMS) more formally. Such changes may enable patients to consider QOL factors when deciding on treatment.</p>", "<title>Methods</title>", "<p>Patients who underwent laparoscopic surgery for rectal cancer between 2005 and 2015 at a single institution were identified and sent European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29 QOL questionnaires. QOL and the impact of radiotherapy, chemotherapy and formation of end colostomy were assessed.</p>", "<title>Results</title>", "<p>Some 141 patients were identified: 12 died and 118 (83.7%) responded, of whom 101 completed the questionnaires and 17 declined to participate; 11 were lost to follow-up. Mean age was 67 years, median follow-up was 58 months. Median QOL score was 6 (maximum 7) and 4.5% of patients reported a poor QOL score (<4). Significant rectal/perianal pain, sexual dysfunction and urinary symptoms were reported in 3.6%, 10.9% and 2.7% of respondents, respectively. Significant differences between treatment groups were uncommon. All cohorts reported similar QOL, functional and symptom scores.</p>", "<title>Conclusions</title>", "<p>These results compare favourably with the published data. Future studies may benefit from baseline assessment to better assess treatment impact, prescient in an increasingly elderly and comorbid population. This paper establishes that good PROMs are achievable with laparoscopic surgery for rectal cancer. It identifies limited differences in QOL between treatment modalities. Restoration of intestinal continuity and end colostomy result in similar QOL. This may address common concerns regarding stomata, sexual function and low anterior resection syndrome in this cohort.</p>" ]	[]	[]	[]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0156TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Breakdown of patients by treatment modalities</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"1\" colspan=\"1\">Treatment Modality</th><th rowspan=\"1\" colspan=\"1\">\n<italic>n</italic>\n</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Surgery alone</td><td rowspan=\"1\" colspan=\"1\">37</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Preoperative chemotherapy</td><td rowspan=\"1\" colspan=\"1\">35</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Preoperative radiotherapy</td><td rowspan=\"1\" colspan=\"1\">33</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Postoperative chemotherapy</td><td rowspan=\"1\" colspan=\"1\">44</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Preoperative chemotherapy and radiotherapy</td><td rowspan=\"1\" colspan=\"1\">31</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Preoperative radiotherapy and postoperative chemotherapy</td><td rowspan=\"1\" colspan=\"1\">18</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0156TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Complications</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"1\" colspan=\"1\">Complication</th><th rowspan=\"1\" colspan=\"1\">\n<italic>n</italic>\n</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Anastomotic leak</td><td rowspan=\"1\" colspan=\"1\">8 (6 defunctioned, 2 managed conservatively)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Pulmonary embolus</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">High-output stoma</td><td rowspan=\"1\" colspan=\"1\">2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Bleed requiring transfusion</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Perineal hernia</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Rectovesical fistula</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Cardiac arrest, return of spontaneous circulation</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Adhesional small bowel obstruction</td><td rowspan=\"1\" colspan=\"1\">1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Anastomotic stricture</td><td rowspan=\"1\" colspan=\"1\">1</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0156TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Statistically significant results by questionnaire and comparator group</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/></colgroup><tbody><tr><td rowspan=\"1\" colspan=\"1\">EORTC QLQ-C30</td></tr><tr><td rowspan=\"1\" colspan=\"1\">APR patients reported better scores for diarrhoeal symptoms</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Chemotherapy patients reported better overall health and overall quality-of-life scores</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Patients above the mean age reported more positive scores for physical, emotional and cognitive function</td></tr><tr><td rowspan=\"1\" colspan=\"1\">EORTC QLQ-CR29</td></tr><tr><td rowspan=\"1\" colspan=\"1\">APR patients reported higher scores for sexual interest</td></tr><tr><td rowspan=\"1\" colspan=\"1\">AR patients reported higher scores for sexual difficulties</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Chemotherapy patients reported worse scores for dysuria, problems with taste and sore skin</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Radiotherapy patients reported worse scores for faecal incontinence</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Patients with a stoma reported higher scores for sexual interest</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Patients more than 36 months from their operation reported greater scores for worries about weight and health</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Patients more than 36 months from their operation reported higher scores for sexual interest</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Patients less than 60 months from their operation reported more worries about weight</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Patients more than 60 months from their operation reported worse symptoms with regards to bloating and abdominal pain</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Patients who suffered complications reported worse scores for hair loss and mouth dryness</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><p>APR = abdominoperineal excision of the rectum; AR = anterior resection</p></table-wrap-foot>" ]	[]	[]	[{"label": ["1."], "collab": ["UK Department of Health"], "article-title": ["Quality of life of colorectal cancer survivors in England"], "fpage": ["179"], "ext-link": ["https://www.england.nhs.uk/wp-content/uploads/2015/03/colorectal-cancer-proms-report-140314.pdf"]}, {"label": ["3."], "collab": ["National Institute for Health Care and Excellence (NICE)"], "italic": ["Colorectal cancer: diagnosis and management"], "ext-link": ["https://www.nice.org.uk/guidance/ng151"]}, {"label": ["5."], "mixed-citation": ["Mcnair AGK, Whistance RN, Forsythe RO "], "italic": ["et al.", "Color Dis"], "article-title": ["Synthesis and summary of patient-reported outcome measures to inform the development of a core outcome set in colorectal cancer surgery"], "year": ["2015"], "bold": ["17"], "fpage": ["O217"], "lpage": ["O229"]}, {"label": ["6."], "surname": ["Camilleri-Brennan", "Steele"], "given-names": ["J", "RJC"], "article-title": ["Objective assessment of morbidity and quality of life after surgery for low rectal cancer"], "italic": ["Color Dis"], "year": ["2002"], "bold": ["4"], "fpage": ["61"], "lpage": ["66"]}, {"label": ["9."], "mixed-citation": ["Gosselink MP, Busschbach JJ, Dijkhuis CM "], "italic": ["et al.", "Color Dis"], "article-title": ["Quality of life after total mesorectal excision for rectal cancer"], "year": ["2006"], "bold": ["8"], "fpage": ["15"], "lpage": ["22"]}, {"label": ["11."], "surname": ["Pachler", "Wille-J\u00f8rgensen"], "given-names": ["J", "P"], "article-title": ["Quality of life after rectal resection for cancer, with or without permanent colostomy"], "italic": ["Cochrane Database Syst Rev"], "year": ["2012"]}, {"label": ["13."], "surname": ["Calandra", "Di Mauro", "Cutugno", "Di Martino"], "given-names": ["DM", "D", "F", "S"], "article-title": ["Navigating wall-sized displays with the gaze: A proposal for cultural heritage"], "italic": ["CEUR Workshop Proc"], "year": ["2016"], "bold": ["1621"], "fpage": ["36"], "lpage": ["43"]}, {"label": ["17."], "mixed-citation": ["Varpe P, Huhtinen H, Rantala A "], "italic": ["et al.", "Color Dis"], "article-title": ["Quality of life after surgery for rectal cancer with special reference to pelvic floor dysfunction"], "year": ["2011"], "bold": ["13"], "fpage": ["399"], "lpage": ["405"]}, {"label": ["18."], "comment": ["Smith-Gagen J, Cress RD, Dramke CM. Quality-of-life and surgical treatments for rectal cancer \u2014 a longitudinal analysis using the California Cancer Registry. "], "italic": ["Psychooncology"], "bold": ["19"]}, {"label": ["19."], "mixed-citation": ["Thong MSY, Mols F, Lemmens VEPP "], "italic": ["et al.", "Int J Radiat Oncol Biol Phys"], "article-title": ["Impact of preoperative radiotherapy on general and disease-specific health status of rectal cancer survivors: a population-based study"], "year": ["2011"], "bold": ["81"], "fpage": ["49"], "lpage": ["58"]}, {"label": ["24."], "mixed-citation": ["Hovdenak Jakobsen I, Juul T, Bernstein I "], "italic": ["et al.", "Acta Oncol (Madr)"], "article-title": ["Follow-up after rectal cancer: developing and testing a novel patient-led follow-up program. Study protocol"], "year": ["2017"], "bold": ["56"], "fpage": ["307"], "lpage": ["313"]}]	{ "acronym": [], "definition": [] }	24	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 7; 106(1):13-18	oa_package/33/02/PMC10757878.tar.gz
PMC10757879	36688848	[ "<title>Introduction</title>", "<p>Patients present to ear, nose and throat (ENT) clinics with asymmetrical palatine tonsils without other symptoms, or in association with pathological cervical lymphadenopathy, or incidentally found on examination or imaging. Traditionally, such cases are investigated by tonsillectomy for histological diagnosis.</p>", "<p>The rate of malignancy in asymmetrical tonsils without associated signs and symptoms of malignancy is negligible.<sup>##REF##17711770##1##, ####REF##16834797##2##, ##UREF##0##3##, ##REF##15243564##4####15243564##4##</sup> Tonsil biopsy offers a means of obtaining histological diagnosis without a general anaesthetic, preoperative assessment, and the morbidity of tonsillectomy including pain and bleeding.<sup>##UREF##1##5##</sup></p>", "<p>The option of tonsil biopsy has been standard practice in our departments (which collaborate as a joint head and neck multidisciplinary team) for several years. Tonsil biopsy is performed at the discretion of the clinician under local anaesthetic in the outpatient department for patients with asymmetry or focal abnormality. In our experience, this approach facilitates earlier diagnosis compared with tonsillectomy without associated morbidity.</p>", "<p>The aim of this retrospective service evaluation is to assess the usage of tonsil biopsy in our network and quantify delays to tissue sampling compared with tonsillectomy.</p>", "<title>Tonsil biopsy technique in the outpatient setting</title>", "<p>Patients are typically seen in the head and neck suspected cancer clinic, which incorporates a one-stop neck lump clinic. We have established that each clinician (consultant, associate specialist, staff grade and/or specialist registrar) would be allocated seven patients, with 25-minute slots per patient. Through a process of trial and error, we identified this as the ideal clinic template to allow timely running of the clinic while allowing discussion of ultrasound results, taking consent for future procedures, undertaking all administrative tasks and performing biopsies under local anaesthetic (oropharyngeal and laryngeal) where appropriate. In cases in which it is not clear whether a tonsil biopsy is appropriate, this can be discussed with the consultant leading the clinic session.</p>", "<p>Once a patient has agreed to proceed to tonsil biopsy in clinic, written consent is obtained having explained the procedure and risks including infection, bleeding and failure to make a diagnosis, which may require further investigation or procedure. The World Health Organization surgical safety checklist is completed. The oropharynx is inspected using a headlight and metal tongue depressor. Approximately five sprays of xylocaine 10mg anaesthetic spray are applied to the oropharynx on the side to be biopsied because this helps to minimise the gag reflex. After 1min, the oropharynx is again inspected with the tongue depressed. A single-use cervical rotating biopsy punch (DTR Medical Ltd, Swansea, UK) is used to obtain a biopsy of the tonsil which is then sent for histology. The oropharynx is reinspected to ensure there is no significant ongoing bleeding, which can be managed with bipolar cautery, prior to the patient leaving the outpatients department. The patient is advised to remain nil by mouth until the local anaesthetic has worn off.</p>" ]	[ "<title>Methods</title>", "<p>A two-centre service evaluation was undertaken involving a retrospective case note review of palatine tonsil biopsy and tonsillectomy for histology between 1 January 2013 and 31 December 2018 inclusive. The study period allowed a minimum follow-up period of 36 months in which patients may have presented again with missed diagnoses or needed further investigations.</p>", "<p>Cases were identified by interrogating hospital pathology information systems for the presence of the terms ‘tonsil’, ‘tonsillectomy’ or ‘oropharynx’ in the histology report. The histology reports and electronic case notes were reviewed to identify only those cases relating to palatine tonsils.</p>", "<p>Cases were excluded where the clinical scenario would preclude tonsil biopsy; carcinoma of unknown primary cases because the tonsils would look unremarkable; and tonsil sampling as a secondary procedure to other operations such as neck dissection or branchial cyst excision. Patients were excluded if the decision to send tonsils for histology was made on the day of surgery; typically these were patients with recurrent tonsillitis who had asymmetrical tonsils noted at time of tonsillectomy.</p>", "<p>Data collected included patient demographics, date of initial presentation, indication for biopsy, nature of procedure, date of specimen collection and final histological diagnosis. It was also noted whether patients required a further procedure, either as part of their initial presentation or following re-referral.</p>", "<title>Statistical analysis</title>", "<p>Data were recorded on an Excel spreadsheet (Microsoft Corp., Redmond, US), which was used to produce descriptive statistics. The delay from initial ENT consultation to tissue sampling was compared with the Mann–Whitney <italic>U</italic> test using IBM SPSS Statistics for Windows, version 28 (IBM Corp., Armonk, US). The rate of success and failure of tonsil biopsy was established, with failure being defined as the need to repeat the tonsil biopsy or proceed to formal tonsillectomy for histological diagnosis. We also explored the variation in techniques over time (tonsil biopsy in clinic, tonsil biopsy under general anaesthetic and tonsillectomy).</p>", "<p>The project was registered with institutional audit and quality improvement departments. Because this was a retrospective service evaluation ethical approval was not required.</p>" ]	[ "<title>Results</title>", "<p>From 2014 to 2018, 984 adult patients were identified who had samples of palatine tonsils taken for histological diagnosis. Forty-seven patients were excluded because clinical information was incomplete (4.4%).</p>", "<p>Some 937 patients were included for analysis, consisting of 485 males (mean age 49.0 years, range 16–87 years) and 452 females (mean age 47.1 years, range 16–90 years).</p>", "<p>Of the patients in the study, 375 (40.0%) had a biopsy, of which 191 (50.9%) were performed under topical anaesthesia in clinic and 182 (48.5%) were performed under general anaesthesia in theatre. Some 562 patients had a formal tonsillectomy. The number of biopsies vs tonsillectomies over time is demonstrated in ##TAB##0##Table 1##. The histology results for all patients are shown in ##TAB##1##Table 2##.</p>", "<p>The mean duration from initial appointment with ENT to tissue sample collection was 17.6 days (range 0–327 days, median 0 days) for all biopsies performed in clinic or theatre, reducing to 0.2 days (range 0–17 days, median 0 days) for biopsies performed in clinic. For tonsillectomies, the mean duration was 38.9 days (range 0–444 days, median 28 days).</p>", "<p>The median duration between clinic appointment and collection of tissue sample for tonsillectomy was 28 days, compared with a median of 0 days for tonsil biopsy. Mann–Whitney <italic>U</italic> test demonstrated a statistically significant difference in time from initial consultation to tissue sampling between patients undergoing a tonsillectomy and those who had a biopsy (<italic>p<</italic>0.01).</p>", "<p>Three patients waited more than 300 days from when they were seen in clinic to their histology being reported. On further interrogation of the notes, these patients were felt to have benign pathology when seen in clinic and were therefore listed routinely for procedures under general anaesthetic.</p>", "<p>Of the 375 patients who underwent a biopsy, 14 (3.7%) underwent a further procedure to obtain tissue for histology.\n<list list-type=\"simple\"><list-item><label>•</label><p>Ten patients required a further procedure to aid in diagnostics, six of whom were subsequently diagnosed with malignancy (see below):</p></list-item><list-item><label>•</label><p>Two patients diagnosed with Squamous Cell Carcinoma (SCC) on biopsy underwent treatment, then subsequently underwent further panendoscopy with tonsil biopsies owing to a concern regarding recurrence found at surveillance follow-up;</p></list-item><list-item><label>•</label><p>two patients re-presented to ENT 2 years after being diagnosed with benign tonsillar asymmetry on biopsy, repeat biopsy showed no malignancy.</p></list-item></list>\n<list list-type=\"simple\"><list-item><label>•</label><p>Six patients (1.6%) who underwent biopsy were later diagnosed with malignancy that was not found during initial biopsy:</p></list-item><list-item><label>•</label><p>two were symptomatic of lymphoma with normal tonsil biopsies and diagnosis was made on subsequent core biopsy of cervical lymph nodes;</p></list-item><list-item><label>•</label><p>one had lymphoma in repeat tonsil biopsies taken in theatre;</p></list-item><list-item><label>•</label><p>one had mucoepidermoid carcinoma diagnosed on tonsillectomy, with earlier clinic biopsy showing features in keeping with a mucocele, although it was noted at the time that this was a technically difficult procedure that was poorly tolerated, with the clinician indicating that the sample may not be representative;</p></list-item><list-item><label>•</label><p>one had a clinically suspicious tonsil lesion with a negative tonsil biopsy in clinic, and underwent further tonsil biopsies under general anaesthetic which confirmed SCC;</p></list-item><list-item><label>•</label><p>one had a tonsil biopsy in clinic reported as dysplasia, diagnosed as p16-positive SCC following tonsillectomy. On subsequent MDT review by the head and neck specialist lead histopathologist, the initial tonsil biopsy was shown to demonstrate p16-positive SCC rather than dysplasia as initially reported.</p></list-item></list></p>", "<p>No patients discharged from ENT later re-presented with a missed diagnosis of cancer.</p>" ]	[ "<title>Discussion</title>", "<p>We have reported our experience of 937 patients across two sites who had tonsil tissue sent for histology over a 6-year period. Some 375 patients underwent a tonsil biopsy, 191 of which were performed in clinic; 562 patients had a tonsillectomy. The patients who underwent a tonsil biopsy would have received a tissue diagnosis significantly faster than those who had a tonsillectomy, more so for those patients who had a tonsil biopsy performed in clinic rather than in theatre. Our data demonstrate that the proportion of patients having a biopsy instead of tonsillectomy has increased over time.</p>", "<p>Of 375 patients who underwent a tonsil biopsy, only 6 (1.6%) had malignancy diagnosed on subsequent histology. In all these cases there was a negative tonsil biopsy despite a high index of suspicion of malignancy prompting further investigation, as detailed earlier.</p>", "<p>The involvement of specialist head and neck pathologists is preferable because they are more aware of some of the peculiar diagnostic pitfalls in the diagnosis of Human Papilloma Virus (HPV)-related oropharyngeal SCC. For example, the non-infiltrative pushing pattern of invasion in small biopsies is often misinterpreted as dysplasia by a less experienced generalist.<sup>##REF##28060372##6##</sup></p>", "<p>The results of tonsil biopsy should not be viewed in isolation, however. Clinical judgement must be applied in conjunction with histology results to establish whether further investigation is warranted. Any patient who had a malignancy that was not diagnosed on biopsy was later diagnosed on tonsillectomy or further biopsy under a general anaesthetic. The combined approach of clinical judgement and tonsil biopsy appears to be successful as, importantly, no patients were discharged from ENT following a negative biopsy who then re-presented with a malignancy.</p>", "<p>The rate of malignancy in unilateral enlarged tonsils without associated symptoms is negligible. If there are associated symptoms, and high clinical suspicion, the rate for malignancy is 5%–9%.<sup>##REF##17711770##1##, ####REF##16834797##2##, ##UREF##0##3##, ##REF##15243564##4####15243564##4##</sup> This would support our proposition that tonsil biopsies are a safe and effective tool that can be particularly useful in the following situations:\n<list list-type=\"simple\"><list-item><label>• </label><p>In patients with asymmetrical tonsils, no concerning symptoms and low clinical suspicion, a negative biopsy can be useful to reassure and discharge the patient.</p></list-item><list-item><label>• </label><p>Patients diagnosed with malignancy on tonsil biopsy where the primary site is too extensive for surgical management will benefit from immediate referral for oncological treatment following radiological staging and multidisciplinary team discussion.</p></list-item></list>Patients in whom the clinician has a high level of clinical suspicion for malignancy, and either suspected to have an unrepresentative sample, or a negative tonsil biopsy result, would be offered formal tonsillectomy for histology.</p>", "<p>We do not advocate the use of tonsil biopsies in patients with an SCC of unknown primary. Waltonen <italic>et al</italic><sup>##REF##19117304##7##</sup> found that occult tonsil malignancies are more likely to be diagnosed on tonsillectomy (29.6%) than tonsil biopsy (3.2%), and one patient in that study was subsequently diagnosed with an SCC that had been missed on tonsil biopsy.</p>", "<p>We have not considered the role of examination under anaesthesia of a presumed oropharyngeal primary to assess suitability for transoral laser or robotic surgery, which is beyond the remit of this service evaluation. Historically, it has been suggested that tonsil biopsy may impair subsequent staging imaging; it is the opinion of the radiologists at our institutions that this is rarely an issue provided the reporting radiologist is made aware of the timing of biopsy.</p>", "<title>Study limitations</title>", "<p>Limitations of our service evaluation include the reliance on retrospective data that were not standardised. The data for waiting time for histology results in patients who underwent tonsillectomy may be skewed by patients who were viewed as low or no clinical risk of malignancy and therefore were not booked urgently, although these are small numbers that do not impact on the overall conclusions. Although there were no patients re-presenting to our ENT departments with a missed malignancy, this service evaluation does not account for patients who may have moved out of the region and presented to ENT departments elsewhere and who we may not have been made aware of.</p>" ]	[ "<title>Conclusions</title>", "<p>Tonsil biopsy is a viable method for obtaining tonsil tissue for diagnosis. Tonsil biopsies represent significantly less waiting time for histological diagnosis, less inconvenience for patients (especially if performed in the clinic under a local anaesthetic) and less overall cost. Although tonsil biopsies should not be used in isolation from clinical judgement, they are particularly useful in the investigation and reassurance of patients presenting with tonsillar asymmetry. The corroboration of benign pathology in the absence of clinical suspicion is of value to patients.</p>", "<p>The response to the coronavirus pandemic has impacted on the availability of operating theatre capacity leading to longer waiting times for surgery. In this climate, clinic-based diagnostic procedures are particularly appealing. The utilisation of tonsil biopsies more widely could help to reduce the burden on waiting times for surgery and expedite patient care.</p>", "<p>In appropriate clinical scenarios involving focal irregularity or gross asymmetry of palatine tonsils, biopsy in the outpatient setting is favourable compared with formal tonsillectomy in terms of reduced surgical morbidity, quicker diagnosis and lower healthcare costs. This can facilitate earlier diagnosis and delivery of definitive treatment.</p>" ]	[ "<title>Introduction</title>", "<p>We aim to evaluate our experience of tonsil biopsies in the investigation of patients presenting with asymmetrical tonsils.</p>", "<title>Methods</title>", "<p>A two-centre retrospective analysis of all patients who underwent histology sampling of the palatine tonsils between 1 January 2013 and 31 December 2018 was completed. Data collected included patient demographics, method of obtaining tonsil tissue, histological diagnosis and need for repeat tissue sampling. A follow-up period of 36 months was allowed to establish whether any patients re-presented with missed diagnoses.</p>", "<title>Results</title>", "<p>In total, 937 patients were included for analysis: 375 (40.0%) had a biopsy, of which 191 (50.9%) were performed in clinic. The mean duration from initial appointment with the ear, nose and throat clinic to tissue sample collection was 17.6 days (range 0–327 days) for all biopsies, reducing to 0.2 days (range 0–17 days) for biopsies performed in clinic. This was significantly shorter than for tonsillectomies (mean 38.9 days, range 0–444 days; <italic>p</italic><0.05). Of the patients who underwent tonsil biopsy, six (1.6%) had malignancy that was not unequivocally diagnosed on initial biopsy. In all six patients, prior clinical suspicion was high, and repeat tissue sampling was undertaken on receipt of negative histology results.</p>", "<title>Conclusions</title>", "<p>Tonsil biopsy is a viable alternative to tonsillectomy for histology in the assessment of tonsil asymmetry. Tonsil biopsy in the outpatient setting has reduced surgical morbidity, significantly less delay in diagnosis, less inconvenience for patients and lower healthcare costs compared with formal tonsillectomy. Although tonsil biopsies should not be used in isolation, they can be useful in the investigation of patients presenting with tonsillar asymmetry.</p>" ]	[]	[]	[]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0122TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Frequency of diagnostic tonsillectomies and tonsil biopsies by year</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\"/><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>2013</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>2014</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>2015</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>2016</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>2017</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>2018</bold>\n</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Total tonsillectomies and tonsil biopsies sent for histology (<italic>n</italic>)</td><td rowspan=\"1\" colspan=\"1\">87</td><td rowspan=\"1\" colspan=\"1\">160</td><td rowspan=\"1\" colspan=\"1\">181</td><td rowspan=\"1\" colspan=\"1\">182</td><td rowspan=\"1\" colspan=\"1\">166</td><td rowspan=\"1\" colspan=\"1\">161</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Tonsillectomies (<italic>n</italic>)<break/> Percentage of total sent for histology</td><td rowspan=\"1\" colspan=\"1\">64<break/>73.6</td><td rowspan=\"1\" colspan=\"1\">107<break/>66.9</td><td rowspan=\"1\" colspan=\"1\">116<break/>64.1</td><td rowspan=\"1\" colspan=\"1\">107<break/>58.8</td><td rowspan=\"1\" colspan=\"1\">76<break/>45.8</td><td rowspan=\"1\" colspan=\"1\">92<break/>57.1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Tonsil biopsies (in theatre or in clinic) (<italic>n</italic>)<break/> Percentage of total sent for histology</td><td rowspan=\"1\" colspan=\"1\">23<break/>26.4</td><td rowspan=\"1\" colspan=\"1\">53<break/>33.1</td><td rowspan=\"1\" colspan=\"1\">65<break/>35.9</td><td rowspan=\"1\" colspan=\"1\">75<break/>41.2</td><td rowspan=\"1\" colspan=\"1\">90<break/>54.2</td><td rowspan=\"1\" colspan=\"1\">69<break/>42.9</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Tonsil biopsies performed in theatre (<italic>n</italic>)<break/> Percentage of all tonsil biopsies</td><td rowspan=\"1\" colspan=\"1\">19<break/>82.6</td><td rowspan=\"1\" colspan=\"1\">27<break/>50.9</td><td rowspan=\"1\" colspan=\"1\">38<break/>58.5</td><td rowspan=\"1\" colspan=\"1\">41<break/>54.7</td><td rowspan=\"1\" colspan=\"1\">31<break/>34.4</td><td rowspan=\"1\" colspan=\"1\">28<break/>40.6</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Tonsil biopsies performed in clinic (<italic>n</italic>)<break/> Percentage of all tonsil biopsies</td><td rowspan=\"1\" colspan=\"1\">4<break/>17.4</td><td rowspan=\"1\" colspan=\"1\">26<break/>49.1</td><td rowspan=\"1\" colspan=\"1\">27<break/>41.5</td><td rowspan=\"1\" colspan=\"1\">34<break/>45.3</td><td rowspan=\"1\" colspan=\"1\">59<break/>65.6</td><td rowspan=\"1\" colspan=\"1\">41<break/>59.4</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0122TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Histological diagnoses in patients undergoing tonsillectomy (<italic>N</italic>=562) and biopsy (<italic>N</italic>=375)</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>Diagnosis</bold>\n</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">\n<bold>Tonsillectomy</bold>\n<break/>\n<bold><italic> n</italic> (%)</bold>\n</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">\n<bold>Biopsy </bold>\n<break/>\n<bold><italic>n</italic> (%)</bold>\n</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Normal/reactive</td><td rowspan=\"1\" colspan=\"1\">477 (84.9)</td><td rowspan=\"1\" colspan=\"1\">145 (38.7)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Benign lesion</td><td rowspan=\"1\" colspan=\"1\">20 (3.6)</td><td rowspan=\"1\" colspan=\"1\">101 (26.9)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">SCC p16 positive</td><td rowspan=\"1\" colspan=\"1\">40 (7.1)</td><td rowspan=\"1\" colspan=\"1\">65 (17.3)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">SCC p16 negative</td><td rowspan=\"1\" colspan=\"1\">6 (1.1)</td><td rowspan=\"1\" colspan=\"1\">13 (3.5)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">SCC p16 not known</td><td rowspan=\"1\" colspan=\"1\">4 (0.7)</td><td rowspan=\"1\" colspan=\"1\">22 (5.8)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Lymphoma</td><td rowspan=\"1\" colspan=\"1\">10 (1.8)</td><td rowspan=\"1\" colspan=\"1\">24 (6.4)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Other malignancy</td><td rowspan=\"1\" colspan=\"1\">4 (0.7)</td><td rowspan=\"1\" colspan=\"1\">2 (0.5)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Dysplasia</td><td rowspan=\"1\" colspan=\"1\">1 (0.2)</td><td rowspan=\"1\" colspan=\"1\">3 (0.8)</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>SCC = Squamous Cell Carcinoma </p></fn></table-wrap-foot>" ]	[]	[]	[{"label": ["3."], "surname": ["Al Marzooq", "Abdulla", "Al Sindi"], "given-names": ["J", "J", "M"], "article-title": ["Incidence of malignancy in asymmetrical tonsillar enlargement"], "italic": ["Int J Otolaryngol Head Neck Surg"], "year": ["2017"], "bold": ["6"], "fpage": ["6"], "lpage": ["10"]}, {"label": ["5."], "surname": ["Seshamani", "Vogtmann", "Gatwood"], "given-names": ["M", "E", "J"], "italic": ["et al.", "Otolaryngol Head Neck Surg (United States)"], "article-title": ["Prevalence of complications from adult tonsillectomy and impact on health care expenditures"], "year": ["2014"], "bold": ["150"], "fpage": ["574"], "lpage": ["581"]}]	{ "acronym": [], "definition": [] }	7	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 23; 106(1):41-44	oa_package/e1/ec/PMC10757879.tar.gz
PMC10757880	36779445	[ "<title>Introduction</title>", "<p>Thoracic outlet syndrome (TOS) is caused by compression of the neurovascular structures passing through the thoracic inlet (##FIG##0##Figure 1##). It is categorised into three subtypes: neurogenic TOS (NTOS), venous TOS (VTOS) and arterial TOS (ATOS). These subtypes occur secondary to compression of brachial plexus, subclavian vein or subclavian artery. Thoracic outlet compression has multiple aetiologies, it may result from anomalous ribs, congenital cervical fibro-cartilaginous bands, muscular anomalies or injury.</p>", "<p>The most common subtype is NTOS, which accounts for approximately 95% of cases; VTOS accounts for 3% of cases and ATOS accounts for 1% of cases.<sup>##REF##31859722##1##</sup> Symptoms of brachial plexus compression include pain, weakness, numbness and paraesthesia of the upper limb. Venous compression may result in arm swelling and deep vein thrombosis. Arterial compression may cause upper limb claudication symptoms, embolic events and acute limb ischaemia. Symptoms may be aggravated by activities that involve prolonged use of arms or hands and elevation of upper extremity.<sup>##REF##17826254##2##</sup></p>", "<p>Initial management of NTOS is physiotherapy and some centres offer adjunctive medical therapy with local anaesthetic, steroids and botulinum toxin.<sup>##REF##25840533##3##</sup> Patients who have failed conservative management are offered thoracic outlet decompression surgery. VTOS and ATOS warrant expedited surgical management owing to the high incidence of secondary complications. The standard for surgical care of TOS patients is first rib resection (FRR).<sup>##REF##27666803##4##</sup> Surgical approaches include supraclavicular, infraclavicular and transaxillary, with the choice of procedure determined by the subtype of TOS and surgeon preference. Recently, thoracoscopic (assisted) and robotic approaches have been described in the literature.<sup>##REF##33220774##5##</sup></p>", "<p>This retrospective observational study aims to evaluate the outcomes of surgical management of thoracic outlet syndrome at a single district general hospital (DGH) over a period of 17 years.</p>" ]	[ "<title>Methods</title>", "<title>Local protocol</title>", "<p>In our institution, diagnosis of NTOS was determined via clinical evaluation, nerve conduction studies and magnetic resonance imaging (MRI) cervical spine. MRI cervical spine is performed routinely in this patient cohort. Nerve conduction studies are performed in cases of diagnostic uncertainty to rule out common differential diagnoses such as carpal tunnel syndrome. Patients with NTOS are offered physiotherapy first line, and cases refractory to conservative management proceed to surgery. NTOS patients are reassessed after completion of physiotherapy in a consultant surgeon outpatient clinic before planned surgical intervention. Adjunctive medical therapy is not offered at our institution. Diagnosis of VTOS is determined via a combination of clinical evaluation, duplex ultrasonography and angiographic imaging studies. Cases of VTOS are treated with anticoagulation and catheter-directed thrombolysis followed by expedited surgical management. Confirmed cases of ATOS proceed to surgery.</p>", "<p>Supraclavicular approach FRR and scalenectomy was performed on patients with NTOS and ATOS in this study. Infraclavicular approach FRR and scalenectomy was performed on all cases of VTOS. Adjunctive cervical rib resection was completed when indicated. Routine use of the minimal traction technique, bipolar cautery and nerve stimulation equipment was employed intraoperatively to reduce risk of iatrogenic nerve injury. Bilateral FRR is performed as two-stage procedure with stages a minimum of 12 months apart and the more symptomatic side operated on in the first instance. All patients completed postoperative outpatient follow-up of at least 6 months.</p>", "<title>Data collection</title>", "<p>Data collection was completed via retrospective review of patient notes at a single DGH. All patients who underwent FRR for TOS from August 2004 to August 2021 were included in the study. Information was gained from the local clinical coding team who identified patients through the general surgery elective list database. Patient notes were obtained via the health records team within the clinical audit department. Patients included in this study were operated on by one consultant surgeon within the general surgical department at the DGH.</p>", "<p>A proforma was created to streamline data collection. Demographic and clinical characteristics included: age, sex, laterality, subtype, aetiology, length of time from initial symptoms to diagnosis, postoperative complications, length of stay and clinical outcome. Clinical outcome was determined via Derkash’s classification validated patient-reported outcome measure.<sup>##REF##27666803##4##,##REF##8067849##6##</sup> Derkash’s classification is a post-procedural assessment of severity of symptoms of TOS. It offers an appraisal of the ability to return to activities of daily living and professional commitments (##TAB##0##Table 1##). For statistical analysis, IBM SPSS Statistics for Windows, version 23.0. (IBM Corp., Armonk, NY, USA) was used. Informed consent was obtained from each patient for inclusion in this study.</p>" ]	[ "<title>Results</title>", "<p>A total of 62 FRRs were performed on 51 individual patients at a single DGH between August 2004 and August 2021. Indications for FRR included 42 NTOS (68%), 6 VTOS (10%) and 14 ATOS (23%). Thirty-four patients (64%) were female and the mean age at the time of surgery was 39 years (range 27 to 64 years). The majority of this patient cohort were American Society of Anesthesia (ASA) grade 1 (79%). The remaining patients were ASA grade 2 (16%) and ASA grade 3 (6%), with no ASA grade 4 patients undergoing FRR for TOS at our centre. There were similar numbers of right (<italic>n</italic> = 33) and left (<italic>n</italic> = 29) TOS, and there was no association between laterality and subtype of TOS (##TAB##1##Table 2##). Eleven patients (21%) underwent bilateral FRR. Seven cases of cervical ribs were observed, which were associated with four cases of NTOS and three cases of ATOS. The mean time from initial symptoms to diagnosis was 18 months (range 2 to 60 months). Forty patients (95%) with NTOS initially completed physiotherapy before proceeding to definitive surgical management. Two NTOS patients were not offered physiotherapy because they had previously completed a course of physiotherapy via community services prior to referral.</p>", "<p>Postoperatively, the mean length of stay for each patient was 1.6 days (range 1 to 5 days). Overall, outcomes after surgery were positive across all subtypes of TOS. Based on the Derkash’s classification, 52 (84%) reported excellent/good, 8 (13%) reported fair and 2 (3%) reported poor resolution of symptoms at 6-month follow-up. The most common complication was pneumothorax with four cases (6%). Other complications included two (4%) wound infections, two (4%) haematomas, one (2%) haemothorax, three (5%) phrenic nerve complications and one (2%) brachial neuropraxia. Two patients with phrenic nerve injury symptoms self-resolved without intervention. One patient with phrenic nerve injury underwent video-assisted thoracoscopic surgery diaphragmatic plication procedure with resultant resolution of symptoms. Subgroup analysis was performed to assess differences in outcomes between subtypes of TOS (##TAB##2##Tables 3## and ##TAB##3##4##). There was no significant difference between clinical outcome or complication rate between subtypes of TOS (<italic>p </italic>> 0.05).</p>" ]	[ "<title>Discussion</title>", "<p>This study appraises clinical outcomes of the surgical management of NTOS, VTOS and ATOS at a single centre over a 17-year period. We present positive outcomes of FRR across all three subtypes of TOS. This series is the first of its kind to assess outcomes of patients undergoing FRR in a DGH environment in the United Kingdom. This study indicates that surgery for TOS in an adult population can be performed safely and effectively in this setting.</p>", "<p>One-third of patients who present with NTOS fail conservative management and proceed to surgery.<sup>##REF##2657417##7##</sup> The literature suggests that surgical management of NTOS leads to a significant improvement in patient-reported quality-of-life metrics and that this is sustained on long-term follow-up.<sup>##REF##19147319##8##,##REF##34148096##9##</sup> This series revealed 78.6% of patients who underwent FRR for NTOS resulted in Derkash’s classification of good or excellent outcomes. Fair and poor outcomes in our patient cohort were associated with increasing age and ASA. Risk factors for poor outcomes after surgery for NTOS include smoking, age, chronic opiate use and comorbidities.<sup>##REF##34148096##9##</sup> Davoli <italic>et al</italic> state that patient selection is the key determinant of success in the surgical management of NTOS.<sup>##UREF##0##10##</sup> In our experience, careful investigative work-up is necessary to prevent misdiagnosis in this patient group.</p>", "<p>VTOS presents with upper extremity venous thrombosis, historically known as Paget–Schroetter syndrome. Initial treatment with catheter-directed thrombolysis has been shown to be almost 100% successful if performed within 2 weeks of diagnosis.<sup>##REF##17264012##11##</sup> Recent studies have recommended early FRR post thrombolysis owing to a risk of venous reocclusion.<sup>##REF##16765247##12##–##UREF##1##14##</sup> Conservative management with long-term anticoagulation is an alternative treatment option in this cohort of patients. Follow-up imaging is essential to assess the patency of the venous system and to assess the requirement for further intervention with both conservative and surgical management. Sheth and Belzberg purport an association of VTOS with repetitive strain injury and thus an association with occupation and hand dominance.<sup>##REF##11525208##15##</sup> This is reflected in our data set with VTOS associated with occupations such as labourers and athletes.</p>", "<p>This series presents a high proportion of ATOS in comparison with the accepted demographic analysis of TOS.<sup>##REF##31859722##1##</sup> This is likely reflective of difficulty in the diagnosis of NTOS and the relative ease of diagnosis of VTOS owing to its clinical presentation and access to diagnostic imaging. Prompt surgical management of ATOS offers excellent clinical outcomes.<sup>##REF##27666803##4##</sup> Conservative management has no place in cases of arterial compression because of high likelihood of secondary complications and risk of acute limb ischaemia. Of note, NTOS and ATOS may coexist. Comprehensive clinical assessment is essential for accurate diagnosis and management.</p>", "<p>The literature suggests that 10% of patients with cervical ribs develop TOS (##FIG##1##Figure 2##). Cervical ribs are more likely to be associated with NTOS and ATOS, and this is reflected in the results of this study (##TAB##1##Table 2##). Cervical ribs are associated with more frequent secondary complications of ATOS including aneurysm, stenosis or occlusion.<sup>##REF##25840533##3##</sup> This patient cohort requires aggressive surgical management with resection of the cervical rib and first rib to successfully treat thoracic compression.</p>", "<p>A supraclavicular approach is recognised as the most appropriate technique for arterial decompression surgery because it allows better exposure and control of the subclavian artery.<sup>##REF##33556514##16##</sup> All patients in our centre underwent this approach for FRR and scalenectomy in all cases of ATOS and NTOS. In our experience, an infraclavicular approach provides optimal access to the subclavian vein and thus is utilised for all patients presenting with VTOS. This method is supported by a recent systematic review revealing an overall secondary venous patency rate of 98.5% with the use of an infraclavicular approach for VTOS.<sup>##REF##29388461##17##</sup> A transaxillary approach is preferred in some centres owing to its superior cosmetic results and it does not require division of musculature.<sup>##REF##29772332##18##</sup> The surgical approach should be determined via patient anatomy and surgeon preference. All techniques for surgical decompression of thoracic outlet have positive results in expert hands.</p>", "<p>Complication rates described in the literature vary between 5% and 40%, with pneumothorax, nerve injury and wound infection reported as the most commonly occurring complications.<sup>##REF##27666803##4##</sup> Supra- and infraclavicular approaches provide clear exposure to neurovascular structures of the thoracic inlet and literature suggests that this results in a reduced incidence of brachial neuropraxia.<sup>##REF##28180101##19##</sup> This is supported by this series with only one episode recorded in our patient cohort. This study revealed three cases of phrenic nerve complications with use of the supraclavicular approach. In this technique, the phrenic nerve is at risk when the anterior scalene muscle is divided to gain access to thoracic outlet neurovascular structures (##FIG##2##Figure 3##). Injury to the phrenic nerve may result in paralysis of the ipsilateral diaphragm. Two cases of phrenic nerve injury were self-resolving. A single case required referral to cardiothoracic centre for diaphragmatic plication with complete resolution of symptoms. Urgent cardiothoracic opinion should be sought in any case of phrenic nerve complication.</p>", "<p>A minimal traction technique on spinal nerves, phrenic nerve and brachial plexus trunk was employed intraoperatively to attempt to avoid iatrogenic nerve injury. In all cases in this series, the phrenic nerve was identified using a nerve stimulator and slung prior to division of the scalenus anterior muscle (##FIG##2##Figure 3##). In no case was the nerve divided and despite precautions such as the use of bipolar diathermy to divide the scalenus muscle we noted three nerve palsies. We postulated that these complications may arise from axonotmesis or neurotmesis due to tissue handling or loss of microvascular blood supply in dissection. Furthermore, aberrant phrenic nerve anatomy not picked up intraoperatively may also have contributed to this result. Phrenic nerve injury is an uncommonly reported complication in the literature and patients should be counselled appropriately on the potential of injury before proceeding to operative management of TOS.</p>", "<p>This study demonstrates the diagnostic challenge associated with TOS by the prolonged time from initial symptoms to diagnosis, with patients waiting on average 18 months before receiving a definitive diagnosis. The diagnosis of NTOS is often one of exclusion with investigations frequently more useful to rule out differential diagnoses than offering clear answers to the clinical question. VTOS frequently presents in the acute setting and is more readily diagnosable on imaging. TOS presents a challenge to primary care with no clear national pathway or guidance for referral to secondary care. Patient referrals in our hospital are often received from subspecialities including neurologists, orthopaedics and pain specialists. High-volume centres in the USA have clear pathways in place for assessment with resultant strongly positive outcomes.<sup>##REF##25840533##3##</sup> The UK has no such system in place and undoubtedly would benefit from development of centres of excellence with clear referral pathways. This study has revealed TOS can be managed safely and effectively in a DGH environment. Thus, providing evidence centres of excellence may be reproducible outside of tertiary centres.</p>", "<title>Study limitations</title>", "<p>This study has limitations because it is a single-centre, retrospective, observational clinical notes review of practice. Despite best efforts in uniformity of data collection, it may be subject to bias. Nonetheless, the study maintains external validity in that data are taken from a high-volume general and vascular surgical department broadly comparable with most centres across the UK. Furthermore, this series provides a novel assessment of surgical practice for TOS within the UK with no comparable study published to date in the wider literature.</p>" ]	[ "<title>Conclusion</title>", "<p>FRR for TOS can be performed safely and effectively in a DGH environment with excellent patient clinical outcomes. This series presents the difficulty of diagnosis of TOS with patients often waiting prolonged periods before receiving definitive treatment.</p>" ]	[ "<title>Introduction</title>", "<p>Thoracic outlet syndrome (TOS) is caused by compression of the neurovascular structures passing through the thoracic inlet. It is categorised into three subtypes: neurogenic TOS (NTOS), venous TOS (VTOS) and arterial TOS (ATOS). This study evaluates the outcomes of patients who underwent first rib resection (FRR) for TOS during a period of 17 years at a single district general hospital.</p>", "<title>Methods</title>", "<p>Retrospective review of patient notes of individuals treated with FRR from August 2004 to August 2021.</p>", "<title>Results</title>", "<p>A total of 62 FRRs were performed on 51 individual patients. Indications for FRR included 42 NTOS (68%), 6 VTOS (10%) and 14 ATOS (23%). Thirty-four patients (64%) were female and the mean age at time of surgery was 39 years (range 27 to 64 years). Eleven patients (21%) underwent bilateral FRR and seven cases of cervical ribs were observed. The mean time from initial symptoms to diagnosis was 18 months (range 2 to 60 months). Overall, outcomes after surgery were positive across all subtypes of TOS. Based on Derkash’s classification, 52 patients (84%) reported excellent/good, 8 (13%) reported fair and 2 (3%) reported poor resolution of symptoms at 6 month follow-up. Complications included four (9%) pneumothorax, two (4%) wound infections, two (4%) haematoma, one (2%) haemothorax, three (5%) phrenic nerve complications and one (2%) brachial neuropraxia.</p>", "<title>Conclusions</title>", "<p>FRR for TOS can be performed safely and effectively in a district general hospital environment with excellent patient clinical outcomes.</p>" ]	[]	[]	[ "<fig position=\"float\" id=\"rcsann.2023.0002F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>Anatomical structures of thoracic outlet</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2023.0002F2\" fig-type=\"figure\"><label>Figure 2<x xml:space=\"preserve\"> </x></label><caption><p>Three-dimensional reconstruction of cervical ribs</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2023.0002F3\" fig-type=\"figure\"><label>Figure 3<x xml:space=\"preserve\"> </x></label><caption><p>(a) Right supraclavicular exposure. (b) Right supraclavicular exposure (labelled)</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"rcsann.2023.0002TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Derkash’s classification</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>\n<italic>Classification</italic>\n</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>Description</bold>\n</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Excellent</italic>\n</td><td rowspan=\"1\" colspan=\"1\">No pain, easy return to preoperative professional and leisure daily activities.</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Good</italic>\n</td><td rowspan=\"1\" colspan=\"1\">Intermittent pain well tolerated, possible return to preoperative professional and leisure daily activities.</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Fair</italic>\n</td><td rowspan=\"1\" colspan=\"1\">Intermittent pain with bad tolerance, difficult return to preoperative professional and leisure daily activities.</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Poor</italic>\n</td><td rowspan=\"1\" colspan=\"1\">Symptoms not improved or aggravated.</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2023.0002TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Subgroup analysis of demographic data</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\"/><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>Neurogenic (<italic>N </italic>= 42)</bold>\n</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">\n<bold>Arterial (<italic>N</italic> = 14)</bold>\n</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">\n<bold>Venous (<italic>N </italic>= 6)</bold>\n</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\"/><th align=\"left\" rowspan=\"1\" colspan=\"1\"><italic>n</italic> (%)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\"><italic>n</italic> (%)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\"><italic>n</italic> (%)</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Male</italic>\n</td><td rowspan=\"1\" colspan=\"1\">14 (33.3)</td><td rowspan=\"1\" colspan=\"1\">9 (64.3)</td><td rowspan=\"1\" colspan=\"1\">3 (50.0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Female</italic>\n</td><td rowspan=\"1\" colspan=\"1\">28 (66.7)</td><td rowspan=\"1\" colspan=\"1\">5 (35.7)</td><td rowspan=\"1\" colspan=\"1\">3 (50.0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>ASA 1</italic>\n</td><td rowspan=\"1\" colspan=\"1\">35 (83.3)</td><td rowspan=\"1\" colspan=\"1\">9 (64.3)</td><td rowspan=\"1\" colspan=\"1\">5 (83.3)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>ASA 2</italic>\n</td><td rowspan=\"1\" colspan=\"1\">6 (14.3)</td><td rowspan=\"1\" colspan=\"1\">3 (21.4)</td><td rowspan=\"1\" colspan=\"1\">1 (16.7)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>ASA 3</italic>\n</td><td rowspan=\"1\" colspan=\"1\">1 (2.4)</td><td rowspan=\"1\" colspan=\"1\">2 (14.3)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>ASA 4</italic>\n</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td><td rowspan=\"1\" colspan=\"1\">0 (0.0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Left</italic>\n</td><td rowspan=\"1\" colspan=\"1\">18 (42.9)</td><td rowspan=\"1\" colspan=\"1\">8 (57.1)</td><td rowspan=\"1\" colspan=\"1\">3 (50.0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Right</italic>\n</td><td rowspan=\"1\" colspan=\"1\">24 (57.1)</td><td rowspan=\"1\" colspan=\"1\">6 (14.3)</td><td rowspan=\"1\" colspan=\"1\">3 (50.0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Cervical rib(s)</italic>\n</td><td rowspan=\"1\" colspan=\"1\">4 (9.5)</td><td rowspan=\"1\" colspan=\"1\">3 (21.4)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2023.0002TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Subgroup analysis of postoperative outcomes</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\"/><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>Neurogenic (<italic>N </italic>= 42)</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>Arterial (<italic>N </italic>= 14)</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>Venous (<italic>N </italic>= 6)</bold>\n</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\"><bold><italic>Derkash</italic></bold> c<bold><italic>lassification</italic></bold></th><th align=\"left\" rowspan=\"1\" colspan=\"1\"><italic>n</italic> (%)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\"><italic>n</italic> (%)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\"><italic>n</italic> (%)</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Excellent/Good</italic>\n</td><td rowspan=\"1\" colspan=\"1\">33 (78.6)</td><td rowspan=\"1\" colspan=\"1\">13 (92.9)</td><td rowspan=\"1\" colspan=\"1\">6 (100)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Fair</italic>\n</td><td rowspan=\"1\" colspan=\"1\">7 (16.7)</td><td rowspan=\"1\" colspan=\"1\">1 (7.1)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Poor</italic>\n</td><td rowspan=\"1\" colspan=\"1\">2 (4.8)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2023.0002TB4\"><label>Table 4<x xml:space=\"preserve\"> </x></label><caption><p>Subgroup analysis of postoperative complications</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"2\" align=\"left\" colspan=\"1\"/><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">\n<bold>Neurogenic (<italic>N </italic>= 42)</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold>Arterial (<italic>N </italic>= 14)</bold>\n</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">\n<bold>Venous (<italic>N </italic>= 6)</bold>\n</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold><italic>n</italic> (%)</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold><italic>n</italic> (%)</bold>\n</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<bold><italic>n</italic> (%)</bold>\n</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Pneumothorax</italic>\n</td><td rowspan=\"1\" colspan=\"1\">3 (7.1)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td><td rowspan=\"1\" colspan=\"1\">1 (16.7)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Wound infection</italic>\n</td><td rowspan=\"1\" colspan=\"1\">1 (2.4)</td><td rowspan=\"1\" colspan=\"1\">1 (7.1)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Haematoma</italic>\n</td><td rowspan=\"1\" colspan=\"1\">2 (4.8)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Haemothorax</italic>\n</td><td rowspan=\"1\" colspan=\"1\">1 (2.4)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Brachial neuropraxia</italic>\n</td><td rowspan=\"1\" colspan=\"1\">1 (2.4)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">\n<italic>Phrenic nerve complication</italic>\n</td><td rowspan=\"1\" colspan=\"1\">2 (4.8)</td><td rowspan=\"1\" colspan=\"1\">1 (7.1)</td><td rowspan=\"1\" colspan=\"1\">0 (0)</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"rcsann.2023.0002.01\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2023.0002.02\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2023.0002.03\" position=\"float\"/>" ]	[]	[{"label": ["10."], "surname": ["Davoli", "Staffa", "Ciarrochi", "Stella"], "given-names": ["F", "G", "A", "F"], "article-title": ["Thoracic outlet syndrome: which surgical approach?"], "italic": ["Curr Challenges Thorac Surg"], "year": ["2021"], "bold": ["3"], "fpage": ["3"]}, {"label": ["14."], "surname": ["Elix\u00e8ne", "Sadaghianloo", "Mousnier"], "given-names": ["JB", "N", "A"], "italic": ["et al.", "J Cardiovasc Surg (Torino)"], "article-title": ["Long-term functional outcomes and subclavian vein patency in patients undergoing thoracic outlet surgery for Paget\u2013Schroetter Syndrome"], "year": ["2017"], "bold": ["58"], "fpage": ["451"], "lpage": ["457"]}]	{ "acronym": [], "definition": [] }	19	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 13; 106(1):51-56	oa_package/80/ec/PMC10757880.tar.gz
PMC10757881	36748797	[ "<title>Introduction</title>", "<p>Benign paroxysmal positional vertigo (BPPV) is a common inner ear disorder that accounts for over half of all cases of peripheral vertigo. Lifetime prevalence is estimated to be 2.4%, with females two to three times more likely to be affected than males, and peak onset occurring in the fifth and sixth decades of life.<sup>##UREF##0##1##,##REF##24645946##2##</sup> BPPV occurs due to the displacement of otoconia within the semi-circular canals of the inner ear, commonly after positional changes of the head, with attacks typically lasting less than a minute.<sup>##REF##21716871##3##</sup> Vertiginous attacks can range in severity, from mild to debilitating episodes that may induce nausea or vomiting, and significantly hinder quality of life.<sup>##REF##21716871##3##,##REF##21808648##4##</sup></p>", "<p>Although repositioning techniques such as the Epley manoeuvre can often be successful in managing BPPV, recurrence of attacks is frequent, with around 70% of patients having a further attack within the first year.<sup>##REF##34630309##5##</sup> This can have profound personal, social and financial implications for both patients and caregivers. Improved patient understanding of BPPV is therefore important to help avoid unnecessary delays in diagnosis and treatment, as well as to better manage expectations.<sup>##UREF##0##1##</sup></p>", "<p>The growing rise in technology and, more recently, social media has led to patients resorting increasingly to the internet for their medical information.<sup>##REF##32699509##6##</sup> This has been amplified further following the COVID-19 pandemic, with an increasing shift towards online consultations and a reduction in face-to-face appointments with healthcare professionals.<sup>##UREF##1##7##,##REF##32836633##8##</sup> The internet, however, is largely unregulated and so online information may be inaccurate and difficult to read.<sup>##REF##24567763##9##</sup> Owing to the high prevalence of BPPV and the potential for recurrent attacks,<sup>##REF##34630309##5##</sup> this is something that patients can ill afford.</p>", "<p>To date, no study has examined the appropriateness of online information on BPPV. This study aimed to assess the readability and quality of online information on BPPV.</p>" ]	[ "<title>Methods</title>", "<title>Internet search methods</title>", "<p>Online information using the search terms ‘benign paroxysmal positional vertigo’ and ‘BPPV’ was assessed separately in March 2022 using Google. Cookies and browser history were deleted before the search to avoid the effects of previous internet use on search results. The first 50 webpages for each search term were assessed for their readability and quality, with Google being used as the main search engine for our study owing to it occupying the vast majority of the market share.<sup>##UREF##2##10##</sup> The workflow of our methodology is shown in ##FIG##0##Figure 1##.</p>", "<p>All the websites were assessed objectively by two independent assessors (H.R. and Z.R.A.). If there was an inconsistency regarding the evaluation of a website, then a third independent assessor evaluated the website and made the final decision.</p>", "<title>Eligibility criteria</title>", "<p>Websites that were only accessible and written in English were included. If websites provided irrelevant information or did not discuss treatment for BPPV, they were excluded. Other exclusion criteria included: if target audience was healthcare professionals, the word count was below the lower limit for readability scoring and duplicates.</p>", "<title>Readability assessment</title>", "<p>Readability was assessed using four validated scoring tools: the Flesch–Kincaid Grade Level (FKGL), Flesch Reading Ease Score (FRES), Gunning Fog Index (GFOG) and Simple Measure of Gobbledygook (SMOG) score (##TAB##0##Table 1##). Written information from each of the websites was scored using an online scoring tool.<sup>##UREF##3##13##</sup> The scoring for each tool and how scores correspond to reading difficulty is shown in ##TAB##1##Table 2##.</p>", "<title>Quality assessment</title>", "<p>Quality of online information was assessed using the DISCERN tool. This validated scoring tool consists of 15 questions designed to evaluate both the reliability and quality of information using a 5-point Likert scale. An additional 16th question consisting of an overall rating is also included, with a score of 1 representing serious and extensive omissions of information, whereas a score 5 means that there are only minor and minimal omissions.<sup>##REF##12088606##15##</sup> Total DISCERN scores can be interpreted as the following: very poor (16–29), poor (30–40), fair (41–51), good (52–63) and excellent (>64).</p>", "<title>Correlation assessment</title>", "<p>Spearman’s correlation was used to determine whether there was a trend between quality (DISCERN scores) and readability (FRES scores).</p>", "<title>Statistical analysis</title>", "<p>Statistical analyses were performed using Microsoft Excel® 2019. Statistical significance was set at <italic>p </italic>< 0.05.</p>" ]	[ "<title>Results</title>", "<p>In total, 100 websites were screened against the exclusion criteria. This resulted in 39 unique websites constituting the main data set (##FIG##0##Figure 1##). The reasons for exclusion of 61 websites were as follows: duplicate websites (<italic>n</italic> = 53), requiring a subscription (<italic>n</italic> = 2), websites containing information irrelevant to BPPV (<italic>n</italic> = 5) and healthcare professionals being the target audience (<italic>n</italic> = 1).</p>", "<title>Readability assessment</title>", "<p>Mean readability scores and 95% confidence intervals (CI) for FRES, FKGL, SMOG and GFOG were 50.2 (46.1–54.3), 10.6 (9.87–11.4), 10.1 (9.5–10.7) and 13.6 (12.7–14.4), respectively (##TAB##2##Table 3##). These scores are equivalent to the reading age of a 15–18 year old, 15–16 year old, 11–12 year old and 15–17 year old, respectively.</p>", "<p>On sub-analysis of the search term ‘benign paroxysmal positional vertigo,’ the 44 websites had an average score and 95% CI of 12.1 (11.4–12.8), 50.6 (46.8–54.4), 15.3 (14.5–16.1) and 10.3 (9.2–18.2) for FKGL, FRES, GFOG and SMOG, respectively. These scores are equivalent to the reading age of a 15–18 year old, 21 year old, 15–17 year old and 12–13 year old, respectively.</p>", "<p>On sub-analysis of the search term ‘BPPV,’ the ten websites had average scores and 95% CI of 10.3 (8.5–12.2), 43.2 (39.8–46.6), 12.8 (10.8–14.8) and 9.5 (8.2–10.8) for FKGL, FRES, GFOG and SMOG, respectively These scores are equivalent to the reading age of an 18–21 year old, 21 year old, 17–18 year old and an 11–12 year old, respectively.</p>", "<title>Quality assessment</title>", "<p>The average DISCERN score and 95% CI when using the main data set was 36.7 (34.6–38.7). Only one website had a DISCERN score of good, with none having a score of excellent. Some 78.9% of websites had poor/very poor reliability and 59% had poor/very poor quality. All websites had potentially important but not serious deficiencies.</p>", "<p>With regards to quality and reliability, the average DISCERN score and 95% CI across the websites using the search term ‘benign paroxysmal positional vertigo’ was 37.9 (35.6–40.2). Some 57% of websites had poor/very poor quality information, with 77% of websites having poor/very poor reliability. All websites had potentially important but not serious deficiencies.</p>", "<p>When using the search term ‘BPPV’, the average DISCERN score and 95% CI for quality and reliability was 43.7 (35.6–40.2). This means that the websites were overall fair in terms of quality, with 20% of the websites having a DISCERN score of good, and none scoring as excellent. Some 70% of the websites were of poor/very poor reliability with 30% being of poor/very poor quality. In terms of quality, two websites had a quality deemed as excellent. Three websites were found to have a poor quality of information.</p>", "<title>Correlation between FRES and DISCERN</title>", "<p>There was a weak negative correlation between the FRES and DISCERN scores (<italic>r<sub>s</sub></italic> = −0.22599, <italic>p</italic> = 0.17; ##FIG##1##Figure 2##).</p>" ]	[ "<title>Discussion</title>", "<p>The internet is a growing and significant source of healthcare information for patients. It can aid communication, empower patients with decision making and improve the patient–doctor relationship. Caution should be exercised, however, because the internet can be largely unregulated, with potential for misinformation to surface that can lead to adverse health outcomes. To our knowledge, this is the first study to have comprehensively evaluated the readability and quality of websites providing information on BPPV for patients. Online information on BPPV was generally found to be of poor quality and written at a reading difficulty beyond what the average person would be able to understand.</p>", "<p>Our readability data showed that a significant proportion of websites have a reading level greatly beyond the recommendation of 11 years.<sup>##REF##32836633##8##</sup> Given that the average reading age in the United Kingdom (UK) is between 9 and 15 years old,<sup>##REF##15929685##16##,##REF##24548781##17##</sup> we found that many websites are written beyond what the average patient is capable of understanding. The 39 websites from the main data set were shown to have a high reading level in line with that of a 15–16 year old or higher, ranging from fairly difficult to read to very difficult to read. However, these findings contradict those obtained from SMOG scoring, which suggested that a significant proportion of the websites had a reading level of an 11–12 year old. This discrepancy may be explained by the fact that SMOG is calculated on the principle that the frequency of polysyllabic words within a sentence correlates with the reading difficulty of the text, even though not all polysyllabic words are difficult to understand.<sup>##UREF##4##18##</sup> In the context of BPPV, this discrepancy suggests that the polysyllable count may not be an effective discriminator of reading difficulty. Overall, the fact that three of the four readability scores were consistent with the websites having a high reading level is strong evidence in favour of this being the case. This is further enforced by the fact that individually none of the websites were at the recommended reading level for FKGL and GFOG scoring, with only one website individually being at the recommended reading level based on FRES scoring.<sup>##UREF##5##19##</sup></p>", "<p>When comparing trends for the individual search terms, the search term ‘BPPV,’ resulted in websites having lower average scores for FRES and FKGL, meaning that they were more difficult to read than websites for the search term ‘benign paroxysmal positional vertigo’. However, ‘BPPV’ also resulted in the websites having a higher average GFOG and SMOG score, which correlates with an easier reading level. This suggests that using the full search term or abbreviated search term makes no difference to the reading difficulty across websites. It is of note, however, that because 35 duplicates were removed when conducting the search term ‘BPPV’ the impact that they would have had on the reading difficulty if they had been included is unknown.</p>", "<p>Overall, these findings about readability raise major concerns with regards to the extent that patients are able to understand and interpret information on BPPV. This is problematic because it can lead to delays in patients receiving medical support and appropriate treatment for BPPV. As a result, patients may have an increased likelihood of experiencing adverse events, such as falls, and a lower quality of life. These concerns, however, are not only limited to BPPV, with the issue of reading difficulty of online material also being apparent in other conditions within otorhinolaryngology.<sup>##REF##34154676##20##,##REF##28885483##21##</sup></p>", "<p>Improving the readability of online material on BPPV could take the form of implementing more pictograms, diagrams and images to accommodate individuals who have a reading ability below that of a fifth grader.<sup>##UREF##6##22##,##REF##12841808##23##</sup> Other approaches could include greater spacing of the text and a change of font in terms of style and size.<sup>##UREF##6##22##</sup> We also suggest direct involvement of patients in the writing of health information of BPPV to further enhance readability.<sup>##REF##34154676##20##</sup> However, in an attempt to avoid patronising the patient with simplified information and to ensure that those with higher reading abilities obtain sufficient information and understanding, it would be advisable to provide more complex sources of information alongside the basic information provided on websites. Additionally, we suggest that authors test the readability level of their content prior to publication, using readability tools such as FRES and FKGL scoring, although not SMOG, to ensure that their content is set at the target readability level of 11 years of age.</p>", "<p>In terms of the quality of online information relating to BPPV, we found that it was generally poor. This was mainly due to websites providing sparse information or lacking information on how treatment will affect patients’ quality of life and a discussion of treatment options. The category that scored the lowest when assessing the reliability of information was the clarity of aims. This was followed by referral to areas of uncertainty. The two categories that scored the lowest when assessing information quality were provision of support for shared decision making and describing risks for each treatment. These areas should, therefore, be prioritised to improve the quality of online information relating to BPPV. This is important because it will facilitate better doctor–patient decision making, leading to improved treatment adherence and patient outcomes, and ensuring that patients are aware of which information is evidence-based.</p>", "<p>When analysing DISCERN scoring for the separate search terms, ‘BPPV’ was shown to be of fair quality, whereas ‘benign paroxysmal positional vertigo’ was shown to be of poor quality overall. In terms of reliability, ‘BPPV’ scored higher than ‘benign paroxysmal positional vertigo’, with a score of 48.5% compared with 46%, although both were classed as fair. In terms of quality, ‘BPPV’ scored significantly higher than ‘benign paroxysmal positional vertigo’ at 60.3% compared with 48%. This translates to fair and poor quality, respectively. The categories that scored the lowest in terms of reliability were clarity of the aims and referral to areas of uncertainty for both search terms. The categories that scored the lowest in terms of quality were providing support for shared decision making and how treatment affects the quality of life for both. This demonstrates that information obtained using the search term ‘BPPV’ yields more reliable, high-quality information than the search term ‘benign paroxysmal positional vertigo’.</p>", "<p>Weak correlation was found between the readability and quality of online material for BPPV. This is problematic because, although high-quality websites that are hard to read would pose little difficulty for highly educated patients, the layperson will struggle to fully comprehend the information provided. Similarly, easily readable content that lacks quality can misinform patients and adversely affect health outcomes. Although further work is needed to improve online information on BPPV, we recommend that patients are directed to use Association of Chartered Physiotherapists Interested in Vestibular Rehabilitation and Healthline websites because they were best in terms of both quality and readability.<sup>##UREF##7##24##,##UREF##8##25##</sup></p>", "<p>Although benign and often self-limiting, BPPV can have a considerable impact on quality of life. It is, therefore, important to improve health literacy of these patients, defined as the ability to understand and use information to appropriately manage health, by directing them towards or creating easily readable and high-quality online material. Importantly, we suggest that healthcare professionals become more heavily involved in the production of online information for BPPV. This will ensure that important information is not omitted and content is accurate and comprehensive. We also recommend that there is increased patient involvement in the production of online content to ensure that information is easy to read, understandable and based on patients’ needs. To ensure patients are using accurate and reliable sources of information that are in line with their reading ability, we also propose that all healthcare websites on BBPV provide information about the reading age, reliability and quality of their content, so that patients can make an informed choice about which websites are most suitable to use.</p>", "<title>Limitations</title>", "<p>Our study had several limitations. First, readability tools fail to assess audio-, image- or video-based information, including the presentation of information online. These are important factors that aid comprehension of online material.<sup>##REF##20496023##26##</sup> We may have, therefore, underestimated the readability of websites. Second, scoring quality of information using the DISCERN tool requires subjective evaluation, which somewhat reduces the reproducibility of our results. Third, Google was the only search engine used to identify information on BPPV. It is likely that we may not have produced findings that are truly representative of the patient experience as other search engines, such as Bing or Yahoo, could have resulted in different findings. Finally, the internet is a fluid, ever-changing system so our search results may differ in the future.</p>" ]	[ "<title>Conclusion</title>", "<p>This is the first study to have systematically evaluated the quality and readability of online information for BPPV. We found that websites about BPPV were generally of poor quality and written at a reading level above the recommended reading age. A weak correlation was noted between readability and quality of online material for BPPV. Healthcare professionals should be aware of these limitations and advocate for improved online patient education resources that are both high quality and easy to comprehend.</p>" ]	[ "<p>Haseem Raja and Zahra Rose Almansoor contributed equally to this work</p>", "<title>Introduction</title>", "<p>Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vertigo. It can have a significant impact on quality of life, with individuals often seeking information online for reassurance and education. The aim of this study is to assess the readability and quality of online information on BPPV.</p>", "<title>Methods</title>", "<p>The terms ‘benign paroxysmal positional vertigo’ and ‘BPPV’ were entered into Google. The first 50 websites generated for each search term were screened. Readability was assessed using the Flesch–Kincaid Reading Ease Score (FRES), Flesch–Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG) Index and Gunning Fog Index (GFOG). Quality was assessed using the DISCERN instrument. Spearman’s correlation between quality and readability was calculated.</p>", "<title>Results</title>", "<p>A total of 39 websites met the inclusion criteria. The mean and 95% confidence intervals for the FRES, FKGL, SMOG, GFOG and DISCERN scores were 50.2 (46.1–54.3), 10.6 (9.87–11.4), 10.1 (9.5–10.7), 13.6 (12.7–14.4) and 36.7 (34.6–38.7), respectively. Weak correlation was noted between DISCERN and FRES (<italic>r<sub>s</sub></italic> = −0.23, <italic>p</italic> = 0.17).</p>", "<title>Conclusion</title>", "<p>Online information on BPPV is generally of poor quality and low readability. It is essential that healthcare professionals inform their patients of this limitation and advocate for improved online patient education resources that are both high quality and easy to comprehend.</p>" ]	[ "<title>Author contributions</title>", "<p>H.R. conceived the idea of writing the manuscript. H.R. and Z.R.A. equally designed the methodology, acquired and analysed the data, and drafted the manuscript. H.R. approved the manuscript for submission. H.R. agrees to be accountable for all aspects of the work.</p>" ]	[]	[ "<fig position=\"float\" id=\"rcsann.2022.0150F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>Flow diagram displaying the systematic search methodology. The searches were performed in March 2022.</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2022.0150F2\" fig-type=\"figure\"><label>Figure 2<x xml:space=\"preserve\"> </x></label><caption><p>Scatter graph of Flesch Reading Ease Score (FRES) against DISCERN score for the main data set</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0150TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Formulae for readability tools</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Readability tool</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Formula</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">FKGL</td><td rowspan=\"1\" colspan=\"1\">0.39 × (average number of words per sentence) + (11.8 × average number of syllables per word) – 15.59</td></tr><tr><td rowspan=\"1\" colspan=\"1\">FRES</td><td rowspan=\"1\" colspan=\"1\">206.835 – (1.015 × number of words/ number of sentences) – (84.6 × number of syllables/ number of words)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">GFOG</td><td rowspan=\"1\" colspan=\"1\">0.4 × [words/sentences) + 100 (complex words/total words)]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">SMOG</td><td rowspan=\"1\" colspan=\"1\">√number of polysyllabic words + 3</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0150TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Scoring of readability tools and their corresponding difficulty</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th colspan=\"4\" align=\"left\" rowspan=\"1\">Readability tool scoring</th><th rowspan=\"2\" align=\"left\" colspan=\"1\">Reading difficulty</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">FRES</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">FKGL</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">SMOG</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">GFOG</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">0–30</td><td rowspan=\"1\" colspan=\"1\">College graduate</td><td rowspan=\"1\" colspan=\"1\">17+</td><td rowspan=\"1\" colspan=\"1\">17+</td><td rowspan=\"1\" colspan=\"1\">Very difficult</td></tr><tr><td rowspan=\"1\" colspan=\"1\">31–50</td><td rowspan=\"1\" colspan=\"1\">College level</td><td rowspan=\"1\" colspan=\"1\">13–16</td><td rowspan=\"1\" colspan=\"1\">13–16</td><td rowspan=\"1\" colspan=\"1\">Difficult</td></tr><tr><td rowspan=\"1\" colspan=\"1\">51–60</td><td rowspan=\"1\" colspan=\"1\">High school</td><td rowspan=\"1\" colspan=\"1\">9–12</td><td rowspan=\"1\" colspan=\"1\">10–12</td><td rowspan=\"1\" colspan=\"1\">Fairly difficult</td></tr><tr><td rowspan=\"1\" colspan=\"1\">61–70</td><td rowspan=\"1\" colspan=\"1\">Eighth–ninth grade</td><td rowspan=\"1\" colspan=\"1\">8</td><td rowspan=\"1\" colspan=\"1\">8–9</td><td rowspan=\"1\" colspan=\"1\">Standard</td></tr><tr><td rowspan=\"1\" colspan=\"1\">71–80</td><td rowspan=\"1\" colspan=\"1\">Seventh grade</td><td rowspan=\"1\" colspan=\"1\">7</td><td rowspan=\"1\" colspan=\"1\">7</td><td rowspan=\"1\" colspan=\"1\">Fairly easy</td></tr><tr><td rowspan=\"1\" colspan=\"1\">81–90</td><td rowspan=\"1\" colspan=\"1\">Sixth grade</td><td rowspan=\"1\" colspan=\"1\">6</td><td rowspan=\"1\" colspan=\"1\">6</td><td rowspan=\"1\" colspan=\"1\">Easy</td></tr><tr><td rowspan=\"1\" colspan=\"1\">91–100</td><td rowspan=\"1\" colspan=\"1\">Fifth grade</td><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">Very easy</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0150TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Summary of readability and quality data for the terms ‘benign paroxysmal positional vertigo’ and ‘BPPV’</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"2\" align=\"left\" colspan=\"1\">Test</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Main data set search term analysis</th><th colspan=\"3\" align=\"left\" rowspan=\"1\">Search term-specific subgroup analysis</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">‘Benign paroxysmal positional vertigo’ and ‘BPPV’ (<italic>n</italic> = 39)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">‘Benign paroxysmal positional vertigo’ (<italic>n</italic> = 44)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">‘BPPV’ (<italic>n</italic> = 10)</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\"><italic>p</italic>-value</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Flesch Reading Ease Score mean (95% CI)</td><td rowspan=\"1\" colspan=\"1\">50.2 (46.1–54.3)</td><td rowspan=\"1\" colspan=\"1\">50.6 (46.8–54.4)</td><td rowspan=\"1\" colspan=\"1\">43.2 (39.8–46.6)</td><td rowspan=\"1\" colspan=\"1\">0.167</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Flesch–Kincaid Grade Level mean (95% CI)</td><td rowspan=\"1\" colspan=\"1\">10.6 (9.87–11.4)</td><td rowspan=\"1\" colspan=\"1\">12.1 (11.4–12.8)</td><td rowspan=\"1\" colspan=\"1\">10.3 (8.5–12.2)</td><td rowspan=\"1\" colspan=\"1\">0.084</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Simple Measure of Gobbledygook mean (95% CI)</td><td rowspan=\"1\" colspan=\"1\">10.1 (9.5–10.7)</td><td rowspan=\"1\" colspan=\"1\">10.3 (9.2–18.2)</td><td rowspan=\"1\" colspan=\"1\">9.5 (8.2–10.8)</td><td rowspan=\"1\" colspan=\"1\">0.276</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Gunning Fog Index mean (95% CI)</td><td rowspan=\"1\" colspan=\"1\">13.6 (12.7–14.4)</td><td rowspan=\"1\" colspan=\"1\">15.3 (14.5–16.1)</td><td rowspan=\"1\" colspan=\"1\">12.8 (10.8–14.8)</td><td rowspan=\"1\" colspan=\"1\">0.084</td></tr><tr><td rowspan=\"1\" colspan=\"1\">DISCERN score mean (95% CI)</td><td rowspan=\"1\" colspan=\"1\">36.7 (34.6–38.7)</td><td rowspan=\"1\" colspan=\"1\">37.9 (35.6–40.2)</td><td rowspan=\"1\" colspan=\"1\">43.7 (35.6–40.2)</td><td rowspan=\"1\" colspan=\"1\">0.026</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>FKGL = Flesch–Kincaid Reading Ease Score; FRES = Flesch–Kincaid Grade Level; GFOG = Gunning Fog Index; SMOG = Simple Measure of Gobbledygook</p></fn><fn><p>Adapted from Wang <italic>et al</italic><sup>##REF##22835706##11##</sup> and O’Connell Ferster and Hu<sup>##REF##28346643##12##</sup></p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>FKGL = Flesch–Kincaid Reading Ease Score; FRES = Flesch–Kincaid Grade Level; GFOG = Gunning Fog Index; SMOG = Simple Measure of Gobbledygook</p></fn><fn><p>Adapted from O’Connell Ferster and Hu<sup>##REF##28346643##12##</sup> and Boztas <italic>et al</italic><sup>##REF##29137057##14##</sup></p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>BPPV = benign paroxysmal positional vertigo; CI = confidence interval</p></fn><fn><p><italic>p </italic>< 0.05 for significance.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"rcsann.2022.0150.01\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2022.0150.02\" position=\"float\"/>" ]	[]	[{"label": ["1."], "surname": ["Bhattacharyya", "Gubbels", "Schwartz"], "given-names": ["N", "SP", "SR"], "italic": ["et al.", "Otolaryngol Head Neck Surg"], "article-title": ["Clinical practice guideline: benign paroxysmal positional vertigo (update)"], "year": ["2017"], "bold": ["156"], "fpage": ["S1"], "lpage": ["S47"]}, {"label": ["7."], "surname": ["Litchfield", "Shukla", "Greenfield"], "given-names": ["I", "D", "S"], "article-title": ["Impact of COVID-19 on the digital divide: a rapid review"], "italic": ["BMJ Open"], "year": ["2021"], "bold": ["11"], "fpage": ["e053440"]}, {"label": ["10."], "collab": ["Statista"], "source": ["Worldwide desktop market share of leading search engines from January 2010 to January 2022"], "ext-link": ["https://www.statista.com/statistics/216573/worldwide-market-share-of-search-engines/"], "comment": ["(cited December 2023)"]}, {"label": ["13."], "mixed-citation": ["\n"], "comment": ["Automatic readability checker: readability formulas. https://readabilityformulas.com/free-readability-formula-tests.php (cited March 2022)."]}, {"label": ["18."], "surname": ["Mclaughlin"], "given-names": ["GM"], "article-title": ["SMOG grading - a new readability formula"], "italic": ["J Read"], "year": ["1969"], "bold": ["12"], "fpage": ["639"], "lpage": ["646"]}, {"label": ["19."], "collab": ["WebMD"], "source": ["Home remedies for vertigo"], "ext-link": ["https://www.webmd.com/brain/home-remedies-vertigo"], "comment": ["(cited December 2023)."]}, {"label": ["22."], "surname": ["Swain"], "given-names": ["D"], "article-title": ["Producing patient information \u2013 how to research, develop and produce effective information resources"], "italic": ["Health Expect"], "year": ["2003"], "bold": ["6"], "fpage": ["274"], "lpage": ["275"]}, {"label": ["24."], "collab": ["Association of Charted Physiotherapists Interested in Vestibular Rehabilitation (ACPIVR)"], "ext-link": ["https://acpivr.com/bppv-benign-paroxysmal-positional-vertigo/"], "comment": ["(cited December 2023)"]}, {"label": ["25."], "collab": ["Healthline"], "source": ["Healthline: benign positional vertigo"], "ext-link": ["https://www.healthline.com/health/benign-positional-vertigo"], "comment": ["(cited March 2022)"]}]	{ "acronym": [], "definition": [] }	26	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 7; 106(1):45-50	oa_package/e3/f0/PMC10757881.tar.gz
PMC10757882	36927080	[ "<title>Introduction</title>", "<p>Pancreas transplantation is a highly effective life-saving therapy for patients with insulin-dependent diabetes and end-organ damage from renal failure or unavoidable episodes of severe hypoglycaemia. Owing to a well-documented shortage of organs for transplantation, there is a need to optimise methods for the assessment and selection of high-quality pancreases. Outcomes are improving, but historically remain far from ideal: six of ten pancreas grafts have failed at 5 years when transplanted alone, and three of ten have failed at 5 years when the pancreas is transplanted together with a kidney.<sup>##UREF##0##1##</sup> Technical considerations provide one explanation for these poorer outcomes and these have evolved and improved considerably over time.<sup>##REF##11303130##2##</sup> Immunological factors including sensitisation from prior kidney transplants is a probable factor behind the discrepancy in outcomes between synchronous pancreases and kidney transplants compared with pancreases transplanted after kidney transplantation.<sup>##REF##29893956##3##</sup></p>", "<p>In organ donors, the process of brainstem death results in high levels of systemic catecholamines affecting all organs, including the pancreas.<sup>##REF##24142035##4##,##REF##14633854##5##</sup> Catecholamine-based vasoactive drugs (VaDs) are commonly used to correct the hypotension and reduced cardiac output experienced by organ donors in intensive care units. However, this may inadvertently affect organ quality. The donor care bundle produced by NHS Blood and Transplant recommends aiming to achieve mean arterial pressure values between 60 and 80mmHg by correction of hypovolaemia, with the administration of fluid boluses in the first instance and then vasopressors.<sup>##UREF##1##6##</sup> Vasopressin is recommended as the vasopressor of choice, and it is advised to wean or stop catecholamines. If inotropes are to be used then dopamine is recommended as the agent of choice, although dobutamine is often used.</p>", "<p>Pancreatic beta cells receive sympathetic autonomic innervation and express α2-adrenergic receptors that inhibit insulin secretion and β2-adrenergic receptors that stimulate insulin secretion.<sup>##UREF##2##7##,##REF##12615955##8##</sup> Adrenergic receptors are G protein-coupled receptors (GPCRs). VaDs vary in their affinity for certain GPCRs and as such may have variable impacts on insulin secretion (##TAB##0##Table 1##).</p>", "<p>The relationship between VaDs and outcomes after pancreas transplantation is unknown. Because these drugs have effects on insulin secretion, we hypothesised that some VaDs might impact pancreas transplant outcomes. This study aimed to assess relationships of VaD use to pancreas transplant graft survival.</p>" ]	[ "<title>Methods</title>", "<p>Data on all pancreas transplants performed between 1 January 2004 and 1 November 2016 from the UK Transplant Registry, held by NHS Blood and Transplant, were reviewed. All data were collected prospectively with written informed consent from donor families and transplant recipients.</p>", "<p>All-cause pancreas graft failure was defined as the time from transplant to loss of insulin independence. Patients dying with a functioning graft were censored.</p>", "<p>The distributions of all donor and recipient variables were assessed for form and completeness. Cases with missing outcome data (<italic>n</italic> = 88) were excluded. Data for cold ischaemic time were missing in 9% of cases, donor creatinine in 12% of cases and recipient body mass index (BMI) in 27% of cases – this was addressed by using pooled results from multiple imputation using the fully conditional specification (Markov Chain Monte Carlo) algorithm. Missing data for all other variables were infrequent (< 1%) and cases with missing data relating to independent variables were excluded from individual analyses at that level.</p>", "<title>Statistical analyses</title>", "<p>We assessed relationships between exposures (VaDs) and donor or recipient clinical variables to identify potential confounders of relationships between exposures (VaDs) and outcome (graft failure) using Fisher’s exact test, Student’s <italic>t</italic>-test or the Mann–Whitney <italic>U</italic>-test as appropriate. Univariable Cox regression determined hazard ratios (HR [95% confidence interval {CI}]) for graft failure associated with clinical variables identified as being related to exposures to increase understanding of their potential role as confounders (<italic>p </italic>< 0.1). The association between VaD use and graft failure was determined using a Cox regression model, which was adjusted for co-administration of VaDs and also clinical variables related to graft failure in a Cox regression model (<italic>p </italic>< 0.05).</p>", "<p>Statistical analyses were performed using IBM SPSS statistics version 22 (IBM, Armonk, NY).</p>" ]	[ "<title>Results</title>", "<p>Some 2,271 pancreas transplants were performed in the UK during the study period, of which 88 (3.9%) were excluded because of missing survival data, leaving 2,183 cases in the analysis. Simultaneous pancreas and kidney (SPK) transplantation comprised 1,879 (86.1%) of complete cases, pancreas after kidney (PAK) transplantation accounted for 153 (7.0%) cases and pancreas transplantation alone (PTA) accounted for 151 (6.9%). All-cause pancreas graft failures totalled 525 (24.0%) over a median (interquartile range) follow-up period of 4 (1–8) years.</p>", "<p>VaDs were used in the following numbers (proportions) of donors: dobutamine 76 (3.5%), dopamine 84 (3.8%), adrenaline 161 (7.4%), noradrenaline 1,589 (72.8%) and vasopressin 1,219 (55.8%). No VaDs were received by 359 (16.4%) donors, whereas 737 (33.8%) received one VaD, 1,023 (46.9%) received two, 141 (6.5%) received three, 13 (0.6%) received four and 1 (< 0.1%) donor received all five VaDs. In all patients receiving inotropes (dobutamine or dopamine), vasopressors (noradrenaline, adrenaline or vasopressin) were also co-administered. Noradrenaline was co-administered in 67 (88.2%) donors receiving dobutamine and in 55 (65.5%) donors receiving dopamine.</p>", "<p>Use of noradrenaline in donors was associated with both donor and recipient non-White ethnicity, previous history of hypertension, previous history of cardiac disease, peri-retrieval hypotension, donation after brain death (DBD), trauma and hypoxic brain injury as cause of death, higher donor creatinine and amylase values, and greater use of vasopressin and insulin (##TAB##1##Tables 2## and ##TAB##2##3##).</p>", "<p>In a univariable Cox regression model, use of noradrenaline was related to a lower risk of pancreas graft failure (HR [95% CI] 0.74 [0.61–0.89], <italic>p</italic> = 0.001) (##TAB##2##Table 4##). In the same analysis the following were related (<italic>p </italic>< 0.1) to all-cause pancreas graft failure: increasing donor age; increasing donor BMI; donor history of previous hypertension; cardiac arrest (but not its duration) during the donation phase; donor cause of death involving trauma, intracranial haemorrhage and hypoxic brain injury; increasing recipient age; type of transplant; and increasing cold ischaemic time (##TAB##2##Table 4##). SPK transplantation was associated with superior graft survival compared with PTA/PAK (HR [95% CI] for graft survival 0.38 [0.31–0.46], <italic>p </italic>< 0.001), whereas transplantation of solitary pancreas grafts, either as PTA (2.13 [1.63–2.77], <italic>p </italic>< 0.001) or PAK (2.63 [2.07–3.34], <italic>p </italic>< 0.001), was associated with poorer graft survival.</p>", "<p>Use of donor noradrenaline was not related to patient survival (HR [95% CI] 0.94 [0.72–1.23], <italic>p</italic> = 0.666), nor was duration of cardiac arrest.</p>", "<p>After adjusting for co-administration and non-administration of donor drugs, only noradrenaline use was associated with better graft survival (HR [95% CI] 0.70 (0.53–0.92), <italic>p</italic> = 0.01) although dobutamine use was associated with a non-significant trend for adverse graft survival (1.50 [0.99–2.27], <italic>p</italic> = 0.055) (##TAB##3##Table 5##). After including all potential confounders in a multivariable-adjusted Cox regression model, donor noradrenaline use was significantly related to a 26% lower risk of pancreas graft loss (HR [95% CI] 0.77 [0.64–0.94], <italic>p </italic>= 0.01) (##TAB##4##Table 6##; ##FIG##0##Figure 1##).</p>" ]	[ "<title>Discussion</title>", "<p>This study demonstrates that donor use of noradrenaline was associated with better pancreas graft survival after pancreas transplantation. Noradrenaline use appeared beneficial irrespective of the type of pancreas transplant (PTA or PAK procedures rather than SPK). If validated, these data have implications for donor selection and the optimal management of pancreas transplant donors.</p>", "<title>Prior studies</title>", "<p>Only one previous study investigated the relationship between VaDs and outcome after pancreas transplantation. In this small case series of 59 pancreas transplant recipients, there was no difference in outcomes in relation to the use of catecholamine-based VaDs or desmopressin.<sup>##UREF##3##9##</sup> This small study may have been underpowered to detect differences in outcomes in relation to the exposure.</p>", "<p>Poorer graft survival in patients receiving PAK remains a topic of on-going interest and debate regarding the factors accounting for this difference. Immunological factors are likely to be key contributors, and our data report that more than 60% of patients undergoing pancreas transplantation were in mismatch group 4 ([1 DR and 2 B] or [2 DR]). The effects of high mismatch in the PAK cohort are likely to compound the effects of prior sensitisation from initial kidney transplantation. These data are corroborated by an analysis of UK Transplant Registry data comparing live donor kidney transplantation with SPK, where only 30% of live donor kidney transplants were in group 4.<sup>##REF##28319322##10##</sup> In patients with a pancreas graft functioning for more than 90 days, survival was superior to that experienced by recipients of live donor kidney transplantation. These data illustrate the important beneficial effects of good glycaemic control on patient survival. Interestingly, in a single-centre analysis from Spain, pancreas graft survival was worse with live donor kidney transplantation compared with deceased donor transplantation.<sup>##REF##29893956##3##</sup></p>", "<title>Mechanistic insights</title>", "<p>It is unclear how noradrenaline use is associated with better graft outcomes and what underlying mechanisms may contribute to this finding. However, we can speculate that the inhibition of pancreatic insulin secretion leads to a period of beta-cell ‘rest’. Beta-cell rest is an important concept in diabetes medicine, and can lead to improvements in glycaemic control and a reduction in beta-cell death.<sup>##REF##18221429##11##</sup> This hypothesis is supported by our data: donors who received noradrenaline were significantly more likely to have also required insulin to treat hyperglycaemia.</p>", "<p>Noradrenaline has a high affinity for α2 receptors and little effect on β2 receptors. Noradrenaline exerts its potent inhibitory effect on insulin secretion by activating GPCRs in several ways. The predominant mechanism is through inhibition of the exocytosis of secretory granules, also termed the ‘distal’ effect, by its action on G<sub>βγ</sub> protein.<sup>##REF##19365392##12##,##REF##20643776##13##</sup> Heterotrimeric Gi proteins (subsets 1 and 2) also act by retarding the process of refilling empty insulin secretory granules, thus disrupting the state of the readily releasable pool of insulin-containing granules.<sup>##REF##7641683##14##</sup> Go proteins reduce the number of docked granules (i.e. those granules at an immediate state of secretory readiness).<sup>##REF##7641683##14##</sup> Activation of K<sub>ATP</sub> channels by Gi/Go proteins hyperpolarises the beta cell and prevents gating of voltage-dependent Ca<sup>2+</sup> channels, which increase intracellular Ca<sup>2+</sup> concentration and trigger insulin release.<sup>##REF##18162464##15##</sup> Adenylyl cyclase, the enzyme that catalyses the conversion of ATP to cyclic-AMP and plays a major role in mediating glucose-stimulated insulin secretion, is also subject to regulation by Gz proteins and hence is inhibited by noradrenaline.<sup>##REF##16157560##16##, ####REF##18096703##17##, ##REF##10449730##18####10449730##18##</sup> Finally, Gz proteins regulate endocytosis of insulin secretory vesicles.<sup>##REF##20643775##19##</sup></p>", "<p>The data in this study were suggestive of a potentially adverse effect of donor dobutamine use on graft survival, although the results were not statistically significant. Dobutamine is a synthetic catecholamine with a complex mixture of affinity to adrenergic receptors. The (–)-isomer of dobutamine is a potent partial alpha agonist, whereas the (+)-isomer is a potent beta agonist and alpha antagonist.<sup>##REF##6270308##20##</sup> When dobutamine is administered clinically (in its racemic form) it exerts a partial alpha agonist effect and antagonises the alpha effect in physiological circumstances of high sympathetic nervous activity, such as brain death.<sup>##REF##6109772##21##</sup> It exerts a strong beta-1 activity, but only partial agonism of the beta-2 receptor and competitively inhibits the effect of adrenaline at the beta-2 receptor.<sup>##REF##6270308##20##,##REF##8549185##22##</sup> Racemic dobutamine is reported to have a higher affinity for the β1-adrenergic receptor than for the β2-adrenergic receptor in a 3:1 ratio.<sup>##REF##18765387##23##</sup> As such, dobutamine has been shown to stimulate insulin secretion in healthy normal men.<sup>##REF##1310921##24##</sup></p>", "<p>Adrenaline, which is synthesised through the methylation of the primary amine of noradrenaline, has a lower affinity for α2-adrenoceptors (AR) but a greater affinity for β2-receptors.<sup>##REF##6270308##20##</sup> Its mechanism of action upon the α2-AR in the pancreatic beta cell is the same as for norepinephrine. However, the underlying mechanism of action and mediators of β2-AR-induced insulin secretion are less well understood. Nonetheless, there is a clear causal<sup>##REF##6109772##21##</sup>, and dose-dependent relationship between β2 agonists and insulin secretion from islet cells.<sup>##REF##8549185##22##,##REF##18765387##23##</sup> Glucagon secretion from pancreatic alpha cells was initially believed to be regulated by β-Ars; however, this evidence was based primarily in non-human subjects, and not supported by data from human studies.<sup>##REF##8549185##22##,##REF##1310921##24##, ####REF##18589086##25##, ##REF##20121753##26####20121753##26##</sup></p>", "<p>Dopamine, the most basic catechol structure, is the upstream molecule from which both norepinephrine and epinephrine are derived. Dopamine receptors can be classified into two groups: D1-like, which include D1 and D5 receptors; and D2-like, which include D2, D3 and D4. The presence of D2-like receptors on pancreatic beta cells has been confirmed, and agonism of these receptors inhibits glucose-stimulated insulin secretion via modulation of Gα<sub>i</sub> receptors.<sup>##REF##16129680##27##,##REF##33589583##28##</sup> These findings were confirmed by Simpson <italic>et al</italic> who also demonstrated an autocrine role for dopamine in the regulation of insulin secretion.<sup>##REF##22915827##29##</sup></p>", "<p>Vasopressin, meanwhile, via Gq proteins, stimulates both insulin and glucagon secretion.<sup>##REF##23073632##30##,##REF##34787082##31##</sup> Vasopressin receptors have been identified on both pancreatic alpha and beta cells, and the co-stimulation of both insulin and glucagon secretion may account for the absence of any effect on graft outcomes in this study.</p>", "<p>Co-activation of α2 and β2 receptors has been a poorly understood aspect of adrenergic receptor research. There is some evidence to support an acceleration of agonist-stimulated α2-receptor endocytosis under β2 co-activating conditions.<sup>##REF##23965992##32##</sup> Other research, however, suggests that co-activation of α2 and β2 receptors leads to desensitisation and downregulation of α2 receptors and results in a 67-fold reduction in the threshold concentration of adrenaline required for α2 downregulation.<sup>##UREF##4##33##</sup> Given that noradrenaline was co-administered with dobutamine in 88% of cases, this hypothesis may provide an explanation for the lost attenuation of α2 receptor activity in the dobutamine subgroup.</p>", "<p>Beta-cell rest may also be induced by the administration of exogenous insulin, and use of supplementary insulin therapy in both organ donors and pancreas and islet transplant recipients has been investigated.<sup>##REF##30924574##34##</sup> We have previously shown that use of insulin therapy to treat hyperglycaemia (glucose > 10mmol/L) in organ donors is associated with worse glycaemic control at 3 months after islet transplantation and also higher rates of isolated islet failure at 3 months following pancreas transplantation.<sup>##REF##33665687##35##,##REF##32452110##36##</sup> It is conceivable that outcomes may have been poorer still in the cohort of donors experiencing hyperglycaemia had they not received exogenous insulin because of unattenuated beta-cell stress.</p>", "<title>Clinical and research implications</title>", "<p>If these results can be replicated, then these data could make a valuable contribution to decision-making processes in donor pancreas selection. Existing donor pancreas risk prediction indices such as the Preprocurement Pancreas Suitability Score and Pancreas Donor Risk Index are poor predictors of outcomes.<sup>##REF##18589086##25##,##REF##20121753##26##,##REF##26474435##37##, ####REF##26036510##38##, ##REF##23711225##39####23711225##39##</sup> However, information on noradrenaline use has the potential to improve the selection of pancreases for transplantation. In vitro and in vivo mechanistic studies may help determine whether the observed relationships are causal. Identification of alternative methods of initiating beta-cell rest without instituting the concomitant side effects associated with VaDs could also be valuable.</p>", "<p>Use of noradrenaline was considerably lower in donations after circulatory death (DCDs) compared with DBDs. This is most likely because, upon coning, DBDs experience a significant catecholamine and cytokine surge that is followed by a profound slump during which vasopressors and inotropes are commonly required to maintain adequate global perfusion. By their nature, DCDs do not experience these profound physiological changes prior to donation. During the assessment process for donation, DCDs are frequently more stable. Adverse outcomes in the DCD subgroup are more commonly associated with warm ischaemia arising between the withdrawal of life-sustaining therapies and the perfusion of cold preservation solutions.</p>", "<title>Strengths and weaknesses</title>", "<p>This study has several strengths: it is the largest to assess relationships between VaDs and graft failure after pancreas transplantation; the entire UK experience of pancreas transplantation between 2004 and 2016 is reported; and several variables were accounted for that could confound relationships between exposures and outcome.</p>", "<p>We acknowledged some limitations. First, the majority of donors received at least two VaDs, which means that there may be uncertainty around whether the data indicate that noradrenaline is ‘beneficial’ or that comparator drugs are ‘harmful’. However, for the mechanistic reasons outlined above, the former explanation may be more likely. We addressed the issue by also reporting data from the cohort of patients that received no other drugs, and by adjusting for all permutations of drug use and co-linearity in the multivariable model. Second, the study used routinely collected registry data with its inherent potential limitations: retrospective design, potential for variation in data quality and missing data. However, we were fortunate that the data quality in the study was relatively high with limited missing data. Third, even though the study was large, there were limited numbers of events in some subgroups. For example, important relationships between dobutamine use and graft failure may not have been adequately captured because of limited statistical power. Finally, the focus on graft failure limits the ability to identify relationships that could lead to the early identification of deteriorating graft function. The Igls criteria on defining outcomes in beta-cell replacement therapy addresses this to some extent, but because of the small numbers of transplants performed annually, accrual of a comprehensive dataset may take some time.<sup>##REF##29453879##40##</sup></p>" ]	[ "<title>Conclusion</title>", "<p>Noradrenaline use was associated with better graft survival after adjusting for potentially confounding donor and recipient variables – these benefits may be related to inhibition of pancreatic insulin secretion initiating beta-cell ‘rest’. Further research is required to validate these findings and to establish whether relationships are causal. Identification of alternative methods of initiating beta-cell rest could be valuable in improving graft outcomes.</p>" ]	[ "<p>Martin K Rutter and David van Dellen contributed equally to this work.</p>", "<title>Introduction</title>", "<p>Outcomes following pancreas transplantation are suboptimal and better donor selection is required to improve this. Vasoactive drugs (VaD) are commonly used to correct the abnormal haemodynamics of organ donors in intensive care units. VaDs can differentially affect insulin secretion positively (dobutamine) or negatively (noradrenaline). The hypothesis was that some VaDs might induce beta-cell stress or rest and therefore impact pancreas transplant outcomes. The aim of the study was to assess relationships between VaD use and pancreas transplant graft survival.</p>", "<title>Methods</title>", "<p>Data from the UK Transplant Registry on all pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Univariable- and multivariable-adjusted Cox regression analyses determined risks of graft failure associated with VaD use.</p>", "<title>Results</title>", "<p>In 2,183 pancreas transplants, VaDs were used in the following numbers of donors: dobutamine 76 (3.5%), dopamine 84 (3.8%), adrenaline 161 (7.4%), noradrenaline 1,589 (72.8%) and vasopressin 1,219 (55.8%). In multivariable models, adjusted for covariates and the co-administration of other VaDs, noradrenaline use (vs non-use) was a strong predictor of better graft survival (hazard ratio [95% confidence interval] 0.77 [0.64–0.94], <italic>p</italic> = 0.01).</p>", "<title>Conclusions</title>", "<p>Noradrenaline use was associated with better graft survival in models adjusted for donor and recipient variables – this may be related to inhibition of pancreatic insulin secretion initiating pancreatic beta-cell ‘rest’. Further research is required to replicate these findings and establish whether relationships are causal. Identification of alternative methods of inducing beta-cell rest could be valuable in improving graft outcomes.</p>" ]	[]	[ "<title>Acknowledgements</title>", "<p>The authors are grateful to the UK Transplant Registry, held by NHS Blood and Transplant, for providing the raw data.</p>", "<title>Funding</title>", "<p>This study was funded by the Medical Research Council and Royal College of Surgeons of Edinburgh.</p>", "<title>Author Contributions</title>", "<p>All aspects of the study and senior author: I.M.S., M.K.R. and D.v.D. All aspects of the study, but not data collection: A.S. Data analysis, statistical oversight and writing: C.F. Data collection, data interpretation and writing: P.Y. Deputy chair of the pancreas advisory group at NHS Blood and Transplant with oversight over national data collection; study concept and oversight and writing: T.A.</p>" ]	[ "<fig position=\"float\" id=\"rcsann.2022.0161F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>Kaplan–Meier curves showing the survival probability after pancreas transplantation stratified by vasoactive drug use: (a) noradrenaline, (b) dobutamine</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0161TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Effect of vasoactive drugs on insulin and glucagon secretion</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Vasoactive drug</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Receptor affinity</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Affinity</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Net effect on glycaemic control</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Noradrenaline</td><td rowspan=\"1\" colspan=\"1\">α2 adrenergic<break/>β2 adrenergic</td><td rowspan=\"1\" colspan=\"1\">++++<break/>+</td><td rowspan=\"1\" colspan=\"1\">Inhibits insulin secretion<break/>Stimulates glucagon secretion</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Adrenaline</td><td rowspan=\"1\" colspan=\"1\">α2 adrenergic<break/>β2 adrenergic</td><td rowspan=\"1\" colspan=\"1\">+<break/>+++</td><td rowspan=\"1\" colspan=\"1\">Stimulates insulin secretion</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Vasopressin</td><td rowspan=\"1\" colspan=\"1\">V1a<break/>V1b</td><td rowspan=\"1\" colspan=\"1\">+++<break/>+++</td><td rowspan=\"1\" colspan=\"1\">Simulates both insulin and glucagon secretion</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Dobutamine</td><td rowspan=\"1\" colspan=\"1\">α1/2 adrenergic<break/>β1 adrenergic<break/>β2 adrenergic</td><td rowspan=\"1\" colspan=\"1\">+ (−ve isomer)<break/>− (+ve isomer)<break/>++++<break/>+</td><td rowspan=\"1\" colspan=\"1\">Stimulates insulin secretion<break/>Stimulates glucagon secretion</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Dopamine</td><td rowspan=\"1\" colspan=\"1\">D2-like (D2/D3)<break/>α2 adrenergic<break/>β2 adrenergic</td><td rowspan=\"1\" colspan=\"1\">++++<break/>+<break/>+</td><td rowspan=\"1\" colspan=\"1\">Inhibits insulin secretion<break/>Stimulates glucagon secretion</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0161TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Donor and recipient characteristics associated with noradrenaline use in pancreas transplant donors</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"2\" align=\"left\" colspan=\"1\">Donor and recipient variables</th><th colspan=\"2\" align=\"center\" rowspan=\"1\">Donor noradrenaline use</th><th char=\".\" rowspan=\"2\" align=\"char\" colspan=\"1\"><italic>p</italic>-value</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">No (<italic>n </italic>= 594)</th><th align=\"char\" char=\"(\" rowspan=\"1\" colspan=\"1\">Yes (<italic>n </italic>= 1,589)</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Donor variables</td><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\"> Age</td><td rowspan=\"1\" colspan=\"1\">36 (13.7)</td><td rowspan=\"1\" colspan=\"1\">35 (13.4)</td><td rowspan=\"1\" colspan=\"1\">0.083</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Sex (male)</td><td rowspan=\"1\" colspan=\"1\">293 (48)</td><td rowspan=\"1\" colspan=\"1\">845 (51)</td><td rowspan=\"1\" colspan=\"1\">0.171</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Ethnicity (White)</td><td rowspan=\"1\" colspan=\"1\">576 (96%)</td><td rowspan=\"1\" colspan=\"1\">1523 (93)</td><td rowspan=\"1\" colspan=\"1\">0.036</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> BMI</td><td rowspan=\"1\" colspan=\"1\">24 (4)</td><td rowspan=\"1\" colspan=\"1\">24 (4)</td><td rowspan=\"1\" colspan=\"1\">0.542</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Smoking</td><td rowspan=\"1\" colspan=\"1\">304 (50)</td><td rowspan=\"1\" colspan=\"1\">830 (51)</td><td rowspan=\"1\" colspan=\"1\">0.740</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Alcohol excess</td><td rowspan=\"1\" colspan=\"1\">53 (9)</td><td rowspan=\"1\" colspan=\"1\">113 (8)</td><td rowspan=\"1\" colspan=\"1\">0.121</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Past hypertension</td><td rowspan=\"1\" colspan=\"1\">69 (11)</td><td rowspan=\"1\" colspan=\"1\">125 (8)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0.007</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Past cardiac disease</td><td rowspan=\"1\" colspan=\"1\">25 (4)</td><td rowspan=\"1\" colspan=\"1\">41 (3)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0.048</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Cardiac arrest</td><td rowspan=\"1\" colspan=\"1\">195 (32)</td><td rowspan=\"1\" colspan=\"1\">479 (29)</td><td rowspan=\"1\" colspan=\"1\">0.195</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Peri-retrieval hypotension</td><td rowspan=\"1\" colspan=\"1\">333 (5)</td><td rowspan=\"1\" colspan=\"1\">1,082 (67)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0.001</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Donor type (DBD)</td><td rowspan=\"1\" colspan=\"1\">451 (74)</td><td rowspan=\"1\" colspan=\"1\">1,427 (86)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0.001</bold>\n</td></tr><tr><td colspan=\"4\" rowspan=\"1\"> Cause of death</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Trauma</td><td rowspan=\"1\" colspan=\"1\">82 (13)</td><td rowspan=\"1\" colspan=\"1\">292 (18)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>014</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Meningitis</td><td rowspan=\"1\" colspan=\"1\">15 (2)</td><td rowspan=\"1\" colspan=\"1\">39 (2)</td><td rowspan=\"1\" colspan=\"1\">0.92</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Stroke (thromboembolic)</td><td rowspan=\"1\" colspan=\"1\">36 (6)</td><td rowspan=\"1\" colspan=\"1\">88 (5)</td><td rowspan=\"1\" colspan=\"1\">0.61</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Intracranial haemorrhage</td><td rowspan=\"1\" colspan=\"1\">296 (48)</td><td rowspan=\"1\" colspan=\"1\">843 (51)</td><td rowspan=\"1\" colspan=\"1\">0.254</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Hypoxic brain damage</td><td rowspan=\"1\" colspan=\"1\">140 (23)</td><td rowspan=\"1\" colspan=\"1\">281 (17)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0</bold>\n<bold>.</bold>\n<bold>001</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Brain tumour</td><td rowspan=\"1\" colspan=\"1\">13 (2)</td><td rowspan=\"1\" colspan=\"1\">22 (1)</td><td rowspan=\"1\" colspan=\"1\">0.175</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Other</td><td rowspan=\"1\" colspan=\"1\">32 (5)</td><td rowspan=\"1\" colspan=\"1\">91 (6)</td><td rowspan=\"1\" colspan=\"1\">0.791</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Creatinine</td><td rowspan=\"1\" colspan=\"1\">76 (42)</td><td rowspan=\"1\" colspan=\"1\">83 (50)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0.003</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Creatinine > 2.5mg/dl</td><td rowspan=\"1\" colspan=\"1\">9 (2)</td><td rowspan=\"1\" colspan=\"1\">38 (2)</td><td rowspan=\"1\" colspan=\"1\">0.397</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Amylase, IU/L†</td><td rowspan=\"1\" colspan=\"1\">57 (36–100)</td><td rowspan=\"1\" colspan=\"1\">64 (38–121)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0.004</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> CIT</td><td rowspan=\"1\" colspan=\"1\">12 (3)</td><td rowspan=\"1\" colspan=\"1\">12 (3)</td><td rowspan=\"1\" colspan=\"1\">0.598</td></tr><tr><td colspan=\"4\" rowspan=\"1\"> HLA group</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 1</td><td rowspan=\"1\" colspan=\"1\">4 (<1)</td><td rowspan=\"1\" colspan=\"1\">10 (<1)</td><td rowspan=\"1\" colspan=\"1\">0.772</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 2</td><td rowspan=\"1\" colspan=\"1\">39 (7)</td><td rowspan=\"1\" colspan=\"1\">95 (6)</td><td rowspan=\"1\" colspan=\"1\">n.a.</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 3</td><td rowspan=\"1\" colspan=\"1\">170 (29)</td><td rowspan=\"1\" colspan=\"1\">497 (31)</td><td rowspan=\"1\" colspan=\"1\">n.a.</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 4</td><td rowspan=\"1\" colspan=\"1\">373 (63)</td><td rowspan=\"1\" colspan=\"1\">995 (63)</td><td rowspan=\"1\" colspan=\"1\">n.a.</td></tr><tr><td colspan=\"4\" rowspan=\"1\">Donor vasoactive drug use</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> None</td><td rowspan=\"1\" colspan=\"1\">338 (57)</td><td rowspan=\"1\" colspan=\"1\">n.a.</td><td rowspan=\"1\" colspan=\"1\">n.a.</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Noradrenaline</td><td rowspan=\"1\" colspan=\"1\">n.a.</td><td rowspan=\"1\" colspan=\"1\">n.a.</td><td rowspan=\"1\" colspan=\"1\">n.a.</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Adrenaline</td><td rowspan=\"1\" colspan=\"1\">50 (8)</td><td rowspan=\"1\" colspan=\"1\">111 (7)</td><td rowspan=\"1\" colspan=\"1\">0.23</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Dobutamine</td><td rowspan=\"1\" colspan=\"1\">9 (2)</td><td rowspan=\"1\" colspan=\"1\">67 (4)</td><td rowspan=\"1\" colspan=\"1\">0.002</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Dopamine</td><td rowspan=\"1\" colspan=\"1\">31 (5)</td><td rowspan=\"1\" colspan=\"1\">55 (3)</td><td rowspan=\"1\" colspan=\"1\">0.062</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Vasopressin</td><td rowspan=\"1\" colspan=\"1\">213 (36)</td><td rowspan=\"1\" colspan=\"1\">1,011 (64)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0</bold>\n<bold>.</bold>\n<bold>00001</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Insulin</td><td rowspan=\"1\" colspan=\"1\">222 (37)</td><td rowspan=\"1\" colspan=\"1\">900 (57)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0</bold>\n<bold>.</bold>\n<bold>00001</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Triiodothyronine</td><td rowspan=\"1\" colspan=\"1\">139 (24)</td><td rowspan=\"1\" colspan=\"1\">542 (34)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0</bold>\n<bold>.</bold>\n<bold>00001</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Methylprednisolone</td><td rowspan=\"1\" colspan=\"1\">195 (33)</td><td rowspan=\"1\" colspan=\"1\">598 (37)</td><td rowspan=\"1\" colspan=\"1\">0.079</td></tr><tr><td colspan=\"4\" rowspan=\"1\">Recipient variables</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Age</td><td rowspan=\"1\" colspan=\"1\">42 (8)</td><td rowspan=\"1\" colspan=\"1\">42 (8)</td><td rowspan=\"1\" colspan=\"1\">0.147</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Sex (male)</td><td rowspan=\"1\" colspan=\"1\">338 (57)</td><td rowspan=\"1\" colspan=\"1\">912 (57)</td><td rowspan=\"1\" colspan=\"1\">0.845</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Ethnicity (White)</td><td rowspan=\"1\" colspan=\"1\">541 (91)</td><td rowspan=\"1\" colspan=\"1\">1,422 (89)</td><td rowspan=\"1\" colspan=\"1\">0.039</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> BMI</td><td rowspan=\"1\" colspan=\"1\">25 (4)</td><td rowspan=\"1\" colspan=\"1\">25 (5)</td><td rowspan=\"1\" colspan=\"1\">0.204</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Transplant type (SPK)</td><td rowspan=\"1\" colspan=\"1\">492 (83)</td><td rowspan=\"1\" colspan=\"1\">1,387 (87)</td><td rowspan=\"1\" colspan=\"1\">0.094</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0161TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>HLA mismatch groups</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Level</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">HLA mismatch summary</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">HLA mismatch combinations included</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">0</td><td rowspan=\"1\" colspan=\"1\">0</td></tr><tr><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\">[0 DR and 0/1 B]</td><td rowspan=\"1\" colspan=\"1\">100, 010, 110, 200, 210</td></tr><tr><td rowspan=\"1\" colspan=\"1\">3</td><td rowspan=\"1\" colspan=\"1\">[0 DR and 2 B] or [1 DR and 0/1 B]</td><td rowspan=\"1\" colspan=\"1\">020, 120, 220, 001, 101, 201, 011, 111, 211</td></tr><tr><td rowspan=\"1\" colspan=\"1\">4</td><td rowspan=\"1\" colspan=\"1\">[1 DR and 2 B] or [2 DR]</td><td rowspan=\"1\" colspan=\"1\">021, 121, 221, 002, 102, 202, 012, 112, 212, 022, 122, 222</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0161TB4\"><label>Table 4<x xml:space=\"preserve\"> </x></label><caption><p>Donor and recipient factors predicting risk of graft failure after pancreas transplantation</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Predictor variables</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">\n<italic>N</italic>\n</th><th align=\"char\" char=\".\" rowspan=\"1\" colspan=\"1\">HR</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">95% CI</th><th align=\"char\" char=\".\" rowspan=\"1\" colspan=\"1\"><italic>p</italic>-value</th></tr></thead><tbody><tr><td colspan=\"5\" rowspan=\"1\">Donor variables</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Age<bold></bold></td><td rowspan=\"1\" colspan=\"1\">35 (13)</td><td rowspan=\"1\" colspan=\"1\">1.02</td><td rowspan=\"1\" colspan=\"1\">1.01–1.02</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0</bold>\n<bold>.</bold>\n<bold>001</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Sex (male)</td><td rowspan=\"1\" colspan=\"1\">1,138 (52)</td><td rowspan=\"1\" colspan=\"1\">1.05</td><td rowspan=\"1\" colspan=\"1\">0.89–1.25</td><td rowspan=\"1\" colspan=\"1\">0.57</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Ethnicity (White)</td><td rowspan=\"1\" colspan=\"1\">2,099 (96)</td><td rowspan=\"1\" colspan=\"1\">1.13</td><td rowspan=\"1\" colspan=\"1\">0.77–1.65</td><td rowspan=\"1\" colspan=\"1\">0.53</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> BMI, kg/m<sup>2</sup><bold></bold></td><td rowspan=\"1\" colspan=\"1\">24 (4)</td><td rowspan=\"1\" colspan=\"1\">1.03</td><td rowspan=\"1\" colspan=\"1\">1.00–1.05</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>03</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Smoking</td><td rowspan=\"1\" colspan=\"1\">1,134 (52)</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">0.84–1.12</td><td rowspan=\"1\" colspan=\"1\">0.99</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Alcohol excess</td><td rowspan=\"1\" colspan=\"1\">166 (8)</td><td rowspan=\"1\" colspan=\"1\">1.26</td><td rowspan=\"1\" colspan=\"1\">0.94–1.70</td><td rowspan=\"1\" colspan=\"1\">0.13</td></tr><tr><td rowspan=\"1\" colspan=\"1\"><bold> </bold>Past hypertension</td><td rowspan=\"1\" colspan=\"1\">194 (9)</td><td rowspan=\"1\" colspan=\"1\">1.33</td><td rowspan=\"1\" colspan=\"1\">1.00–1.77</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>05</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Past cardiac disease</td><td rowspan=\"1\" colspan=\"1\">65 (3)</td><td rowspan=\"1\" colspan=\"1\">1.04</td><td rowspan=\"1\" colspan=\"1\">0.64–1.69</td><td rowspan=\"1\" colspan=\"1\">0.87</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Cardiac arrest</td><td rowspan=\"1\" colspan=\"1\">674 (31)</td><td rowspan=\"1\" colspan=\"1\">0.82</td><td rowspan=\"1\" colspan=\"1\">0.67–1.01</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>06</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Peri-retrieval hypotension</td><td rowspan=\"1\" colspan=\"1\">1,415 (65)</td><td rowspan=\"1\" colspan=\"1\">1.04</td><td rowspan=\"1\" colspan=\"1\">0.87–1.26</td><td rowspan=\"1\" colspan=\"1\">0.65</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Donor type (DBD)</td><td rowspan=\"1\" colspan=\"1\">1,878 (86)</td><td rowspan=\"1\" colspan=\"1\">0.85</td><td rowspan=\"1\" colspan=\"1\">0.67–1.07</td><td rowspan=\"1\" colspan=\"1\">0.16</td></tr><tr><td colspan=\"5\" rowspan=\"1\"> Cause of death</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Trauma</td><td rowspan=\"1\" colspan=\"1\">374 (17)</td><td rowspan=\"1\" colspan=\"1\">0.79</td><td rowspan=\"1\" colspan=\"1\">0.63–1.00</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>05</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Meningitis</td><td rowspan=\"1\" colspan=\"1\">54 (2)</td><td rowspan=\"1\" colspan=\"1\">0.65</td><td rowspan=\"1\" colspan=\"1\">0.34–1.26</td><td rowspan=\"1\" colspan=\"1\">0.20</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Stroke (thromboembolic)</td><td rowspan=\"1\" colspan=\"1\">124 (6)</td><td rowspan=\"1\" colspan=\"1\">1.78</td><td rowspan=\"1\" colspan=\"1\">0.82–1.68</td><td rowspan=\"1\" colspan=\"1\">0.38</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Intracranial haemorrhage</td><td rowspan=\"1\" colspan=\"1\">1,139 (52)</td><td rowspan=\"1\" colspan=\"1\">1.26</td><td rowspan=\"1\" colspan=\"1\">1.06–1.50</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>01</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Hypoxic brain damage</td><td rowspan=\"1\" colspan=\"1\">421 (19)</td><td rowspan=\"1\" colspan=\"1\">0.76</td><td rowspan=\"1\" colspan=\"1\">0.59–0.99</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>04</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Brain tumour</td><td rowspan=\"1\" colspan=\"1\">35 (2)</td><td rowspan=\"1\" colspan=\"1\">1.05</td><td rowspan=\"1\" colspan=\"1\">0.52–2.10</td><td rowspan=\"1\" colspan=\"1\">0.90</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Other</td><td rowspan=\"1\" colspan=\"1\">126 (6)</td><td rowspan=\"1\" colspan=\"1\">1.17</td><td rowspan=\"1\" colspan=\"1\">0.82–1.66</td><td rowspan=\"1\" colspan=\"1\">0.39</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Creatinine</td><td rowspan=\"1\" colspan=\"1\">82 (48)</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">1.00–1.00</td><td rowspan=\"1\" colspan=\"1\">0.63</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Creatinine >2.5mg/dl (221μmol/L)</td><td rowspan=\"1\" colspan=\"1\">47 (2)</td><td rowspan=\"1\" colspan=\"1\">1.31</td><td rowspan=\"1\" colspan=\"1\">0.49–3.48</td><td rowspan=\"1\" colspan=\"1\">0.54</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Amylase†</td><td rowspan=\"1\" colspan=\"1\">61 (37–115)</td><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\">1.0–1.0</td><td rowspan=\"1\" colspan=\"1\">0.21</td></tr><tr><td colspan=\"5\" rowspan=\"1\"> Donor vasoactive drug use</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> None</td><td rowspan=\"1\" colspan=\"1\">359 (16)</td><td rowspan=\"1\" colspan=\"1\">1.29</td><td rowspan=\"1\" colspan=\"1\">1.03–1.61</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>03</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Noradrenaline</td><td rowspan=\"1\" colspan=\"1\">1,589 (73)</td><td rowspan=\"1\" colspan=\"1\">0.74</td><td rowspan=\"1\" colspan=\"1\">0.61–0.89</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>001</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Adrenaline</td><td rowspan=\"1\" colspan=\"1\">161 (7)</td><td rowspan=\"1\" colspan=\"1\">0.79</td><td rowspan=\"1\" colspan=\"1\">0.55–1.12</td><td rowspan=\"1\" colspan=\"1\">0.18</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Dopamine</td><td rowspan=\"1\" colspan=\"1\">76 (4)</td><td rowspan=\"1\" colspan=\"1\">1.13</td><td rowspan=\"1\" colspan=\"1\">0.75–1.70</td><td rowspan=\"1\" colspan=\"1\">0.57</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Dobutamine</td><td rowspan=\"1\" colspan=\"1\">86 (4)</td><td rowspan=\"1\" colspan=\"1\">1.42</td><td rowspan=\"1\" colspan=\"1\">0.94–2.13</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>10</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Vasopressin</td><td rowspan=\"1\" colspan=\"1\">1,224 (56)</td><td rowspan=\"1\" colspan=\"1\">0.94</td><td rowspan=\"1\" colspan=\"1\">0.79–1.12</td><td rowspan=\"1\" colspan=\"1\">0.49</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Insulin</td><td rowspan=\"1\" colspan=\"1\">1,122 (51)</td><td rowspan=\"1\" colspan=\"1\">0.95</td><td rowspan=\"1\" colspan=\"1\">0.8–1.13</td><td rowspan=\"1\" colspan=\"1\">0.59</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Methylprednisolone</td><td rowspan=\"1\" colspan=\"1\">681 (31)</td><td rowspan=\"1\" colspan=\"1\">1.05</td><td rowspan=\"1\" colspan=\"1\">0.87–1.26</td><td rowspan=\"1\" colspan=\"1\">0.60</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Triiodothyronine</td><td rowspan=\"1\" colspan=\"1\">793 (36)</td><td rowspan=\"1\" colspan=\"1\">1.1</td><td rowspan=\"1\" colspan=\"1\">0.92–1.32</td><td rowspan=\"1\" colspan=\"1\">0.30</td></tr><tr><td colspan=\"5\" rowspan=\"1\">Recipient variables</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Age<bold></bold></td><td rowspan=\"1\" colspan=\"1\">42 (8)</td><td rowspan=\"1\" colspan=\"1\">0.99</td><td rowspan=\"1\" colspan=\"1\">0.98–1.00</td><td rowspan=\"1\" colspan=\"1\">0.04</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Sex (male)</td><td rowspan=\"1\" colspan=\"1\">1,250 (57)</td><td rowspan=\"1\" colspan=\"1\">1.03</td><td rowspan=\"1\" colspan=\"1\">0.87–1.22</td><td rowspan=\"1\" colspan=\"1\">0.74</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Ethnicity (white)</td><td rowspan=\"1\" colspan=\"1\">1,963 (90)</td><td rowspan=\"1\" colspan=\"1\">1.11</td><td rowspan=\"1\" colspan=\"1\">0.81–1.51</td><td rowspan=\"1\" colspan=\"1\">0.52</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> BMI</td><td rowspan=\"1\" colspan=\"1\">25 (4)</td><td rowspan=\"1\" colspan=\"1\">1.02</td><td rowspan=\"1\" colspan=\"1\">0.99–1.05</td><td rowspan=\"1\" colspan=\"1\">0.11</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Transplant type (SPK)</td><td rowspan=\"1\" colspan=\"1\">1,879 (86)</td><td rowspan=\"1\" colspan=\"1\">0.38</td><td rowspan=\"1\" colspan=\"1\">0.31–0.46</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0</bold>\n<bold>.</bold>\n<bold>00001</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> CIT</td><td rowspan=\"1\" colspan=\"1\">12 (3)</td><td rowspan=\"1\" colspan=\"1\">1.07</td><td rowspan=\"1\" colspan=\"1\">1.05–1.10</td><td rowspan=\"1\" colspan=\"1\">\n<bold>< 0</bold>\n<bold>.</bold>\n<bold>001</bold>\n</td></tr><tr><td colspan=\"5\" rowspan=\"1\"> HLA group</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 1</td><td rowspan=\"1\" colspan=\"1\">14 (<1)</td><td rowspan=\"1\" colspan=\"1\">1.52</td><td rowspan=\"1\" colspan=\"1\">0.63–3.68</td><td rowspan=\"1\" colspan=\"1\">0.35</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 2</td><td rowspan=\"1\" colspan=\"1\">134 (6)</td><td rowspan=\"1\" colspan=\"1\">0.65</td><td rowspan=\"1\" colspan=\"1\">0.43–0.98</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>04</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 3</td><td rowspan=\"1\" colspan=\"1\">667 (31)</td><td rowspan=\"1\" colspan=\"1\">1.08</td><td rowspan=\"1\" colspan=\"1\">0.90–1.30</td><td rowspan=\"1\" colspan=\"1\">0.40</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> 4</td><td rowspan=\"1\" colspan=\"1\">1,368 (63)</td><td rowspan=\"1\" colspan=\"1\">1.01</td><td rowspan=\"1\" colspan=\"1\">0.85–1.21</td><td rowspan=\"1\" colspan=\"1\">0.88</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0161TB5\"><label>Table 5<x xml:space=\"preserve\"> </x></label><caption><p>Donor vasoactive drug use adjusted for co-administration and non-administration predicting risk of graft failure after pancreas transplantation (<italic>n</italic> = 2,183)</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Donor drug use</th><th align=\"char\" char=\".\" rowspan=\"1\" colspan=\"1\">HR</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">95% CI</th><th align=\"char\" char=\".\" rowspan=\"1\" colspan=\"1\"><italic>p</italic>-value</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">None</td><td rowspan=\"1\" colspan=\"1\">0.94</td><td rowspan=\"1\" colspan=\"1\">0.64–1.36</td><td rowspan=\"1\" colspan=\"1\">0.72</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Noradrenaline</td><td rowspan=\"1\" colspan=\"1\">0.70</td><td rowspan=\"1\" colspan=\"1\">0.53–0.92</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>01</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Adrenaline</td><td rowspan=\"1\" colspan=\"1\">0.75</td><td rowspan=\"1\" colspan=\"1\">0.52–1.09</td><td rowspan=\"1\" colspan=\"1\">0.13</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Dopamine</td><td rowspan=\"1\" colspan=\"1\">1.06</td><td rowspan=\"1\" colspan=\"1\">0.69–1.61</td><td rowspan=\"1\" colspan=\"1\">0.80</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Dobutamine</td><td rowspan=\"1\" colspan=\"1\">1.50</td><td rowspan=\"1\" colspan=\"1\">0.99–2.27</td><td rowspan=\"1\" colspan=\"1\">\n<bold>0</bold>\n<bold>.</bold>\n<bold>06</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Vasopressin</td><td rowspan=\"1\" colspan=\"1\">0.94</td><td rowspan=\"1\" colspan=\"1\">0.76–1.16</td><td rowspan=\"1\" colspan=\"1\">0.56</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Insulin</td><td rowspan=\"1\" colspan=\"1\">0.98</td><td rowspan=\"1\" colspan=\"1\">0.82–1.18</td><td rowspan=\"1\" colspan=\"1\">0.85</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Triiodothyronine</td><td rowspan=\"1\" colspan=\"1\">1.15</td><td rowspan=\"1\" colspan=\"1\">0.94–1.39</td><td rowspan=\"1\" colspan=\"1\">0.17</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Methylprednisolone</td><td rowspan=\"1\" colspan=\"1\">1.04</td><td rowspan=\"1\" colspan=\"1\">1.04–0.86</td><td rowspan=\"1\" colspan=\"1\">0.66</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0161TB6\"><label>Table 6<x xml:space=\"preserve\"> </x></label><caption><p>Donor and recipient factors predicting risk of graft failure after pancreas transplantation (<italic>n </italic>= 2,183)</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"char\" char=\".\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Variables</th><th align=\"char\" char=\".\" rowspan=\"1\" colspan=\"1\">HR</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">95% CI</th><th align=\"char\" char=\".\" rowspan=\"1\" colspan=\"1\"><italic>p</italic>-value</th></tr></thead><tbody><tr><td colspan=\"4\" rowspan=\"1\">Donor variables</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Age</td><td rowspan=\"1\" colspan=\"1\">1.02</td><td rowspan=\"1\" colspan=\"1\">1.01–1.02</td><td rowspan=\"1\" colspan=\"1\">< 0.001</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> BMI</td><td rowspan=\"1\" colspan=\"1\">1.02</td><td rowspan=\"1\" colspan=\"1\">0.99–1.05</td><td rowspan=\"1\" colspan=\"1\">0.22</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Hypertension</td><td rowspan=\"1\" colspan=\"1\">0.98</td><td rowspan=\"1\" colspan=\"1\">0.71–1.35</td><td rowspan=\"1\" colspan=\"1\">0.88</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Cardiac arrest</td><td rowspan=\"1\" colspan=\"1\">0.92</td><td rowspan=\"1\" colspan=\"1\">0.71–1.20</td><td rowspan=\"1\" colspan=\"1\">0.53</td></tr><tr><td colspan=\"4\" rowspan=\"1\"> Cause of death</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Trauma</td><td rowspan=\"1\" colspan=\"1\">0.82</td><td rowspan=\"1\" colspan=\"1\">0.62–1.20</td><td rowspan=\"1\" colspan=\"1\">0.38</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> ICH</td><td rowspan=\"1\" colspan=\"1\">0.99</td><td rowspan=\"1\" colspan=\"1\">0.76–1.29</td><td rowspan=\"1\" colspan=\"1\">0.95</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> HBI</td><td rowspan=\"1\" colspan=\"1\">0.82</td><td rowspan=\"1\" colspan=\"1\">0.62–1.20</td><td rowspan=\"1\" colspan=\"1\">0.31</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Noradrenaline use</td><td rowspan=\"1\" colspan=\"1\">0.77</td><td rowspan=\"1\" colspan=\"1\">0.64–0.94</td><td rowspan=\"1\" colspan=\"1\">0.01</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Dobutamine use</td><td rowspan=\"1\" colspan=\"1\">1.52</td><td rowspan=\"1\" colspan=\"1\">0.97–2.39</td><td rowspan=\"1\" colspan=\"1\">0.07</td></tr><tr><td colspan=\"4\" rowspan=\"1\">Recipient variables</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Age</td><td rowspan=\"1\" colspan=\"1\">0.98</td><td rowspan=\"1\" colspan=\"1\">0.97–0.99</td><td rowspan=\"1\" colspan=\"1\">< 0.01</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Transplant type</td><td rowspan=\"1\" colspan=\"1\">0.36</td><td rowspan=\"1\" colspan=\"1\">0.30–0.45</td><td rowspan=\"1\" colspan=\"1\">< 0.00001</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> CIT</td><td rowspan=\"1\" colspan=\"1\">1.08</td><td rowspan=\"1\" colspan=\"1\">1.05–1.11</td><td rowspan=\"1\" colspan=\"1\">< 0.00001</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> HLA group 2</td><td rowspan=\"1\" colspan=\"1\">0.72</td><td rowspan=\"1\" colspan=\"1\">0.48–1.09</td><td rowspan=\"1\" colspan=\"1\">0.12</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>− = negative; + = weak; ++ = moderate; +++ = strong; ++++ = very strong</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>BMI = body mass index; CIT = cold ischaemic time; DBD = donation after brain death; HLA = human leucocyte antigen; n.a. = not applicable; SPK = simultaneous pancreas–kidney. Alcohol excess = ≥ 7units/day; cardiac arrest = cessation of circulation during the acute event that led to organ donation; cardiac disease = either ischaemic heart disease of valvular disease; donor drug use = presented as use vs non-use; methylprednisolone use = 15mg/kg to a maximum of 1g as outlined in the donor care bundle (data on total prescribed dosage for other drugs were not available); smoking = either past or present</p></fn><fn><p>Age (years), BMI (kg/m<sup>2</sup>) and creatinine μmol/L) are continuous data presented as mean ± SD. Missing data were handled by multiple imputation (creatinine, 12%; CIT, 9%; recipient BMI, 27% of cases).</p></fn><fn><p>†Amylase is continuous data presented as median (interquartile range).</p></fn><fn><p>All binary data are presented as <italic>n</italic> (%).</p></fn><fn><p>All available variables were included in analysis.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>BMI = body mass index; CI = confidence interval; CIT = cold ischaemic time; DBD = donation after brain death; HLA = human leucocyte antigen; HR = hazard ratio; SPK = simultaneous pancreas–kidney. Alcohol excess = ≥7 units/day; cardiac arrest = cessation of circulation during the acute event that led to organ donation; cardiac disease = either ischaemic heart disease of valvular disease; donor drug use = presented as use vs non-use; methylprednisolone use = 15mg/kg to a maximum of 1g as outlined in the donor care bundle (data on total prescribed dosage for other drugs were not available); smoking = either past or present</p></fn><fn><p>Age (years), BMI (kg/m<sup>2</sup>), creatinine (μmol/L) and CIT are continuous data presented as mean ± SD. Missing data were handled by multiple imputation (creatinine, 12%; CIT, 9%; recipient BMI, 27% of cases).</p></fn><fn><p>†Amylase is continuous data presented as median (IQR).</p></fn><fn><p>All binary data are presented as <italic>n</italic> (%).</p></fn><fn><p>All available variables were included in analysis</p></fn></table-wrap-foot>", "<table-wrap-foot><p>CI = confidence interval; HR = hazard ratio</p></table-wrap-foot>", "<table-wrap-foot><fn><p>A = BMI = body mass index; CI = confidence interval; CIT = cold ischaemic time; HBI = hypoxic brain injury; HLA = human leucocyte antigen; HR = hazard ratio; ICH = intracranial haemorrhage</p></fn><fn><p>Data are hazard ratios (95% CI) from multivariable Cox regression. Variables were included in the model if they were related to graft failure.</p></fn><fn><p>HLA group 2 (inclusive of 100, 010, 110, 200, 210 HLA-A, -B and -DR mismatches)</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"rcsann.2022.0161.01\" position=\"float\"/>" ]	[]	[{"label": ["1."], "collab": ["NHS Blood and Transplant"], "italic": ["Annual report on pancreas and islet transplantation (2015/2016)"], "ext-link": ["https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/1316/organ_specific_report_pancreas_2016.pdf"], "comment": ["(cited December 2023)"]}, {"label": ["6."], "collab": ["NHS Blood and Transplant"], "italic": ["Donation after brainstem death (DBD) donor optimisation extended care bundle"], "ext-link": ["https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/4522/donor-optimisation-extended-care-bundle.pdf"], "comment": ["cited December 2023)"]}, {"label": ["7."], "surname": ["Rosengren", "Jokubka", "Tojjar"], "given-names": ["AH", "R", "D"], "italic": ["et al.", "Science (80-)"], "article-title": ["Overexpression of Alpha2A-adrenergic receptors contributes to type 2 diabetes"], "year": ["2010"], "bold": ["327"], "fpage": ["217"], "lpage": ["220"]}, {"label": ["9."], "surname": ["Decraemer", "Cathenis", "Troisi", "Hesse"], "given-names": ["I", "K", "R", "UJ"], "article-title": ["The influence of desmopressin and vasopressors in the donor management on graft function following pancreas"], "italic": ["Transplantation"], "year": ["2004"], "bold": ["1044"], "fpage": ["1042"], "lpage": ["1044"]}, {"label": ["33."], "surname": ["Desai", "Standifer", "Eikenburg"], "given-names": ["AN", "KM", "DC"], "article-title": ["Simultaneous alpha2B- and beta2-adrenoceptor activation sensitizes the alpha2B-adrenoceptor for agonist-induced down-regulation"], "italic": ["J Pharmacol Exp The"], "year": ["2004"], "bold": ["311"], "fpage": ["794"], "lpage": ["802"]}]	{ "acronym": [], "definition": [] }	40	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 16; 106(1):19-28	oa_package/e1/9e/PMC10757882.tar.gz
PMC10757883	36239948	[ "<title>Introduction</title>", "<p>The majority of new UK bladder cancer diagnoses are made in people aged over 75 years, with the highest incidence in the 80–85 years age group.<sup>##UREF##0##1##</sup> Some 75% of bladder cancers are diagnosed as non-muscle-invasive (NMIBC). Treatment and follow-up depend on various prognostic factors such as patient age, tumour size, multiplicity, stage, grade, recurrence rate and histological variance.<sup>##REF##31443960##2##</sup></p>", "<p>NMIBC has a strong tendency to recur so there exists a period of risk-stratified cystoscopic surveillance of varying intensity after initial treatment with transurethral resection of bladder tumour (TURBT). Flexible cystoscopy itself has been shown to be a painful experience for a large proportion of patients.<sup>##REF##17888042##3##</sup> There are also significant financial and service costs to health providers, with bladder cancer having the highest lifetime treatment cost per patient of all cancers.<sup>##REF##19271220##4##</sup></p>", "<p>Frailty is a clinical syndrome characterised by increased vulnerability resulting from ageing-associated physiological decline across many systems and the inability to cope with everyday acute stressors.<sup>##REF##23395245##5##</sup> In addition to chronological age, the Charlson Comorbidity (Ch) Index<sup>##REF##3558716##6##</sup> and American Society of Anesthesiologists (ASA) physical status score<sup>##REF##30648259##7##</sup> are often used as proxies for frailty, but they are not synonymous.</p>", "<p>Rockwood’s nine-point Clinical Frailty Scale (CFS) is a compromise between a simple test that can be used routinely in the clinical setting and one that is sensitive enough to detect small differences in frailty.<sup>##UREF##1##8##</sup> Frailty is of particular interest to surgeons because it is an independent risk factor for major morbidity, mortality, protracted length of stay and institutional discharge<sup>##REF##22345294##9##</sup> across multiple care settings.<sup>##REF##30778528##10##,##REF##33028215##11##</sup> Furthermore, the CFS has been validated both prospectively<sup>##REF##27250650##12##,##UREF##2##13##</sup> and retrospectively<sup>##REF##29581815##14##,##REF##31342763##15##</sup> when used by junior clinical staff outside the geriatric setting.</p>", "<p>Watchful waiting is a joint decision to delay treatment of a disease until the symptoms become significant with the aim of not altering disease-specific survival. It is commonly used in the setting of prostate cancer.<sup>##REF##30575473##16##</sup></p>", "<p>There are risk nomograms for disease recurrence and progression for NMIBC, but no national or international guidance advocating watchful waiting for certain NMIBC patients. The European Association of Urology (EAU) asks that low-risk patients are followed-up for 5 years and high-risk patients for life, with intermediate-risk patients having an ‘in-between’ follow-up scheme.<sup>##REF##31443960##2##</sup> National Institute for Health and Care Excellence (NICE) guidelines suggest low- and intermediate-risk patients are followed-up for 1 and 5 years, respectively.<sup>##UREF##3##17##</sup> Our primary aim is to study the natural history of NMIBC in patients of varying frailty with the goal of determining whether there is justification for a watchful waiting cohort. Our secondary aim is to study how different Charlson and ASA scores associate with the natural history of NMIBC.</p>" ]	[ "<title>Methods</title>", "<p>Suitable patients from a single institution were identified from clinical coding. All patients had died during a 3-year period between 1 January 2017 and 31 December 2019 with a diagnosis of bladder cancer and had undergone flexible cystoscopy within the 2 years prior to death. The maximum interval between cystoscopies is approximately 12 months so we inferred that this should capture all patients on surveillance for NMIBC. Relevant clinical information was obtained from electronic patient records. Where key information was lacking, paper notes were interrogated. Patients were excluded if they had an index diagnosis of muscle-invasive bladder cancer or if they previously had upper tract urothelial cancer. Similarly, patients who did not have full records of all histological analyses were also excluded; this was usually the case for index diagnoses made prior to electronic documentation (circa 2004) and/or in different hospital trusts.</p>", "<p>Patients were added to the Stockport bladder cancer database, an electronic record of local patients who have had or are on surveillance for NMIBC. This resource was established in 2018 and maintained prospectively. It aims to interrogate the data for information about the natural history of the disease as well as to record and analyse local practice. Data were recorded using Microsoft Access (Microsoft Corporation, 2010).<sup>##UREF##4##18##</sup> Features of the index TURBT were recorded including date of operation, and size and number of lesions. Tumour histology was recorded as per TNM staging and World Health Organization grading (1973 and 2004 versions).<sup>##REF##31443960##2##</sup> All subsequent surveillance cystoscopy dates and findings were recorded. Any interventions required from these were also documented in a manner similar to the index TURBT.</p>", "<p>Progression was defined as per the International Bladder Cancer Group’s recommendation for NMIBC.<sup>##REF##26811532##19##</sup> Recurrence was confirmed either by histological analysis or visual confirmation prior to fulguration when a specimen was not obtained. Patients who died were categorised as a bladder cancer death or non-bladder cancer death based on the death certificate and/or electronic hospital notes where available. For patients who died outside hospital or where the relevant documentation was not available to review, a consultant urologist reviewed the patient’s case and categorised accordingly.</p>", "<p>Frailty assessment was performed using the nine-point CFS<sup>##UREF##5##20##</sup> based on the patient’s preoperative assessment at their index TURBT. Similarly, comorbidity burden using the Charlson index and anaesthetic risk via the ASA score were taken at this time. When there was not enough information to confidently score a patient, a consultant urologist’s opinion was sought. If the latter did not yield a score, then the data point was left blank. We stratified these scores into three categories for analysis. CFS scores were divided into ≤3 (not frail), 4 (vulnerable) and ≥5 (frail) as per their nine-point CFS definitions. ASA scores were divided into ≤2 (mild systemic disease), 3 (severe systemic disease) and ≥4 (life-threatening systemic disease). Charlson indices were divided into ≤5, 6–7 and ≥8. All study patients scored for age and a further two points for having a solid tumour. Patients with CFS ≤3, Charlson ≤5 and ASA ≤2 were used as reference categories for comparison.</p>", "<p>The rates of surveillance flexible cystoscopies and non-surveillance procedures were extrapolated based on the number of these during individual follow-up periods and expressed as number of procedures per year.</p>", "<p>Statistical analysis was performed by the authors. Kaplan–Meier was used to analyse overall survival (OS), recurrence-free survival (RFS) and progression-free survival (PFS). This was performed on RStudio (2021).<sup>##REF##33419683##21##</sup> Student’s <italic>t</italic> test (assuming unequal variances) was used to compare the reference category against the other remaining two categories. This was done for rates of surveillance flexible cystoscopies and non-surveillance procedures. Fisher’s exact test was used to check for significance between frailty groups with respect to bladder cancer mortality and/or progression and EAU NMIBC risk categories<sup>##REF##29581815##14##</sup> (##TAB##0##Tables 1## and ##TAB##1##2##). Significance was accepted when <italic>p</italic> < 0.05.</p>", "<p>The proportion of patients who had a bladder cancer recurrence as well as those who progressed or died from bladder cancer were analysed in two-by-two matrices with two combined frailty groups: non-frail (CFS ≤ 3) vs frail (CFS ≥ 4) as well as between two combined EAU NMIBC risk groups: low/intermediate vs high/very high.</p>", "<p>Case notes were also reviewed to tally the number of complications within 30 days of a bladder cancer procedure (surveillance or non-surveillance). They were divided into complications directly attributable to the procedure and those that were unrelated but still occurred within 30 days. These complications were expressed as rate per procedure and Fisher’s exact test was used to compare groups. Acute admissions during follow-up that were attributable to complications of the natural history of bladder cancer (e.g. haematuria, bladder infection or upper tract obstruction) were also counted and expressed as a mean per patient; Student’s <italic>t</italic> test was used to compare groups here. When there was ambiguity regarding the nature of an admission, a consultant urologist’s opinion was sought.</p>" ]	[ "<title>Results</title>", "<p>Sixty-nine patients were identified with a mean age of 78.0 years (range 50.2–94.1) and 76.8% were male. The risk profile as per the EAU nomogram was as follows: low, 20.3%; intermediate, 21.7%; high, 52.2%; and very high, 5.80% (##TAB##0##Table 1##). Median OS was 32 months.</p>", "<p>The patients were divided into three categories according to CFS, Charlson and ASA scores. For all these parameters, increasing frailty, comorbidity and anaesthetic risk were associated with reduced OS (##TAB##1##Table 2##). Conversely, there was no statistical significance between categories when RFS or PFS was analysed (##TAB##1##Table 2##). This relationship is shown in the Kaplan–Meier plot (##FIG##0##Figure 1##).</p>", "<p>There was no difference between categories in the rate of flexible cystoscopies, except for fewer cystoscopies in the ‘vulnerable’ (CFS = 4) group when compared with the reference cohort (##TAB##1##Table 2##).</p>", "<p>Similarly, there was no appreciable difference in the rate of non-surveillance procedures between CFS and ASA categories. There was, however, a significant difference when comparing higher Charlson scores (more comorbidity) with the reference cohort (##TAB##1##Table 2##).</p>", "<p>There was no statistical difference in bladder cancer death and/or progression and the proportion of high (including EAU ‘very high’) risk index tumours between the categories (##TAB##2##Table 3##).</p>", "<p>One of 13 patients who had low/intermediate-risk NMIBC and who was frail (CFS ≥4) either died from bladder cancer or progressed. Similarly, only two (of 13) such patients had bladder cancer recurrence during follow-up (##TAB##2##Table 3##).</p>", "<p>There was no significant difference between frail (CFS ≥4) and non-frail patients with regards to acute admissions related to the natural history of bladder cancer. However, frail patients had much higher complication rates following procedures for both procedure-related causes and other causes (##TAB##3##Table 4##).</p>" ]	[ "<title>Discussion</title>", "<p>These data show that there is an unsurprising decrease in OS with increasing CFS score, Charlson index and ASA grade. However, there does not seem to be a statistical difference in RFS or PFS in these groups. Expressed alternatively, there is no difference in the natural history of their NMIBC, but the different confounding patient factors around them significantly alter how we should approach management. We argue that frailer, more comorbid and higher anaesthetic risk patients should not have the same protocol-driven follow-up regime as their healthier counterparts. Such frail patients with a limited life expectancy may wish to prioritise quality of life by minimising unnecessary investigations and procedures.</p>", "<p>Acute admissions due to bladder cancer during surveillance are similar between frail and non-frail patients, which again supports our hypothesis that the natural history of bladder cancer is similar between these groups. The proportion of higher risk NMIBC was similar between frailty groups. Furthermore, we found that complications after procedures were almost three times as high for frail patients. The causes of these complications are multifactorial; both procedure-related complications and other medical ailments brought such patients back into hospital within 30 days (##TAB##3##Table 4##). This will likely have had a negative impact on patient quality of life.</p>", "<p>The causes of the complications were categorised by a consultant urologist and certain inferences were made based on the likelihood of a procedure-related cause. For example, there were nine trauma-related re-admissions, such as a fall within 30 days of a procedure, but these were deemed not related to the procedure itself. Notes were scrutinised to ensure that certain known complications of procedures such as urinary tract infections were not the cause in such cases. A detailed breakdown of the aetiology of non-procedure-related complications is elaborated on in Appendix 1 (available online). These include, but are not limited to, significant cardiovascular and respiratory events, which we believe are a consequence of competing comorbidity and poor physiological reserve.</p>", "<p>All groups underwent broadly similar numbers of surveillance procedures (##TAB##1##Table 2##). This indicates that watchful waiting was not employed routinely. We noted some sporadic and inconsistent significance in the rates of surveillance and non-surveillance procedures between the different categories (##TAB##1##Table 2##), which could be due to the methodology. Many of the frail patients will have died shortly after diagnosis. Cystoscopic surveillance tends to be front-loaded to diagnose the more common early recurrences.<sup>##REF##19576682##22##</sup> However, this results in an overestimate in the rate of procedures when a patient dies early. This could explain the high rate of flexible cystoscopies in the CFS ≥ 5 group compared with the CFS = 4 group.</p>", "<p>Very few patients who are both frail (CFS ≥ 4) and have a lower risk NMIBC (EAU low/intermediate) went on to have a recurrence or progression prior to death from other causes (##TAB##2##Table 3##). The one patient who progressed only did so from G2 low-grade to carcinoma in situ. This progression was managed with fulguration and surveillance thereafter before his subsequent death from metastatic lung carcinoma 12 months later. The remaining patient who recurred only had biopsies and fulguration on three separate recurrences, all of which were small, low grade and asymptomatic. We suggest that no patient in this potential watchful waiting group had a clinically significant progression.</p>", "<p>There is an economic argument for trying to optimise the follow-up programme for frail patients. Age is one of the most significant risk factors for developing bladder cancer.<sup>##UREF##0##1##</sup> Although the ≥75 years age group accounted for only 8.3% of the total UK population in 2018, this proportion is expected to increase to 10.6% in 2028, and 12.7% in 2038.<sup>##UREF##6##23##</sup> This ageing population may increase the incidence of bladder cancers in the country leading to a significant healthcare and financial burden.</p>", "<p>Non-cancer mortality has been shown to be significant for NMIBC patients aged >85 years regardless of risk category, and many such patients decline ongoing cystoscopic surveillance which supports an upper age limit for this.<sup>##UREF##7##24##</sup> There are few retrospective studies on the impact of differing cystoscopic surveillance schedules for NMIBC patients.<sup>##REF##32203532##25##, ####REF##33833577##26##, ##REF##33617331##27####33617331##27##</sup> These draw different conclusions regarding the best way to time cystoscopies during follow-up, suggesting that this topic requires further research. Studies that advocate the current or even more intense protocol-driven follow-up do not explicitly compare patients of differing frailties.<sup>##REF##33833577##26##,##REF##33617331##27##</sup> The strength of our study is the clear demonstration that frail patients do not have any differing oncological outcomes despite being more prone to dying from non-bladder cancer causes. For NMIBC diagnosed in older patients (aged 85 years), a high-intensity surveillance schedule does not appear to gain the same number of quality-adjusted life years compared with their younger counterparts (aged 65 years).<sup>##REF##30066439##28##</sup></p>", "<title>Study limitations</title>", "<p>The frailty assessment was performed at the time of the primary TURBT when the cancer was risk-stratified and a decision made regarding follow-up. Further attempts to risk stratify any recurrences were not made explicitly. We accept that the risk profile of a NMIBC can change over the course of a patient’s life, which can alter a patient’s treatment and surveillance protocol. We identified patients retrospectively based on a flexible cystoscopy within 2 years prior to death. This method of patient identification may not have captured certain patients, including those who had since been upstaged to muscle-invasive bladder cancer and left the surveillance programme. Furthermore, patients who have since been discharged from the surveillance programme will not have been captured in our analysis. It follows that the combination of the above would introduce some bias against the most and least at-risk patient cohorts. When the cause of death was not conclusive from electronic hospital records (e.g. out-of-hospital deaths), a consultant urologist’s opinion was used. This opinion relied on the patient’s general condition prior to death and therefore inferences were made. Our study is limited by its small cohort size, as well as its retrospective nature and the lack of a prospective control group. However, the long follow-up duration for those with no significant frailty should minimise the bias towards underestimating progression with very low disease-specific mortality.</p>" ]	[ "<title>Conclusion</title>", "<p>The surveillance protocol for NMIBC currently does not factor in frailty, comorbidities or anaesthetic risk. We have shown that there is worsening OS for worsening CFS, Charlson and ASA categories despite similar PFS and RFS. Patients with higher scores are receiving broadly similar rates of surveillance cystoscopies and non-surveillance procedures that may not be required. These procedures lead to higher rates of complications and re-admissions for complications in the frail cohort.</p>", "<p>Furthermore, we have identified no frail patients with a low/intermediate-risk index tumour who went on to have clinically significant disease progression. Patients who fall into this group could form a watchful waiting cohort in future management strategies.</p>", "<p>Further prospective research into a lower-intensity follow-up protocol is needed. This can better balance the financial impact and morbidity of multiple care episodes against the detection of a clinically significant recurrence for individual patients, leading to a more personalised approach to bladder cancer surveillance.</p>" ]	[ "<title>Introduction</title>", "<p>Non-muscle-invasive bladder cancer (NMIBC) patients often require multiple invasive procedures during follow-up. Surveillance guidelines do not adjust for increasing frailty or competing comorbidity. We aim to evaluate the influence of these factors on the natural history of NMIBC and whether this may have implications for appropriate follow-up schedules.</p>", "<title>Methods</title>", "<p>NMIBC patients who died in a 3-year period while on cystoscopic surveillance were identified. Frailty was assessed using the Rockwood Clinical Frailty Scale (CFS): 1–3, no frailty; 4, vulnerable; 5–9, mild/severe frailty. Similarly, three-tier categorisations were performed for comorbidity (Charlson Comorbidity Index) and for anaesthetic risk (American Society of Anesthesiologists’ [ASA] score).</p>", "<title>Results</title>", "<p>Of the 69 patients, 26 were categorised as no frailty, 20 as vulnerable and 13 as frail. There was no difference in the proportions of those with higher risk NMIBC between the categories. Increasing frailty was associated with reduced overall survival (median 59, 29 and 13 months; <italic>p </italic>< 0.05) but not recurrence-free survival (<italic>p </italic>= 0.98) or progression-free survival (<italic>p </italic>= 0.58). Similar results were obtained using the Charlson Comorbidity Index or ASA score. No frail patients with low/intermediate-risk NMIBC had clinically significant disease progression prior to death. Frail patients with CFS ≥ 4 were found to have similar complications due to bladder cancer itself (<italic>p </italic>= 0.48) yet almost three times as many complications following cystoscopic procedures during follow-up (<italic>p </italic>< 0.05).</p>", "<title>Conclusions</title>", "<p>For frail patients with low risk of progression, protocol-driven cystoscopic surveillance may not improve survival and watchful waiting may be more appropriate. Further investigation is required to determine the feasibility of this approach.</p>" ]	[]	[]	[ "<fig position=\"float\" id=\"rcsann.2022.0099F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>Kaplan–Meier analyses comparing the Rockwood Clinical Frailty Scale (CFS), Charlson Comorbidity Index (Ch) and American Society of Anesthesiologists (ASA) physical status score categories with respect to overall survival (OS), recurrence-free survival (RFS) and progression-free survival (PFS). Survival time is shown in months. Hashed marks represent censored data. <italic>p</italic>-values are shown for each analysis.</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0099TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Demographics and characteristics of the study population</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"2\" align=\"left\" colspan=\"1\"/><th colspan=\"3\" align=\"center\" rowspan=\"1\">CFS</th><th colspan=\"3\" align=\"center\" rowspan=\"1\">Charlson</th><th colspan=\"3\" align=\"center\" rowspan=\"1\">ASA</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">≤3</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">4</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≥5</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≤5</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">6–7</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≥8</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≤2</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">3</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≥4</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Number, <italic>n</italic></td><td rowspan=\"1\" colspan=\"1\">37</td><td rowspan=\"1\" colspan=\"1\">19</td><td rowspan=\"1\" colspan=\"1\">13</td><td rowspan=\"1\" colspan=\"1\">21</td><td rowspan=\"1\" colspan=\"1\">30</td><td rowspan=\"1\" colspan=\"1\">18</td><td rowspan=\"1\" colspan=\"1\">21</td><td rowspan=\"1\" colspan=\"1\">31</td><td rowspan=\"1\" colspan=\"1\">9</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mean age, years</td><td rowspan=\"1\" colspan=\"1\">76.2</td><td rowspan=\"1\" colspan=\"1\">78.7</td><td rowspan=\"1\" colspan=\"1\">82.3</td><td rowspan=\"1\" colspan=\"1\">71.6</td><td rowspan=\"1\" colspan=\"1\">79.4</td><td rowspan=\"1\" colspan=\"1\">83.4</td><td rowspan=\"1\" colspan=\"1\">76.1</td><td rowspan=\"1\" colspan=\"1\">79.4</td><td rowspan=\"1\" colspan=\"1\">79.4</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Median age, years</td><td rowspan=\"1\" colspan=\"1\">78.1</td><td rowspan=\"1\" colspan=\"1\">80.0</td><td rowspan=\"1\" colspan=\"1\">84.3</td><td rowspan=\"1\" colspan=\"1\">70.5</td><td rowspan=\"1\" colspan=\"1\">80.2</td><td rowspan=\"1\" colspan=\"1\">84.1</td><td rowspan=\"1\" colspan=\"1\">78.0</td><td rowspan=\"1\" colspan=\"1\">81.8</td><td rowspan=\"1\" colspan=\"1\">78.8</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Age standard deviation, years</td><td rowspan=\"1\" colspan=\"1\">9.08</td><td rowspan=\"1\" colspan=\"1\">7.62</td><td rowspan=\"1\" colspan=\"1\">8.81</td><td rowspan=\"1\" colspan=\"1\">6.99</td><td rowspan=\"1\" colspan=\"1\">9.03</td><td rowspan=\"1\" colspan=\"1\">5.55</td><td rowspan=\"1\" colspan=\"1\">8.67</td><td rowspan=\"1\" colspan=\"1\">8.84</td><td rowspan=\"1\" colspan=\"1\">9.21</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Male sex, %</td><td rowspan=\"1\" colspan=\"1\">78.4</td><td rowspan=\"1\" colspan=\"1\">73.7</td><td rowspan=\"1\" colspan=\"1\">76.9</td><td rowspan=\"1\" colspan=\"1\">71.4</td><td rowspan=\"1\" colspan=\"1\">80.0</td><td rowspan=\"1\" colspan=\"1\">77.8</td><td rowspan=\"1\" colspan=\"1\">75.9</td><td rowspan=\"1\" colspan=\"1\">77.4</td><td rowspan=\"1\" colspan=\"1\">77.8</td></tr><tr><td rowspan=\"2\" colspan=\"1\">Higher risk, %</td><td rowspan=\"1\" colspan=\"1\">59.5</td><td rowspan=\"1\" colspan=\"1\">47.4</td><td rowspan=\"1\" colspan=\"1\">69.2</td><td rowspan=\"1\" colspan=\"1\">57.1</td><td rowspan=\"1\" colspan=\"1\">56.7</td><td rowspan=\"1\" colspan=\"1\">61.1</td><td rowspan=\"1\" colspan=\"1\">48.3</td><td rowspan=\"1\" colspan=\"1\">61.3</td><td rowspan=\"1\" colspan=\"1\">77.8</td></tr><tr><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.411)</td><td rowspan=\"1\" colspan=\"1\">(0.742)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(1)</td><td rowspan=\"1\" colspan=\"1\">(1)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.437)</td><td rowspan=\"1\" colspan=\"1\">(0.148)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0099TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>The natural history of NMIBC and follow-up regimes compared across the study groups</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"2\" align=\"left\" colspan=\"1\"/><th colspan=\"3\" align=\"center\" rowspan=\"1\">CFS</th><th colspan=\"3\" align=\"center\" rowspan=\"1\">Charlson</th><th colspan=\"3\" align=\"center\" rowspan=\"1\">ASA</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">≤3</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">4</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≥5</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≤5</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">6–7</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≥8</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≤2</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">3</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">≥4</th></tr></thead><tbody><tr><td rowspan=\"2\" colspan=\"1\">Overall survival, years</td><td rowspan=\"1\" colspan=\"1\">58</td><td rowspan=\"1\" colspan=\"1\">25</td><td rowspan=\"1\" colspan=\"1\">13</td><td rowspan=\"1\" colspan=\"1\">59</td><td rowspan=\"1\" colspan=\"1\">38.5</td><td rowspan=\"1\" colspan=\"1\">20</td><td rowspan=\"1\" colspan=\"1\">60</td><td rowspan=\"1\" colspan=\"1\">30</td><td rowspan=\"1\" colspan=\"1\">21</td></tr><tr><td colspan=\"3\" rowspan=\"1\">(<bold><0.01</bold>)</td><td colspan=\"3\" rowspan=\"1\">(<bold><0.01</bold>)</td><td colspan=\"3\" rowspan=\"1\">(<bold><0.01</bold>)</td></tr><tr><td rowspan=\"2\" colspan=\"1\">Recurrence-free survival, years</td><td rowspan=\"1\" colspan=\"1\">24</td><td rowspan=\"1\" colspan=\"1\">16</td><td rowspan=\"1\" colspan=\"1\">27</td><td rowspan=\"1\" colspan=\"1\">26</td><td rowspan=\"1\" colspan=\"1\">21</td><td rowspan=\"1\" colspan=\"1\">25</td><td rowspan=\"1\" colspan=\"1\">26</td><td rowspan=\"1\" colspan=\"1\">24</td><td rowspan=\"1\" colspan=\"1\">16</td></tr><tr><td colspan=\"3\" rowspan=\"1\">(0.98)</td><td colspan=\"3\" rowspan=\"1\">(0.76)</td><td colspan=\"3\" rowspan=\"1\">(0.53)</td></tr><tr><td rowspan=\"2\" colspan=\"1\">Progression-free survival, years</td><td rowspan=\"1\" colspan=\"1\">144</td><td rowspan=\"1\" colspan=\"1\">n/a</td><td rowspan=\"1\" colspan=\"1\">n/a</td><td rowspan=\"1\" colspan=\"1\">144</td><td rowspan=\"1\" colspan=\"1\">n/a</td><td rowspan=\"1\" colspan=\"1\">n/a</td><td rowspan=\"1\" colspan=\"1\">n/a</td><td rowspan=\"1\" colspan=\"1\">144</td><td rowspan=\"1\" colspan=\"1\">n/a</td></tr><tr><td colspan=\"3\" rowspan=\"1\">(0.58)</td><td colspan=\"3\" rowspan=\"1\">(0.39)</td><td colspan=\"3\" rowspan=\"1\">(0.65)</td></tr><tr><td rowspan=\"2\" colspan=\"1\">Surveillance, per year</td><td rowspan=\"1\" colspan=\"1\">1.73</td><td rowspan=\"1\" colspan=\"1\">0.31</td><td rowspan=\"1\" colspan=\"1\">1.08</td><td rowspan=\"1\" colspan=\"1\">2.00</td><td rowspan=\"1\" colspan=\"1\">1.32</td><td rowspan=\"1\" colspan=\"1\">1.08</td><td rowspan=\"1\" colspan=\"1\">1.78</td><td rowspan=\"1\" colspan=\"1\">1.16</td><td rowspan=\"1\" colspan=\"1\">1.47</td></tr><tr><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(<bold><0.01</bold>)</td><td rowspan=\"1\" colspan=\"1\">(0.105)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.206)</td><td rowspan=\"1\" colspan=\"1\">(0.112)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.128)</td><td rowspan=\"1\" colspan=\"1\">(0.563)</td></tr><tr><td rowspan=\"2\" colspan=\"1\">Non-surveillance, per year</td><td rowspan=\"1\" colspan=\"1\">0.536</td><td rowspan=\"1\" colspan=\"1\">0.404</td><td rowspan=\"1\" colspan=\"1\">0.261</td><td rowspan=\"1\" colspan=\"1\">0.664</td><td rowspan=\"1\" colspan=\"1\">0.370</td><td rowspan=\"1\" colspan=\"1\">0.325</td><td rowspan=\"1\" colspan=\"1\">0.430</td><td rowspan=\"1\" colspan=\"1\">0.525</td><td rowspan=\"1\" colspan=\"1\">0.240</td></tr><tr><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.323)</td><td rowspan=\"1\" colspan=\"1\">(0.102)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(<bold>0</bold>.<bold>0263</bold>)</td><td rowspan=\"1\" colspan=\"1\">(<bold>0</bold>.<bold>0278</bold>)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.432)</td><td rowspan=\"1\" colspan=\"1\">(0.307)</td></tr><tr><td rowspan=\"2\" colspan=\"1\">BCa death, %</td><td rowspan=\"1\" colspan=\"1\">18.9</td><td rowspan=\"1\" colspan=\"1\">5.3</td><td rowspan=\"1\" colspan=\"1\">15.4</td><td rowspan=\"1\" colspan=\"1\">28.6</td><td rowspan=\"1\" colspan=\"1\">10.0</td><td rowspan=\"1\" colspan=\"1\">5.6</td><td rowspan=\"1\" colspan=\"1\">20.7</td><td rowspan=\"1\" colspan=\"1\">9.68</td><td rowspan=\"1\" colspan=\"1\">11.1</td></tr><tr><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.243)</td><td rowspan=\"1\" colspan=\"1\">(1)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.136)</td><td rowspan=\"1\" colspan=\"1\">(0.0985)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.437)</td><td rowspan=\"1\" colspan=\"1\">(0.148)</td></tr><tr><td rowspan=\"2\" colspan=\"1\">BCa death/Prog, %</td><td rowspan=\"1\" colspan=\"1\">29.7</td><td rowspan=\"1\" colspan=\"1\">15.8</td><td rowspan=\"1\" colspan=\"1\">15.4</td><td rowspan=\"1\" colspan=\"1\">33.3</td><td rowspan=\"1\" colspan=\"1\">20.0</td><td rowspan=\"1\" colspan=\"1\">16.7</td><td rowspan=\"1\" colspan=\"1\">20.7</td><td rowspan=\"1\" colspan=\"1\">25.8</td><td rowspan=\"1\" colspan=\"1\">22.2</td></tr><tr><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.338)</td><td rowspan=\"1\" colspan=\"1\">(0.469)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.338)</td><td rowspan=\"1\" colspan=\"1\">(0.290)</td><td rowspan=\"1\" colspan=\"1\">ref</td><td rowspan=\"1\" colspan=\"1\">(0.763)</td><td rowspan=\"1\" colspan=\"1\">(1)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0099TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Two-by-two matrices showing the proportion of patients who died/progressed of bladder cancer as well as those who recurred</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th rowspan=\"2\" align=\"left\" colspan=\"1\"/><th colspan=\"2\" align=\"left\" rowspan=\"1\">Bladder cancer death/progression</th><th colspan=\"2\" align=\"left\" rowspan=\"1\">Bladder cancer recurrence</th></tr><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Lower risk</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Higher risk</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Lower risk</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Higher risk</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Non-frail</td><td rowspan=\"1\" colspan=\"1\">2/16 (12.5%)</td><td rowspan=\"1\" colspan=\"1\">10/21 (47.6%)</td><td rowspan=\"1\" colspan=\"1\">11/16 (68.8%)</td><td rowspan=\"1\" colspan=\"1\">14/21 (66.7%)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Frail</td><td rowspan=\"1\" colspan=\"1\">1/13 (7.69%)</td><td rowspan=\"1\" colspan=\"1\">3/19 (15.8%)</td><td rowspan=\"1\" colspan=\"1\">2/13 (15.4%)</td><td rowspan=\"1\" colspan=\"1\">9/19 (47.4%)</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0099TB4\"><label>Table 4<x xml:space=\"preserve\"> </x></label><caption><p>Complication rates comparing non-frail (CFS ≤ 3) and frail (CFS ≥ 4) patients</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\"/><th align=\"left\" rowspan=\"1\" colspan=\"1\">Non-frail</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Frail</th><th align=\"char\" char=\".\" rowspan=\"1\" colspan=\"1\"><italic>p-</italic>value</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">Number, <italic>n</italic></td><td rowspan=\"1\" colspan=\"1\">37</td><td rowspan=\"1\" colspan=\"1\">32</td><td rowspan=\"1\" colspan=\"1\">n/a</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Higher risk NMIBC (%)</td><td rowspan=\"1\" colspan=\"1\">22 (59.5)</td><td rowspan=\"1\" colspan=\"1\">18 (56.3)</td><td rowspan=\"1\" colspan=\"1\">0.811</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Bladder cancer acute admissions per patient, mean</td><td rowspan=\"1\" colspan=\"1\">0.73</td><td rowspan=\"1\" colspan=\"1\">0.41</td><td rowspan=\"1\" colspan=\"1\">0.479</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Total procedures</td><td rowspan=\"1\" colspan=\"1\">398</td><td rowspan=\"1\" colspan=\"1\">137</td><td rowspan=\"1\" colspan=\"1\">n/a</td></tr><tr><td rowspan=\"1\" colspan=\"1\">30-day complications total (%)</td><td rowspan=\"1\" colspan=\"1\">33 (8.3)</td><td rowspan=\"1\" colspan=\"1\">35 (25.5)</td><td rowspan=\"1\" colspan=\"1\"><bold><0</bold>.<bold>05</bold></td></tr><tr><td rowspan=\"1\" colspan=\"1\">Procedure-related complications (%)</td><td rowspan=\"1\" colspan=\"1\">18 (4.5)</td><td rowspan=\"1\" colspan=\"1\">15 (10.9)</td><td rowspan=\"1\" colspan=\"1\"><bold><0</bold>.<bold>05</bold></td></tr><tr><td rowspan=\"1\" colspan=\"1\">Non-procedure-related complications (%)</td><td rowspan=\"1\" colspan=\"1\">15 (3.7)</td><td rowspan=\"1\" colspan=\"1\">20 (14.6)</td><td rowspan=\"1\" colspan=\"1\"><bold><0</bold>.<bold>05</bold></td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>The total study population (N = 69) was categorised by way of the Rockwood nine-point Clinical Frailty Scale (CFS), Charlson Comorbidity Index and American Society of Anesthesiologists (ASA) score. ‘Higher risk’ non-muscle-invasive bladder cancer is defined as European Association of Urologists ‘high’ or ‘very high’ risk categories.<sup>##UREF##2##13##</sup> Comparisons were made between the healthiest reference (ref) categories against the others; <italic>p</italic>-values (in parentheses) were calculated using Fisher’s exact test.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>Median overall survival, recurrence-free survival and progression-free survival are shown in years. The rates of surveillance and non-surveillance cystoscopies are shown per year. The proportions of bladder cancer (‘BCa’) deaths and/or progressions (‘prog’) are shown. Comparisons were made between the reference (ref) categories against the others. Survival analysis performed using Kaplan–Meier for overall, recurrence-free and progression-free survival with associated <italic>p</italic>-values is shown. <italic>p</italic>-values (in parentheses) were calculated using Student’s <italic>t</italic> test for continuous variables and Fisher’s exact test for categorical variables.</p></fn><fn><p>ASA = American Society of Anesthesiologists; CFS = Rockwood Clinical Frailty Scale; n/a = median not defined.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>Non-frail (CFS ≤ 3) and frail (CFS ≥ 3) patients were compared with lower (low/intermediate) and higher (high/very high) risk NMIBC as defined by the EAU.<sup>##UREF##2##13##</sup></p></fn><fn><p>CFS = Rockwood Clinical Frailty Scale; EAU = European Association of Urology; NMIBC = non-muscle-invasive bladder cancer.</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>Higher risk NMIBC is defined as per EAU ‘high’ and ‘very high’ risk categories; statistical significance was measured using Fisher’s exact test. Bladder cancer acute complications expressed as the mean rate per patient and analysed with Student’s t test. Total procedures include both surveillance flexible cystoscopies and non-surveillance procedures. Thirty-day complication rates following a procedure are expressed as total, procedure-related causes and non-procedure-related causes which were analysed with Fisher’s exact test.</p></fn><fn><p>CFS = Rockwood Clinical Frailty Scale; EAU = European Association of Urology; NMIBC = non-muscle-invasive bladder cancer; n/a = median not defined.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"rcsann.2022.0099.01\" position=\"float\"/>" ]	[]	[{"label": ["1."], "collab": ["Cancer Research UK"], "italic": ["Bladder cancer statistics"], "ext-link": ["https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer"], "comment": ["(cited December 2023)"]}, {"label": ["8."], "surname": ["Moorhouse", "Rockwood"], "given-names": ["P", "K"], "article-title": ["Frailty and its quantitative clinical evaluation"], "italic": ["J R Coll Physicians Edin"], "year": ["2012"], "bold": ["42"], "fpage": ["333"], "lpage": ["340"]}, {"label": ["13."], "surname": ["Marincowitz", "Turner", "Allgar"], "given-names": ["C", "V", "V"], "italic": ["et al.", "Adv Geriatric Med Res"], "article-title": ["Can patient frailty be estimated from inpatient records? A prospective cohort study"], "year": ["2019"], "bold": ["2"], "fpage": ["e200004"]}, {"label": ["17."], "collab": ["National Institute for Health and Care Excellence"], "italic": ["Bladder cancer: diagnosis and management. [London]: NICE; 2015"], "ext-link": ["https://www.nice.org.uk/guidance/ng2"], "comment": ["(updated April 2019; cited December 2023)."]}, {"label": ["18."], "collab": ["Microsoft Access"], "italic": ["Microsoft Corporation"], "year": ["2010"]}, {"label": ["20."], "collab": ["RStudio"], "italic": ["RStudio"]}, {"label": ["23."], "collab": ["National population projections - Office for National Statistics"], "italic": ["Ons.gov.uk"], "ext-link": ["https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationprojections/bulletins/nationalpopulationprojections/2018based"], "comment": ["(cited December 2023)."]}, {"label": ["24."], "surname": ["Parsons", "Hill", "Warren"], "given-names": ["S", "G", "K"], "italic": ["et al", "J Clin Urol"], "article-title": ["Bladder cancer in the elderly: A retrospective analysis of bladder cancer in individuals older than 85 years"], "year": ["2019"], "bold": ["13"], "fpage": ["110"], "lpage": ["115"]}]	{ "acronym": [], "definition": [] }	28	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 14; 106(1):57-63	oa_package/6f/4c/PMC10757883.tar.gz
PMC10757884	37458196	[ "<title>Introduction</title>", "<p>Pathogenic variants of the <italic>BRCA1</italic> and <italic>BRCA2</italic> genes confer a 72% and 69% risk of a woman developing breast cancer by the age of 80 years, respectively, with the average age at diagnosis some 20 years younger than for sporadic cancers.<sup>##REF##28632866##1##</sup> For <italic>BRCA1</italic> carriers there is also an increased risk of developing a more aggressive cancer phenotype (triple negative) with a worse prognosis.<sup>##REF##14519755##2##,##REF##17671126##3##</sup></p>", "<p>Increased awareness of familial risk and improved availability of testing mean that more women are being identified as “at risk” when they have not had cancer themselves. However, becoming risk aware may have profound psychological consequences.<sup>##REF##14551306##4##,##REF##11426450##5##</sup></p>", "<p>Women identified as being at high risk of developing breast cancer may be offered a number of risk-management strategies, broadly divided into surveillance (plus or minus chemoprevention) or risk-reducing surgery (RRS).</p>", "<p>Due to the relative insensitivity of mammography in younger women,<sup>##REF##15800894##6##</sup> magnetic resonance imaging (MRI) surveillance is often used and is effective in the early diagnosis of cancer with improved cancer detection compared with mammography alone.<sup>##REF##15910949##7##,##REF##20177029##8##</sup> However, MRI surveillance is associated with a high recall rate for nonsignificant abnormalities,<sup>##REF##16720823##9##</sup> and even if a cancer is diagnosed at an earlier stage when it is more likely to be cured, it is associated with cancer-related anxiety and substantial treatment-related morbidity (which may include mastectomy, radiotherapy, chemotherapy and consequent fertility issues). Anxiety symptoms are reported to increase around the time of scans and results.<sup>##REF##15199386##10##</sup> Whereas surveillance does not prevent the development of cancer, a fact that causes some women considerable anxiety, this strategy is associated with a survival benefit and is likely to reduce the burden of treatment due to diagnosis at an earlier stage.<sup>##REF##24687378##11##</sup></p>", "<p>Risk-reducing mastectomy (RRM) offers the most effective risk reduction for these women, estimated at between 85% and 100%.<sup>##REF##9887158##12##–##REF##25808098##14##</sup> However, this is major surgery that may have variable cosmetic outcomes and a risk of potentially severe physical and psychological complications.<sup>##REF##9887158##12##–##REF##10761795##16##</sup> Most women undergo RRM without developing major emotional distress, but postoperative distress scores are frequently raised to clinically significant levels.<sup>##REF##17095208##17##</sup> Up to half of women undergoing RRS will suffer negative effects on body-image and sexuality,<sup>##REF##17081926##18##</sup> although this finding is variable and satisfaction is generally been reported to be high.<sup>##REF##24690515##19##</sup></p>", "<p>Risk-reducing oophorectomy, if undertaken in a premenopausal woman, may also result in a reduction in breast cancer risk for women who have completed their families if <italic>BRCA2</italic> gene carriers.<sup>##REF##31948486##20##</sup> Use of tamoxifen and aromatase inhibitors may also be added to the risk-management strategy, although once again is more likely to be effective in <italic>BRCA2</italic> gene carriers due to the biological subtypes of cancer predisposed to.</p>", "<p>The impact on partners of affected women has rarely been explored. A systematic review of men’s experiences of their partners’ mastectomy found that men struggled to talk openly to their partners about body image after surgery, with lack of communication leading to conflict and poor psychological wellbeing.<sup>##REF##24800690##21##</sup> Another study using an online survey attached to cancer support boards found that partners reported changes in intimacy, attraction and communication after disclosure of familial breast cancer risk. Concern about postsurgical appearance, attraction, health and concern about sexual relationship were noted in men whose partners were awaiting surgery.<sup>##REF##26250348##22##</sup></p>", "<p>This mixed methods study aimed to identify the psychosocial outcomes for women at high risk of breast cancer and their partners, and assess factors impacting on risk-management decisions, and decision satisfaction.</p>" ]	[ "<title>Methods</title>", "<title>Study design</title>", "<p>The study followed an exploratory, sequential, mixed methods design,<sup>##UREF##0##23##</sup> using semi-structured qualitative interviews to explore the views and experiences of individuals’ choice of, and satisfaction with, their risk-management strategy. Themes raised in these interviews informed the development of a validated questionnaire to quantify their importance. A mixed methods strategy was chosen to allow the benefits of the different components and to avoid the weaknesses of each from impacting on the overall findings. Data from both strands have been integrated throughout the analysis to provide quantification and explanation of each finding throughout and identify corroboration of results, or lack thereof, between different methodologies.</p>", "<title>Regulatory approvals</title>", "<p>Research ethics approval was obtained from the UK National Research Ethics Service (ref 09/H1308/121) and local research governance approval was obtained.</p>", "<title>Semi-structured qualitative interviews</title>", "<p>Participants were identified and recruited from a locally held database or recruited prospectively from breast clinics between 2010 and 2012.</p>", "<title>Eligibility</title>", "<p>Women judged to be at high breast cancer risk (≥30% lifetime risk) or a known carrier of a pathogenic mutation in <italic>BRCA1</italic> or <italic>2</italic>, attending family history clinic at a single UK teaching hospital.</p>", "<p>Offered a choice of RRS or surveillance.</p>", "<p>Partners of eligible women.</p>", "<title>Recruitment</title>", "<p>Purposive sampling was used, aiming to ensure recruitment of a range of ages of both women who had chosen RRS with and without reconstruction, and those who opted for enhanced surveillance.</p>", "<p>Women were approached informally in the family history clinic to participate over a two-year period. Women expressing an interest were sent a formal study pack by post (comprising a letter of invitation, study information form, interview guide, consent form, study reply form and a freepost reply envelope).</p>", "<title>Interviews</title>", "<p>The interview schedule was based on existing literature from a systematic literature review (results not reported here) and expert opinion, focussing on the drivers for, and satisfaction with, choice of risk management.<sup>##REF##15199386##10##,##REF##22105017##24##–##UREF##1##40##</sup> Women with partners were asked for permission to invite their partners to interview (by letter). Those whose partners responded positively were invited to participate by sending them a study pack (as above). Informed written consent was obtained from all participants. Interviews were digitally recorded and transcribed verbatim. Analysis was performed by two researchers (EM/SE) using the National Centre for Social Research “Framework” approach to identify themes in the data using Nvivo10 software.<sup>##UREF##2##41##,##UREF##3##42##</sup> Recruitment ceased once data saturation had occurred.</p>", "<title>Questionnaire</title>", "<title>Questionnaire design</title>", "<p>A postal questionnaire was developed based on the relevant literature and themes identified in the interviews, in conjunction with an expert reference group and a patient focus group composed of four women who had faced this decision, to maximise face and content validity, usability and acceptability. A revised version was then piloted with two service users and modified according to feedback before use (Supplemental material).</p>", "<title>Questionnaire recruitment</title>", "<p>A two-stage invitation process was used to minimise the risk of psychological distress, as advised by the focus group participants, whereby an initial invitation letter to take part was sent out, followed by the questionnaire itself to positive responders. It was felt that the questionnaire might cause distress (as it covered some sensitive issues) to some women who might not wish to take part but might read the questionnaire if it was sent directly.</p>", "<p>Participants were identified from a hospital database of women at high familial risk of breast cancer who had either been offered RRS or enhanced surveillance when attending family history clinic. For the purposes of determining the required number of respondents to the questionnaire survey, we assume the primary outcome for the survey was to estimate the proportion of responders who had high levels of decision satisfaction. Assuming a level of around 50% for this outcome, then, to estimate this proportion with a precision of ±15%, i.e. 95% confidence interval from 35% to 65%, would require 34 responders to the survey.</p>", "<title>Questionnaire analysis</title>", "<p>Questionnaires were sent out between 2012 and 2013. Descriptive statistics included medians and ranges for patient demographics. Where association between a demographic and a view were being assessed, Fisher’s exact test was used. Where comparison was drawn between, for example, women opting for surveillance versus surgery women, the Mann–Whiney <italic>U</italic> test was used. Data were analysed using IBM SPSS Statistics version 24. A <italic>p</italic>-value of <0.05 was regarded as being statistically significant.</p>" ]	[ "<title>Results</title>", "<title>Qualitative interview demographics</title>", "<p>A total of 32 women aged between 22 and 68 years (median age 44 years) were interviewed; 19 had undergone RRS, of whom 5 had a previous breast cancer diagnosis and 1 was awaiting RRS. Twelve had opted for enhanced surveillance. Of the 27 women who were in stable relationships at the time of their risk-management decision, 26 agreed to allow the study team to contact their partners for interview invitation. In total, seven partners (27%) responded positively and six were ultimately interviewed. Five were partners of women who had undergone RRS, two of whom had chosen not to have a reconstruction; the sixth was a partner of a woman who was awaiting RRS. The length of relationship at time of interview varied from 4 to 38 years, with risk-management decisions occurring after between 2 and 30 years together. Partner demographics were not collected but all were aged over 18 and all were male.</p>", "<title>Quantitative postal questionnaire survey demographics</title>", "<p>Of 157 women invited to participate, 51 (32.5%) responded favourably and were sent the full questionnaire and, of these, 71% (36/51) (70.6%) returned the questionnaire; 17(47%) from women who had had RRS and 19 (53%) from women undergoing high risk surveillance. Demographics of respondents are shown in ##TAB##0##Table 1##.</p>", "<title>Synthesis of qualitative and quantitative findings</title>", "<p>Thematic analysis of the interviews categorised data into four main themes, summarising their psychosocial outcomes and decision-making around risk management. These are summarised in ##TAB##1##Table 2## with representative quotes. The four themes are expanded below with data from the questionnaire to quantify findings and highlight variance between women choosing surveillance over RRS.</p>", "<title>Theme 1: perception of risk and the impact of increased risk</title>", "<p>Individuals’ perception of risk varied and was often based upon family members’ experience. Women undergoing surveillance estimated their risk of developing cancer as being lower than those who had undergone surgery (median 50% lifetime risk vs 80–90% for the RRM group) but this did not reach statistical significance (<italic>p</italic>=0.330). There was also a difference between the two groups in the level of impact that discovering their risk prediction or genetic diagnosis engendered (##FIG##0##Figure 1##), with a greater proportion of the surgery group recalling stronger feelings of fear and shock than those who chose surveillance (<italic>p</italic>=0.004). However, there was little difference in the level of cancer anxiety associated with their current risk-management choice (##FIG##1##Figure 2##).</p>", "<p>The impact of RRM on risk perception was substantial for most women (##TAB##2##Table 3##) (<italic>p</italic>=0.001). It is apparent that some underestimated their risk before surgery and a few overestimated their residual risk after surgery.</p>", "<p>Women with a diagnosed gene mutation (<italic>n</italic>=20) had higher cancer-related anxiety than those without a known gene mutation (##FIG##2##Figure 3##). Those with a known pathogenic variant had a median risk perception of 80–90% (presurgery or surveillance) compared with a risk perception of 50% in those without, which was significantly less (<italic>p</italic>=0.027). They also described stronger feelings on confirmation of their risk (<italic>p</italic><0.001) (Figure 4 supplemental).</p>", "<p>Women with children frequently described feelings of guilt and 26/29 (89.6%) respondents with children admitted to feeling guilty about passing on the risk to their children.</p>", "<title>Theme 2: risk-management strategy decision-making</title>", "<p>For some women, the decision of how to manage their risk was straightforward, whereas others continued to feel uncertain after making their decision, particularly those without a recognised gene mutation. Overall, women broadly fell into one of three groups: those who chose RRS (“it’s the only thing that makes sense”), those who might consider it in the future (“not yet”) and those who felt they would never consider it (“no way!”).</p>", "<p>A few of the women interviewed felt they had been pressurised into surgery/reconstruction, either by family or following the advice of their doctor. However, this was not substantiated in the questionnaire results, with no participants agreeing with either the statements “I felt pressurised to have surgery by my partner/family” or “I felt pressurised to have surgery by my doctor/surgeon”.</p>", "<p>Many of the women who chose surgery felt they “had” to do it, either feeling the need to be there in future for their children or because they felt it was their only choice given the risk of cancer they had been presented with. In the questionnaire, 14/15 (93%) women with children stated positively that they had chosen surgery to be there for their children in the future. A greater number of women without children chose surveillance (14/19 had children in the surveillance group vs 15/17 in the surgery group), although numbers were small.</p>", "<p>Women who opted for surgery more frequently noted that surveillance could not reduce the risk of cancer developing in the future and expressed concerns about the effectiveness of the test. This was also true in the questionnaire results, where 13/17 (76.5%) of women who chose surgery agreed with the statement “I didn’t feel confident that screening would protect me”. Women who chose surgery expressed greater concern about the possibility that surveillance could miss cancer compared with those who chose surveillance (66.67% vs 42.1%) or that interval cancers could develop (84.6% vs 47.1%), but neither result was significant. The surveillance group also appeared to be more optimistic about the likelihood that any cancer detected would be at an early stage than the surgical group, although this was not a significant difference (<italic>p</italic>=0.13).</p>", "<p>For some women, the decision to undergo enhanced breast surveillance was an active choice and one with which they felt satisfied. For others, surveillance was merely accepted as an alternative to surgery (or to delay that decision).</p>", "<p>Some felt that surgery was too drastic given that they may not ever develop cancer, with many stating that they would leave surgery until that situation changed. Others were more concerned with the actual effects of surgery and the loss of their breasts.</p>", "<p>Given that cancer-related anxiety is a frequently quoted reason that women choose RRS, women were also asked to indicate how likely they thought they would be to survive cancer if it did develop. No significant difference was apparent in perception of cancer cure between women who chose surveillance and those who chose surgery (<italic>p</italic>=0.34).</p>", "<p>Only 8 of 19 in the surveillance group recalled ever being offered RRS. This may reflect their lower level of risk such that RRS was not appropriate or their own lack of interest in the option such that it was not further explored by counsellors.</p>", "<p>Of women who had chosen RRM, the reasons for the choice are presented in ##FIG##3##Figure 4##. Figure 6 (supplemental) shows the attitudes of women who chose surveillance towards RRS, with the main drivers away from surgery being fear of the consequences of surgery and that it was more treatment than required, which fits with their generally lower risk perception.</p>", "<title>Theme 3: impact of risk-management strategy</title>", "<title>Surgery</title>", "<p>In the interview group, 19 of the 20 (95.0%) women who opted for surgery had reconstruction, with 6 (30.0%) requiring planned or unplanned further surgery and 13 (65.0%) reporting postoperative complications. In the questionnaire group, 16/17 (94.1%) had reconstruction, 6 (35.3%) required planned or unplanned revision surgery and 10 (58.8%) reported postoperative complications.</p>", "<p>The availability of reconstruction was an important factor in making a decision for some, but not all. There was a mixed reaction to the question, “I do not mind what my breasts look like as long as I got rid of the cancer risk” which was “not important” to some and “very important” to others. However 86.7% of questionnaire respondents felt it was very important to have a normal appearance when dressed.</p>", "<p>From the partners’ perspective, reconstruction was described as being for the benefit of the woman and not from any desire of the partner for reconstruction.</p>", "<p>Although most women expressed a welcome reduction in cancer worry following surgery, several felt that their cancer worry was merely reduced and not gone. Dealing with the loss of their natural breasts and the impact of the operation itself was a frequent cause of distress. Of the questionnaire respondents who had surgery, 13/17 (77.9%) rated the outcomes either okay, good or excellent; 22.1% rated results as poor or very poor. Sensation was poor in the majority (62.5%) and 24% rated their feel, comfort and appearance as either poor or very poor. Of the 17 patients who had reconstruction surgery, 8 had implant-only reconstruction, 5 had autologous-only and 4 had autologous latissimus dorsi reconstruction with implant; 9 (52.9%) of the patients who underwent reconstruction felt their reconstructed breasts were not their own.</p>", "<p>Some women felt guilty about having had RRS, agreeing that they did not feel as deserving as patients who had cancer. That being said, 100% of women who had RRS and who answered the question either agreed or strongly agreed with “I feel I made the right decision to have my breasts removed”; however, 3/15 (20%) would have chosen a different type of operation and 2 of 15 would have preferred, in hindsight, to have simple mastectomy without reconstruction. ##FIG##4##Figure 5## shows the questionnaire responses to questions about the outcomes of surgery, which shows the impact on body image, despite which the majority of women do not regret having RRS.</p>", "<title>Surveillance</title>", "<p>All interviewed women who chose surveillance over surgery felt they had made the right decision and were reassured by the surveillance process, with 17/19 of questionnaire respondents also agreeing with the statement “I feel confident that screening will identify any problems in my breast at an early stage” and less than half 9/19 (47.4%) were concerned about interval cancers or that surveillance would miss something (8/19; 42.1%). The vast majority felt MRI was a better test (than mammography), offering a more thorough assessment of their breasts and equating to greater levels of reassurance from the surveillance process.</p>", "<p>Most women with experience of surveillance were circumspect about any inconvenience of the process, acknowledging the process as being necessary and worthwhile for the peace of mind it provided. The wait for results was described by some as a period of increased worry.</p>", "<p>Of the questionnaire respondents, only 8/19 (42%) agreed with the statement “I felt anxious when attending for screening tests” and 11/19 (57%) agreed with the statement “I felt anxious when waiting for screening results”.</p>", "<title>Theme 4: support needs and partner relationship issues</title>", "<p>A number of women felt that peer-support would have been beneficial, both to aid decision-making and for ongoing support following their decision. Main sources of support differed between women in different RRS groups and between gene carriers and those without a demonstrated gene abnormality, with specialist healthcare professionals (clinic doctors and genetics nurses) playing an important role for more women who chose surgery or had a gene mutation.</p>", "<p>Of the 17 questionnaire respondents who had surgery, 2 had contact with support groups, with 10 of the remaining 15 expressing a desire to have access to a support group. In the surveillance group, 1/19 had contact with a support group, with 6 of the remaining 18 wanting to have had access. Women who had undergone surgery preferred to have access to a support group upfront when they were making decisions about, and going through, the process of surgery. Women in a surveillance programme appeared to want support group access in the long term, likely reflecting their ongoing risk. Women with a gene mutation and those who chose surgery had a greater (unmet) demand for support groups, with a significant minority not wanting to engage in this facility.</p>", "<p>Partners’ role in decision-making was seen as supportive by both the women and partners themselves, regardless of their own views. Those who opted for surgery described a greater impact on their relationships, with women who opted for surveillance tending to discuss the role of their partners less, perhaps reflecting a lesser need for support in this group. Very few partners seemed to have offered opinions or to have been involved in making risk-management decisions. This is reflected in the partner interviews and in the very low uptake by partners to take part in the study.</p>", "<p>Of the questionnaire participants, 16 women were in a relationship at the time of surgery, of whom 8 felt it had changed since surgery. Five felt closer to their partner, none felt more distant. Five felt their physical relationship had changed in bad way, none felt it had improved. Three felt their relationship was better emotionally, two felt it was worse. No partnerships had broken down since surgery.</p>", "<p>Half felt sexual activity had changed since surgery, with six feeling they had less interest in sex, two feeling they had more interest. Three felt their partner had less interest, one felt their partner had more interest.</p>", "<p>Of those 13 women who chose surveillance who were in a relationship at the time they discovered their risk, 1 felt their relationship had changed (more distant and physically worse in a bad way) but 12 felt it had not. Of the 15 who were sexually active, none felt it had changed since finding out about their increased risk. None felt their partner’s attitude to sex had changed either.</p>" ]	[ "<title>Discussion</title>", "<title>Risk</title>", "<p>This study explored topics that have been previously reported, but in the context of enhanced surveillance with MRI, which was not in use at the time of previous similar studies.<sup>##REF##14659349##25##,##REF##11180581##26##,##REF##10891963##31##</sup></p>", "<p>In line with published literature, discovery of risk was, for many, a traumatic event.<sup>##REF##15505627##43##</sup> Fear of cancer, treatment and death was frequently based on first-hand familial experience. For others it was confirmation of something they suspected and was accepted without shock. For some, establishing their risk enabled them to take action and regain control.</p>", "<p>Discovery of risk and risk-management decision-making appear to be, for most women, events that they wish to move beyond, as described by both Lloyd and Lodder in their studies.<sup>##REF##11180582##27##,##REF##12784290##35##</sup> For some women, RRS is an effective way to address their risk; for others, enrolling in a high-frequency surveillance programme provides this risk amelioration, allowing them, in the main, to accept their situation and move on with life. Choice of risk-management strategy needs to match women’s desire for metaphorical recovery and this will be determined by women individually, based on priorities, circumstances and perceptions that will usually be opaque to observers, be they family, friends or healthcare professionals.</p>", "<p>Women with children frequently expressed feelings of guilt around passing on their risk. Another motivating factor driving some women to choose RRS is the idea that they can address the problem and move on more rapidly. That this process involves a mutilating procedure for which there are well-documented adverse outcomes is, for the majority of women who chose it, an acceptable cost for reducing the distress they experienced living at risk.</p>", "<p>Women’s (recalled) reaction to being told they were at increased familial risk seemed to predict their subsequent risk-management decision. Women who reacted more strongly (for example, strong feelings of fear, panic and shock) were more likely to choose RRS than surveillance. High levels of distress upon discovery of risk did not correlate to high cancer-related anxiety and, whereas some studies found that cancer-related anxiety was more common in women who chose surgery, others, including this study, found it to be more common in women who chose surveillance.<sup>##REF##12784290##35##,##REF##17103066##44##</sup> To our knowledge, this strength of feeling correlating with decision management has not been reported before.</p>", "<title>Impact of gene mutation</title>", "<p>In keeping with published studies,<sup>##REF##15282350##46##</sup> those with gene mutations were more likely to choose surgery, reflecting the uncertainty of risk in those without a known mutation. While gene testing has improved significantly over the past few years, it is not yet possible to assume that women without a confirmed mutation are at lower risk.</p>", "<title>Factors impacting on decision making</title>", "<p>This study supports the findings of previous research that cancer worry was the dominant force among women considering RRS.<sup>##REF##10761795##16##</sup> Some women with children felt they had no choice but to have surgery to reduce the risk of their children seeing them suffer with cancer, or worse, dying from it. The desire for control also motivated some women to choose surgery.</p>", "<p>Women’s views of surveillance and surgery were very varied. Despite high numbers of recalls in the surveillance group (21%) compared with national published recall rates (8–17%),<sup>##REF##15800894##6##,##REF##15910949##7##,##REF##15282350##46##–##REF##15367553##48##</sup> all women who had chosen surveillance felt it had been the correct decision. Views expressed by the surveillance group suggest that surveillance is not “a bridge to surgery” for many, but an active choice. It may also be true that healthcare professionals may have recommended surveillance over surgery for this group.</p>", "<p>The majority of women who chose surgery felt that surveillance would not protect them. Most wanted to look normal when dressed, some wanted to look normal undressed too. Managing expectations, particularly pertinent to immediate breast reconstruction, is an important part of the risk-management decision-making counselling process. Without adequate information, women risk feeling disappointed by their choice.</p>", "<title>Outcomes of RRS and surveillance</title>", "<p>Women, following surgery, described a vast array of feelings. Elation was common in the early postoperative period, as was a feeling of loss and a reluctance to look at the chest which, for a minority, persisted for years. Later on, feelings were equally mixed. Some still harboured significant cancer anxiety whereas others felt they had done everything they could and were no longer worried.</p>", "<p>Reconstruction had mixed long-term outcomes. Some were delighted and described their reconstructed breasts as being an improvement over the originals. Others felt their breasts were not really their own. There were some who reported negative views of appearance, confidence and femininity following surgery, but they were in a small minority and of proportions broadly similar to other published studies.<sup>##REF##17081926##18##,##REF##14745742##36##,##REF##24908545##49##</sup> Franzoi demonstrated that body image is often reported as poorer with advancing age,<sup>##REF##9718484##50##</sup> but in this series there was no perceivable age-related difference.</p>", "<p>Women were frequently quite matter-of-fact about the practicalities of their surveillance experiences and were happy with the care offered. Previous studies have highlighted the wait for results as a source of anxiety,<sup>##REF##15199386##10##,##UREF##4##51##</sup> but this was less apparent in this study. Some felt apprehension on receiving the results, but there was not the same distress between scan and results that had been apparent in these other studies. This may reflect the tendency of women who would find this more of a problem choosing RRS instead of surveillance.</p>", "<p>That all responders reported feeling their decision had been the right one for them is reassuring. Although satisfaction with the decision to have surgery was high, this was not mirrored in satisfaction with reconstruction, perhaps reflecting the fact that mastectomy is accompanied by reduction in cancer worry, with no such effect related to the reconstruction, which is viewed more simply on the merits of its cosmetic outcome. In line with previous research, the various short- and long-term effects of surgery and the psychological impact of increased familial risk varied.<sup>##REF##15199386##10##–##REF##12359199##13##</sup></p>", "<title>Interviews with partners</title>", "<p>The overall response rate of the partner’s interviews was disappointing and merits exploration; this should be a focus of future research. One of the few similar studies involved interviews with partners of women who had reconstruction following mastectomy (for cancer).<sup>##REF##16872901##52##</sup> In their study women were not involved in a parallel study and perhaps the single invitation to participate in research carried more weight (for women and/or partners). Another difference is that women had been treated for cancer and perhaps partners felt more engaged or felt that they had more to comment on in interview.</p>", "<p>All partners felt that the decision on how to manage risk was one that needed to be made by the affected partner, essentially independently. They all appeared to have an opinion but were reluctant to share this in case they swayed their partner in her decision. Similarly consistent was the finding that partners did not appear to want their (affected) partner to choose to have reconstruction for their benefit.</p>", "<title>Impact on relationship</title>", "<p>Relationship change was common in the RRS group but rare in the surveillance group. Changes were mixed; some felt closer, some more distant and some felt their physical relationship had suffered. These changes could reflect postoperative recovery times, which, particularly for those having breast reconstruction, are not quick, but are likely to also capture the longer-term sequelae, including changes in body image, confidence and femininity. There is the possibility that some of the participants in the RRS group also had risk-reducing oophorectomy, which may have had an impact on their physical relationship.</p>", "<p>The impact of supporting their partner through the operation and the (in some cases) lengthy recovery was significant. Access to time off and the need to use holidays from work to provide care was a frequent source of difficulty. Changes to sexual relationship were attributed to postoperative pain, tiredness and reduction in confidence after RRS. Some felt emotionally closer to their partner, having tackled the familial risk ‘“as a team”, but others felt their partner had become more distant. Watching their partner deal with the psychological impact of undergoing RRS was difficult and upsetting.</p>", "<p>Several of the partners described simply wanting their partner alive and well, with or without breasts, with surprising ambivalence about breast reconstruction. The views of, and support provided by, partners strongly correlate with good psychosocial outcomes in published studies.<sup>##REF##22105017##24##,##REF##15647082##28##</sup> Assessing partners’ views as part of the risk-management counselling process could be beneficial in providing extra support for women either without a partner or without a supportive, loving partner.</p>", "<title>Limitations</title>", "<p>Limitations of this study include the self-selected nature of the women and their partners who chose to take part, introducing potential selection bias. In addition, despite purposive sampling, the younger and older age ranges were not well represented, nor were patients who opted for surgery without reconstruction. Partner interviews were small in number and all were partners of women who had chosen RRS, so may not be representative of the group as a whole. The main challenge in this study was recruitment, which may be due to the emotive nature of the subject.</p>", "<p>The nature of semi-structured interviews means that the interviewer may introduce bias, although awareness of this phenomenon and the combination of two interviewers aimed to reduce this.</p>", "<p>Previously, nonvalidated questionnaire tools have been shown to overestimate satisfaction.<sup>##REF##3352332##53##</sup> While significant time (from both researcher and focus group participants) and expertise have been spent validating this tool, it is possible that interpretation will improve with greater use. The wording of the questions may have also introduced error, although both the expert reference group and focus group were involved in selecting terminology for questions.</p>", "<p>The questionnaire response rate was disappointing and meant that subgroup analyses were not possible, and that statistical analyses were likely to be underpowered. The focus group felt that participants needed to consent to being sent a questionnaire with potentially emotive and highly personal questions. This two-stage recruitment strategy is likely to have reduced the response rate considerably. In addition to the low response rate, there is the possibility of sampling bias and participation bias, which may limit the generalisability of our results to the target population.</p>", "<p>Data were collected retrospectively, with variation in time from risk-management strategy decision-making to the interview, introducing recall bias, and some questions were hard to interpret without a baseline “norm” to act as a comparator. Comparing groups, be it surgery versus surveillance, or gene positive versus no gene mutation adds potential error. The individuals studied are a heterogeneous population, including those with and without known pathogenic variants, differing surgical procedures in the RRS group, and some of the surveillance group were offered (but declined) RRS, all of which may acts as confounders, limiting any firm conclusions.</p>", "<p>A question was missed from the surveillance questionnaire that should, with hindsight, have been included, exploring the impact of recall. This would have provided a greater understanding of how, in challenging times, surveillance women balance the ongoing risk of cancer against the risks and benefits that are associated with RRS. Similarly, the questionnaire did not explore chemoprophylaxis. This, however, was not inadvertent. At the time of the questionnaire (2012) it was not routinely available, although it would be interesting in future work to look at women’s views of this modality of risk reduction and to see how it impacts on choices.</p>", "<p>Finally, these data were collected from a single centre in 2011–2012, which may limit the generalisability of the results, and there have been advancements in surgical procedures and chemoprophylaxis in this time, although the authors feel these data still have relevance to modern practice.</p>" ]	[ "<title>Conclusions</title>", "<p>This study adds to the existing literature by measuring psychosocial outcomes at a time when options for risk management have recently changed. MRI surveillance is now widely available and represents a valid and effective risk-management strategy that, for some women, better matches their desire for risk amelioration and their tolerance of adverse effects of other options. This study also adds the views of partners, which have rarely been explored and particularly not since the addition of MRI surveillance.</p>", "<p>These data demonstrate the need for high-quality information that is, ideally, tailored to the individual. Women deciding on surgery need to know the likely outcome of their individual choice and be provided with realistic expectations, in order that they can make a truly informed decision with which they remain satisfied in the long term.</p>", "<p>Healthcare professionals involved in assessing risk, informing women of their risk-management options and guiding women through the actual process should explore all options available locally to facilitate a fully informed decision and well-supported journey.</p>", "<p>Further work on a national scale may improve the generalisability and provide support to these data, on what is a very important but underresearched area of study.</p>", "<p>We confirm that all authors have made a significant contribution at the following stages of the study: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content and (3) final approval of the version to be submitted.</p>" ]	[ "<p>Joint first authors</p>", "<title>Introduction</title>", "<p>Female carriers of <italic>BRCA1/2</italic> genes have an increased lifetime risk of breast cancer. Options for managing risk include imaging surveillance or risk-reducing surgery (RRS). This mixed methods study aimed to identify factors affecting risk-management decisions and the psychosocial outcomes of these decisions for high-risk women and their partners.</p>", "<title>Methods</title>", "<p>Semi-structured qualitative interviews were performed with women at high breast cancer risk who had faced these choices. Partners were also interviewed. Analysis used a framework approach. A bespoke questionnaire was developed to quantify and explore associations.</p>", "<title>Results</title>", "<p>A total of 32 women were interviewed. Of these, 27 had partners of whom 7 (26%) agreed to be interviewed. Four main themes arose: perception of risk and impact of increased risk; risk-management strategy decision-making; impact of risk-management strategy; support needs and partner relationship issues. The questionnaire response rate was 36/157 (23%). Decision satisfaction was high in both surveillance and RRS groups. Relationship changes were common but not universal. Common causes of distress following RRS included adverse body image changes. Both groups experienced generalised and cancer-specific anxiety. Drivers for surgery included having children, deaths of close family from breast cancer and higher levels of cancer anxiety.</p>", "<title>Conclusions</title>", "<p>Levels of psychosocial and decision satisfaction were high for women choosing both RRS and surveillance but, for a minority, risk-reducing measures result in long-term psychosocial morbidity. Efforts to recognise women at increased risk of psychological morbidity may allow targeted support.</p>" ]	[ "<title>Funding</title>", "<p>This study was funded by the University of Sheffield.</p>" ]	[]	[ "<fig position=\"float\" id=\"rcsann.2023.0042F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>Christmas tree plot showing risk perception between the two risk-management groups in women at the time of being given their risk prediction or genetic diagnosis.</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2023.0042F2\" fig-type=\"figure\"><label>Figure 2<x xml:space=\"preserve\"> </x></label><caption><p>Current levels of cancer anxiety between risk-management strategy groups</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2023.0042F3\" fig-type=\"figure\"><label>Figure 3<x xml:space=\"preserve\"> </x></label><caption><p>Christmas tree plot showing cancer-related anxiety in those with and without a known pathogenic variant</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2023.0042F4\" fig-type=\"figure\"><label>Figure 4<x xml:space=\"preserve\"> </x></label><caption><p>Reasons for choosing risk-reducing surgery</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2023.0042F5\" fig-type=\"figure\"><label>Figure 5<x xml:space=\"preserve\"> </x></label><caption><p>Women who chose surgery, body image scores after risk-reducing surgery</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"rcsann.2023.0042TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Demographics of questionnaire respondents</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\"/><th align=\"left\" rowspan=\"1\" colspan=\"1\">Screening (<italic>n</italic>=19)</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Surgery (<italic>n</italic>=17)</th></tr></thead><tbody><tr><td rowspan=\"2\" colspan=\"1\">Age</td><td rowspan=\"1\" colspan=\"1\">Median 40</td><td rowspan=\"1\" colspan=\"1\">Median 47</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Range 30–51</td><td rowspan=\"1\" colspan=\"1\">Range 29–69</td></tr><tr><td rowspan=\"5\" colspan=\"1\">Gene mutation</td><td rowspan=\"1\" colspan=\"1\">6 (31.6%) had gene mutations</td><td rowspan=\"1\" colspan=\"1\">15 (88.2%) had gene mutations</td></tr><tr><td rowspan=\"1\" colspan=\"1\">• 1 <italic>BRCA1</italic></td><td rowspan=\"1\" colspan=\"1\">• 5 <italic>BRCA1</italic></td></tr><tr><td rowspan=\"1\" colspan=\"1\">• 4 <italic>BRCA2</italic></td><td rowspan=\"1\" colspan=\"1\">• 9 <italic>BRCA2</italic></td></tr><tr><td rowspan=\"1\" colspan=\"1\">• 1 unstated mutation</td><td rowspan=\"1\" colspan=\"1\">• 1 <italic>ATM</italic></td></tr><tr><td rowspan=\"1\" colspan=\"1\">13 had no proven mutation</td><td rowspan=\"1\" colspan=\"1\">2 had no proven mutation</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Previous personal history of breast cancer</td><td rowspan=\"1\" colspan=\"1\">1 (5.3%) had a previous breast cancer diagnosis</td><td rowspan=\"1\" colspan=\"1\">6 (35.3%) had a previous breast cancer diagnosis</td></tr><tr><td rowspan=\"3\" colspan=\"1\">Partners</td><td rowspan=\"1\" colspan=\"1\">16 (84.2%) were in a relationship</td><td rowspan=\"1\" colspan=\"1\">16 (94.1%) were in a relationship</td></tr><tr><td rowspan=\"1\" colspan=\"1\">1 (5.3%) was divorced</td><td rowspan=\"1\" colspan=\"1\">1 (5.9%) was divorced</td></tr><tr><td rowspan=\"1\" colspan=\"1\">2 (10.5%) were single</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"2\" colspan=\"1\">Children</td><td rowspan=\"1\" colspan=\"1\">14 (73.7%) had children</td><td rowspan=\"1\" colspan=\"1\">15 (88.2%) had children</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Children aged from 1–20 years</td><td rowspan=\"1\" colspan=\"1\">Children aged ranged from 2–48 years</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2023.0042TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Main interview themes with representative quotes</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Theme</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Participant quotes</th></tr></thead><tbody><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Perception of risk and the impact of increased risk</bold>\n</td></tr><tr><td rowspan=\"2\" colspan=\"1\">Women’s awareness and perception of risk</td><td rowspan=\"1\" colspan=\"1\">Perception of their own risk varied “<italic>I was bound to have it already, I was going to die, basically history was going to repeat itself”</italic> [ID2: BRCA, Surgery] “<italic>Yes, my family’s got this predisposition thing, but that’s way off in the future and that’s how I feel, so you know, perhaps concerned enough to look out for signs but not to do something such as [surgery]”</italic> [ID32: No demonstrated gene mutation, screening]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Risk perception altered by family diagnosed with cancer: “<italic>Both my mum and my auntie were both screened regularly, they both had mammograms done regularly… but it came in such an aggressive form with my mum and her sister that in between screenings they had missed it and it was too far advanced too quickly”</italic> [ID20: No demonstrated gene mutation, initially screening, then surgery]</td></tr><tr><td rowspan=\"4\" colspan=\"1\">Women’s account of their risk being confirmed</td><td rowspan=\"1\" colspan=\"1\">Traumatised by the confirmation or discovery of their increased risk of breast cancer: “<italic>…as if she’d told me I’d got cancer, that’s how bad I felt. I went to pieces, didn’t go to work for a week because I couldn’t sleep, I was panicking”</italic> [ID2: BRCA, Surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Women with children felt guilty about the possible inherited risk they may have passed on: “<italic>I felt as if I was handing them a poisoned chalice and I felt um, responsible and guilty although I know there’s no need, but that’s how I felt”</italic> [ID28: BRCA, Screening]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Gained some sense of control: “<italic>Very keen obviously to get tested because I wanted to be in control of what happened not the other way”</italic> [ID4: BRCA, Surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Difficult interfamilial relationships during the time that their risk was established. “<italic>One of my sisters was angry with the way one of my other sisters had reacted to it and one of my sisters questioned my way of reacting to it”</italic> [ID14: BRCA, surgery]</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Risk-management strategy decision making</bold>\n</td></tr><tr><td rowspan=\"4\" colspan=\"1\">Involving others in decision-making</td><td rowspan=\"1\" colspan=\"1\">Most women felt the decision had been their own. “<italic>I tried to get feedback from my husband and a couple of close friends but each one of them wouldn’t commit on the decision, claiming it was entirely up to me</italic>” [ID2: BRCA, surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Pressure from partners/family/doctors: “<italic>I just went along with it and it all got to a point where I felt quite forced and quite pressurised into having surgery”</italic> [ID6: BRCA, Surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Partner’s opinion of their involvement/role in decision-making: “<italic>If she asked my opinion, I told her what I thought, but I only told her what I thought when she asked. It wasn’t my decision to make”</italic> [Partner 1, surgery] “<italic>I think I’d question erm, question her decision as to why she’d go down that route</italic> [Partner 2, Screening] “<italic>I might even suggest well, do you think it might be better if you if you had the mastectomy”</italic> [Partner 5, surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Sense of uncertainty, even once decision had been reached. “<italic>…like shall I shan’t I, yeah I’m going to do it, not I’m not and it’s still like that now”</italic> [ID17: No demonstrated gene mutation, Screening]</td></tr><tr><td rowspan=\"3\" colspan=\"1\">Decision-making in women who chose surgery</td><td rowspan=\"1\" colspan=\"1\">Idea of risk being so high there was not really a choice: “<italic>We’ve all got children, you know, what’s your choice really? For me, I didn’t really have a choice”</italic> [ID3: BRCA, surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Felt that screening didn’t reduce the risk of cancer developing and concerns it would miss something: “<italic>I didn’t want to wait for it to happen, I wanted to be proactive about it I guess”</italic> [ID13: BRCA, surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Reconstruction was an important factor in making a decision for some.:“<italic>I think I’d have felt totally different if I couldn’t have had the reconstruction</italic>” [ID13: BRCA, Surgery]</td></tr><tr><td rowspan=\"3\" colspan=\"1\">Decision-making in women who chose enhanced surveillance</td><td rowspan=\"1\" colspan=\"1\">Idea that surgery was over-treatment: “<italic>I might go through life and never get it and I might have this big operation you know for nothing”</italic> [ID27: No demonstrated gene mutation, screening]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Surgery could be reserved for when/if the situation changed: “<italic>if I get breast cancer I’ll deal with it”</italic> [ID12: BRCA, screening]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Concern over the actual effects of surgery and the loss of their breasts. “<italic>I wouldn’t put myself through that because I think, I just can’t imagine a woman without, er, bre…(breasts) I can’t imagine me without breasts”</italic> [ID25: No demonstrated gene mutation, screening]</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Impact of risk-management strategy</bold>\n</td></tr><tr><td rowspan=\"5\" colspan=\"1\">Surgery</td><td rowspan=\"1\" colspan=\"1\">Trade-off between having breasts and having the constant worry of cancer: “<italic>I wanted rid of them as soon as I’d made up my mind that they had to go because they just seemed… unnecessary”</italic> [ID3: BRCA, Surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Relived cancer-related anxiety: <italic>“breast cancer is not something I worry about more than any of my friends and yet in a sense people probably would expect me too but the fact that I’ve had the surgery really has took all that away”</italic> [ID5: BRCA, Surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Importance of reconstruction: <italic>“I think I’d have felt totally different if I couldn’t have had the reconstruction. I think I struggled enough as it was with the decrease in size”</italic> [ID13: BRCA, surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Partners’ views of reconstruction: “<italic>the reconstruction side of it was more for her than anything else”</italic> [Partner 6: Surgery]: “<italic>it is a bit weird they are there but they are not there”</italic> [Partner 2, Surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Psychological impact of the operation: “<italic>Cosmetically you look fine but dealing with the feelings and the sort of anguish that comes with reconstruction, it’s not, you never get back to normal”</italic> [ID9: BRCA, surgery] “<italic>I liked my back I think my back was probably (my) nicest bit and now I hate it”</italic> [ID8: BRCA post Latissimus dorsi flap reconstruction] “<italic>I am very worried about her, I suppose (more) psychologically than anything else, the impact it has had”</italic> [Partner 6, surgery]</td></tr><tr><td rowspan=\"4\" colspan=\"1\">Surveillance</td><td rowspan=\"1\" colspan=\"1\">Confidence in the process: “<italic>(MRI is) a more in depth test you know so that it shows up early”</italic> [ID27: No demonstrated gene mutation, screening]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Discomfort: “<italic>it was very uncomfortable laid down on that, the bed was very hard, it were very difficult to keep still… it does make you sore for a few, a few days”</italic> [ID45: No mutation, screening]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Provides reassurance: “<italic>I’m getting checks twice a year which is quite reassuring”</italic> [ID30: No demonstrated gene mutation, screening]: “<italic>they were, um, so quick and efficient and I got the results very quickly”</italic> [ID51: No demonstrated gene mutation screening]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Anxiety related to waiting for results: “<italic>I get a bit apprehensive when I open the letter”</italic> [ID45: No demonstrated gene mutation, screening]</td></tr><tr><td colspan=\"2\" rowspan=\"1\">\n<bold>Support needs and partner relationship issues</bold>\n</td></tr><tr><td rowspan=\"3\" colspan=\"1\">Experience of support provided</td><td rowspan=\"1\" colspan=\"1\">Lack of face-to-face support from others who’d experienced it: “<italic>I don’t think I was prepared for how I was going to feel afterwards [re surgery] and I think I would have liked to have spoke(n) to someone who had had it done”</italic> [ID20: No demonstrated gene mutation, surgery] “<italic>You don’t meet anyone else with the condition you don’t kind of get to talk it over with anyone else at all just, that’s it now we’ve told you, goodbye. I found that a bit weird I thought it was all a bit weird; the counselling was all one side”</italic> [ID20: No demonstrated gene mutation, surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Variable experience of support received: “<italic>on the care side we could not have asked for anything better… I don’t think I really have the right to say we have not had enough… as aware as we are that (name) needs the help we are also aware of how strained the services are”</italic> [Partner 6, surgery] “<italic>I don’t think there was any support at all thinking about it”</italic> [Partner 4, surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Support for the partners: “<italic>the only support I could have done with was my employers. Erm they gave me about three days, they did not understand the enormity of the surgery and the support that my partner needed”</italic> [Partner 1, surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Partner’s role in support provision</td><td rowspan=\"1\" colspan=\"1\">Both women and partners felt the partner’s role was that of support, despite their own feelings/opinions: “<italic>He just wasn’t happy but he’ll just have to, you know, it’s my decision in the end, it’s my body, he said ‘but it’s your decision in the end but I don’t agree with it’”</italic> [ID8: BRCA, surgery] “<italic>Mostly I was there for support”</italic> [Partner 1, surgery]</td></tr><tr><td rowspan=\"4\" colspan=\"1\">Impact on relationship</td><td rowspan=\"1\" colspan=\"1\">Variable impact on relationship with partner: “<italic>I think he’s lost a bit of confidence in our relationship”</italic> [ID2: BRCA, screening] “<italic>probably brought us closer together to be honest and he really is supportive”</italic> [ID32: No demonstrated gene abnormality, Screening]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Impact of surgery on body image: “<italic>She always turns round when she gets changed and things like that so it makes it, for me it makes it hard”</italic> [Partner 3, surgery] “<italic>he has very little interest in my breasts anymore</italic>” [ID3: BRCA, Surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Physical symptoms: “<italic>Sex is different. Don’t want it half of the time”</italic> [ID1: BRCA, Surgery] “<italic>sex is painful, is more painful than it used to be, I mean it never used to be so, it’s more painful so that makes me fearful of sex which obviously makes him nervous so that has affected it”</italic> [ID3: BRCA, Surgery]</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Cause of stress for partner “<italic>yeah, I think it worries him more than me actually. I mean, when I go for the MRI scan”</italic> [ID70: No demonstrated gene abnormality, Screening]</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2023.0042TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Perceived cancer risk pre and post RRM</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><thead><tr><th align=\"left\" rowspan=\"1\" colspan=\"1\">Case</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Perceived risk before RRM</th><th align=\"left\" rowspan=\"1\" colspan=\"1\">Perceived risk after RRM</th><th align=\"left\" rowspan=\"1\" colspan=\"1\"><italic>p</italic>-value</th></tr></thead><tbody><tr><td rowspan=\"1\" colspan=\"1\">1</td><td rowspan=\"1\" colspan=\"1\"><1%</td><td rowspan=\"1\" colspan=\"1\"><1%</td><td rowspan=\"1\" colspan=\"1\">0.001</td></tr><tr><td rowspan=\"1\" colspan=\"1\">2</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">3</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\"><1%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">4</td><td rowspan=\"1\" colspan=\"1\">50%</td><td rowspan=\"1\" colspan=\"1\">20%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">5</td><td rowspan=\"1\" colspan=\"1\">50%</td><td rowspan=\"1\" colspan=\"1\">20%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">6</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\"><1%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">7</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">8</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\"><1%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">9</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">10</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">11</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">50%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">12</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\"><1%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">13</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">14</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">15</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">Left blank</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">16</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">10%</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">17</td><td rowspan=\"1\" colspan=\"1\">80–90%</td><td rowspan=\"1\" colspan=\"1\">10%</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><p>RRM = risk-reducing mastectomy</p></table-wrap-foot>" ]	[ "<graphic xlink:href=\"rcsann.2023.0042.01\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2023.0042.02\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2023.0042.03\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2023.0042.04\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2023.0042.05\" position=\"float\"/>" ]	[]	[{"label": ["23"], "surname": ["Creswell", "Plano Clark"], "given-names": ["J", "V"], "italic": ["Designing and Conducting Mixed Methods Research"], "edition": ["2nd edn"], "publisher-loc": ["Thousand Oaks, CA"], "publisher-name": ["Sage"], "year": ["2011"]}, {"label": ["40"], "surname": ["Valdimarsdottir", "Bovbjerg", "Kash"], "given-names": ["HB", "DH", "KM"], "italic": ["et al.", "Psychooncology"], "article-title": ["Psychological distress in women with a familial risk of breast cancer"], "year": ["1995"], "bold": ["4"], "fpage": ["133"], "lpage": ["141"]}, {"label": ["41"], "surname": ["Ritchie", "Lewis", "Ritchie"], "given-names": ["JS", "J", "LJJ"], "italic": ["Carrying out Qualitative Analysis, in Qualitative Research Practice"], "publisher-loc": ["London"], "publisher-name": ["Sage"], "year": ["2003"], "fpage": ["219"], "lpage": ["262"]}, {"label": ["42"], "collab": ["QSR International"], "italic": ["Nvivo10 Qualitative data analysis software"], "ext-link": ["https://www.qsrinternational.com/nvivo-qualitative-data-analysis-software/home"]}, {"label": ["51"], "surname": ["Anderson", "Walker", "Leach"], "given-names": ["J", "LG", "MO"], "article-title": ["Magnetic resonance imaging: an acceptable way of screening women with a family history of breast cancer"], "italic": ["Breast Cancer Res Treat"], "year": ["2004"], "bold": ["88"], "fpage": ["S188"]}]	{ "acronym": [], "definition": [] }	53	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 17; 106(1):78-91	oa_package/4c/b8/PMC10757884.tar.gz
PMC10757886	36622223	[ "<title>Background</title>", "<p>Spontaneous tumour regression is the complete or partial resolution of a tumour without treatment, or in the presence of inadequate therapy.<sup>##UREF##0##1##</sup> Renal cell carcinomas (RCC) have a higher rate of spontaneous regression compared with other cancers and regression is reported in approximately 1% of cases.<sup>##UREF##0##1##</sup> Several studies report regression of RCC metastases following primary tumour treatment; this phenomenon is often postulated to have an immunological basis.<sup>##UREF##0##1##</sup> This case study describes the regression of a primary tumour through an ischaemic mechanism.</p>" ]	[]	[]	[ "<title>Discussion</title>", "<p>This case report documents the regression of a primary renal mass due to infarction. It appears the tumour was preferentially infarcted whereas the remainder of the right kidney enhances normally. We propose several theories to explain this. First, the radius of the tumour feeder vessel is significantly less than that of the renal artery. As per Poiseuille’s relationship, this decrease in radius diminishes flow to the fourth power, thus significantly decreasing blood flow to the tumour compared with the rest of the kidney. Second, tumour neovascularisation is highly aberrant in structure and function. This may make the tumour feeder vessel disproportionately prone to embolic processes compared with healthy arteries, explaining preferential embolisation of the tumour. Lastly, the dissection or infarction may have stimulated an inflammatory response, acting as a sensitising event for an anti-tumour immunological response. RCCs are immunogenic tumours, which may explain their higher rates of spontaneous regression.<sup>##UREF##0##1##</sup> It is conceivable that a combination of these explanations accounts for the spontaneous regression of the renal tumour.</p>", "<p>Spontaneous renal tumour regression due to vascular pathology has been described previously following haemorrhage into a tumour and in association with renal vein emboli.<sup>##UREF##0##1##</sup> Sammut <italic>et al</italic> document a case of complete renal tumour regression following ligation of a tumour feeder vessel during the surgical repair of an abdominal aortic aneurysm.<sup>##REF##22943321##2##</sup></p>", "<p>Small renal masses are increasingly detected on routine abdominal imaging.<sup>##REF##30091047##3##</sup> This has generated increased interest in minimally invasive procedures such as radiofrequency ablation, percutaneous cryotherapy and stereotactic radiotherapy to treat small kidney tumours.<sup>##REF##30091047##3##</sup> The European Association of Urology guidelines conclude that minimally invasive ablative techniques are safe and associated with good long-term survival; however, the current data are inadequate to support their benefit compared with surgery.</p>", "<p>Angioembolisation involves selective arterial occlusion by embolic agents such as coils, plugs, sclerosants or particles.<sup>##REF##20540917##4##</sup> Angioembolisation is utilised to manage local symptoms such as haematuria in patients with non-curable disease or in patients who are unsuitable for surgical management.<sup>##REF##30091047##3##</sup> There are no randomised control trials comparing angioembolisation with nephrectomy for the management of renal masses.<sup>##REF##30091047##3##</sup> There are, however, several retrospective studies showing promising results.<sup>##REF##30091047##3##</sup> Techniques that preserve renal function are particularly important in the context of globally increasing mortality from chronic kidney disease.<sup>##REF##32061314##5##</sup></p>" ]	[ "<title>Conclusions</title>", "<p>This case illustrates a novel mechanism of spontaneous renal tumour regression infarction following renal artery dissection. In an era in which nephron-sparing techniques are preferred for the management of renal tumours, targeted angioembolisation following detailed vascular imaging may offer a potential therapeutic opportunity to achieve cytoreductive tumour ablation.</p>" ]	[ "<p>Spontaneous tumour regression is a rare but well-documented phenomenon, especially for renal cell carcinomas. We describe the case of a 60-year-old male who presented with chest pain and shortness of breath. He was diagnosed with a large type A aortic dissection and an incidental right renal mass, highly suspicious of a renal cell carcinoma. Following repair of the dissection, subsequent imaging showed that the renal mass had largely resolved. Spontaneous tumour regression is commonly thought to occur through immunological mechanisms. A vascular cause of tumour regression through infarction is postulated in this case. Although angioembolisation is a well-recognised management option in the context of palliative treatment of symptomatic renal tumours, this case suggests an extended role for angioembolisation in the treatment of small renal masses.</p>" ]	[ "<title>Case history</title>", "<p>A 60-year-old male presented to a rural hospital with chest pain and shortness of breath on a background of obesity, hypertension and left ventricular hypertrophy. Examination revealed a blood pressure of 183/70mmHg and no chest findings. Workup was negative for acute myocardial infarction. A computed tomography (CT) scan of the T chest abdomen pelvis (##FIG##0##Figure 1a##) showed a type A aortic dissection from the aortic root extending proximally into the pericardium and distally into the right renal artery (##FIG##0##Figure 1a##). A 47×37×46mm tumour was found on the upper pole of the right kidney (##FIG##0##Figure 1a##). There was no evidence of metastatic disease. The patient underwent emergent surgical repair of the aortic dissection.</p>", "<p>A multiphase CT scan of the kidneys at one month, showed a round, heterogeneous, enhancing mass in the right kidney. There was a measurable reduction in diameter by 5mm. In keeping with local protocol, a biopsy of the lesion was not performed. The multidisciplinary team meeting concluded the most likely diagnosis was an RCC. There was no detectable macroscopic fat within the lesion. The differential diagnoses considered included a renal abscess, which was deemed unlikely given there was no ring-enhancing lesion and a lack of perinephric stranding. A renal angiomyolipoma was also considered but thought to be unlikely due to the lack of fat demonstrated on CT. Given the high likelihood that the lesion was malignant, the patient was offered a partial nephrectomy; however, he opted for surveillance while recovering from the aortic dissection surgery.</p>", "<p>A CT scan undertaken 11 months later revealed the right renal mass had largely regressed (##FIG##1##Figure 2b##), measuring 14mm in diameter. The dissection flap in the right renal artery persisted. On retrospective review of the initial scans, a previously seen feeding vessel to the lesion was no longer enhanced on arterial phase imaging (##FIG##0##Figure 2a,b##). It was concluded that the renal artery dissection compromised the tumour feeding vessel with thrombosis and infarction, causing spontaneous tumour regression. Two years following the initial presentation, the patient is well and is under ongoing surveillance with no evidence of tumour growth.</p>", "<title>Author contributions</title>", "<p>Conceptualisation, original draft writing, manuscript editing and review: J.S. Supervising consultant, manuscript editing and review: S.P. Radiological guidance, image selection, manuscript editing and review: S.Y.</p>" ]	[]	[ "<fig position=\"float\" id=\"rcsann.2022.0134F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>(a) Arterial phase computed tomography scan of chest and upper abdomen demonstrating a type A aortic dissection (red arrow). The dissection extends from below the aortic root to below the level of the renal arteries. A 47×37×46mm mass lesion, highly suspicious of a renal cell carcinoma is incidentally found on the upper pole of the right kidney (green arrow). (b) The true and false lumens of the aortic dissection extend into the right renal artery (yellow arrow).</p></caption></fig>", "<fig position=\"float\" id=\"rcsann.2022.0134F2\" fig-type=\"figure\"><label>Figure 2<x xml:space=\"preserve\"> </x></label><caption><p>(a) Computed tomography (CT) scan showing renal mass (white arrow) with a small enhancing feeding vessel (black arrow) arising from renal artery. (b) CT scan of right kidney at 11 months after the initial presentation demonstrates the renal lesion had largely regressed (red arrow) and the feeding vessel no longer enhanced on arterial phase imaging (yellow arrow).</p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"rcsann.2022.0134.01\" position=\"float\"/>", "<graphic xlink:href=\"rcsann.2022.0134.02\" position=\"float\"/>" ]	[]	[{"label": ["1."], "surname": ["Janiszewska", "Poletajew", "Wasiuty\u0144ski"], "given-names": ["AD", "S", "A"], "article-title": ["Spontaneous regression of renal cell carcinoma"], "italic": ["Contemp Oncol"], "year": ["2013"], "bold": ["17"], "fpage": ["123"], "lpage": ["127"]}]	{ "acronym": [], "definition": [] }	5	CC BY	no	2024-01-13 23:40:15	Ann R Coll Surg Engl. 2024 Jan 9; 106(1):96-98	oa_package/20/1d/PMC10757886.tar.gz
PMC10760242	38168254	[ "<title>Introduction</title>", "<p id=\"P2\">Bladder cancer is the sixth most common cancer in the United States and will cause > 17,000 deaths in 2023 [##UREF##0##1##]. Clinically, bladder cancers are categorized as either non-muscle-invasive (NMI) or muscle-invasive (MI) based on their ability to invade stroma and muscular barriers. NMI bladder cancers are mostly low-grade, multifocal, and frequently recur after surgical removal. Approximately 15% of these NMI bladder tumors will progress to MI bladder cancers. MI bladder cancers in which tumors invade through the basement membrane and migrate into the muscularis propria require more aggressive multimodality therapy with chemotherapy, radiation, and surgery. Despite this aggressive and toxic therapy, up to 50% of patients will have lethal metastatic relapses. Thus, invasive progression determines patient outcomes in bladder cancer.</p>", "<p id=\"P3\">Despite the clinical importance, the molecular drivers of invasive progression in bladder cancer are poorly understood. We have previously identified Tripartite Motif-containing protein 29 (TRIM29), also known as Ataxia Telangectasia Group D Complementing (ATDC), as an important driver of bladder cancer initiation and invasive progression [##REF##26471361##2##, ##REF##30643195##3##]. <italic toggle=\"yes\">TRIM29</italic> is part of the basal gene program which drives tumor progression and metastasis [##REF##30643195##3##]. However, the molecular mechanism by which <italic toggle=\"yes\">TRIM29</italic> impacts bladder cancer invasion was not previously well understood.</p>", "<p id=\"P4\">Cell motility plays a key role in cancer invasion and is regulated by a network consisting of highly coordinated cytoskeleton proteins which include actin microfilaments and intermediate filament (IF) proteins such as vimentin and keratins. Keratin 14 (K14), one of the components of IF and a marker of basal epithelium, is upregulated in the leading cells of invading breast tumor and plays an important role in regulating invasion [##REF##24332913##4##]. We previously reported that <italic toggle=\"yes\">TRIM29</italic> and <italic toggle=\"yes\">KRT14</italic> are both upregulated by TP63 in invasive basal bladder cancers [##REF##30643195##3##], but how TRIM29 and K14 interact with the cytoskeleton to coordinate invasion remained unclear.</p>", "<p id=\"P5\">The focal adhesion complex (FA), which serves as an anchor point for cells to attach to the extracellular matrix (ECM), is one of the main structures connecting the ECM to intracellular cytoskeleton networks including actin microfilaments, microtubules, and intermediate filaments [##REF##25460777##5##, ##REF##31358621##6##]. FA are dynamic protein complexes required for proliferation, migration, and invasion of cancer cells [##REF##31582855##7##, ##UREF##1##8##]. The FA complex develops on the cytoplasmic side of the cell membrane, where integrin receptors cluster. FA complexes are comprised of scaffold or adapter proteins like paxillin (PXN), which recruit downstream signaling factors, including focal adhesion kinase (FAK) [##REF##11146675##9##]. Phosphorylation/activation of FAK promotes binding of regulatory proteins such as c-Src, vinculin and talin which leads to polymerized actin assembly and a physical connection between focal adhesion sites and cytoskeleton network, and eventually enhances cell motility and invasion by regulating dynamic rearrangement of the actin cytoskeleton [##UREF##2##10##, ##REF##28401269##11##].</p>", "<p id=\"P6\">In this study, we use 2D and 3D models of migration and invasion to identify the role of TRIM29 in bladder cancer invasion. We find that TRIM29 specifically regulates cell migration by binding to K14 + intermediate filaments (IF), regulating formation of K14 + IFs in the invadopodia of bladder cancer cells. Further, this function regulates the stability of the FA complex during cancer cell migration and invasion. These results provide a better understanding of the regulation of invasive progression in bladder cancer and identify new potential therapeutic targets to prevent progression to the lethal invasive form of bladder cancer.</p>" ]	[ "<title>Materials and Methods</title>", "<title>Cell lines and culture media</title>", "<p id=\"P7\">UM-UC5, UM-UC9, UM-UC10, UM-UC13, UM-UC14 and UM-UC15 were cultured in DMEM culture media supplied with 4.5 g/L D-Glucose, L-Glutamine (2.5 mM), 110 mg/L Sodium Pyruvate, and 10% FBS (Thermo Fisher Scientific, Waltham, MA). All cell lines were fingerprinted and mycoplasma-tested negative. The isogenic UM-UC5, 9 and 14 <italic toggle=\"yes\">TRIM29</italic>-KO cell lines have previously been described [##REF##30643195##3##].</p>", "<title>Immunoblot</title>", "<p id=\"P8\">Immunoblot technique was described previously [##REF##30643195##3##].</p>", "<title>Antibodies</title>", "<p id=\"P9\">TRIM29 (sc-166707, Santa Cruz Biotechnology), TRIM29 (HPA020053, Sigma-Aldrich), K14 (ab7800, Abcam, Cambridge, UK), K14 (HPA023040, Sigma-Aldrich), Paxillin (#2542, Cell Signaling Technology, Danvers, MA), Zyxin (HPA004835, Sigma-Aldrich), FAK (#610087, BD Transduction Laboratories, Franklin Lakes, NJ), β-Actin (A1978, Sigma-Aldrich), FAM83H (HPA024604, Sigma-Aldrich), mCherry (PA5–34974, Thermo Fisher Scientific), secondary antibodies for immunofluorescence staining (A11001, A21244, Thermo Fisher Scientific)</p>", "<title>Expression Vectors and siRNA knock downs.</title>", "<p id=\"P10\">Plasmid for overexpressing mCherry-labeled K14 was purchased from Addgene (#55066). The transfection for bladder cancer cells was described previously [##REF##30643195##3##]. Gene knockdown of K14 or TRIM29 was performed by using siRNA against <italic toggle=\"yes\">KRT14</italic> (E-010602–00-0005, Horizon Discovery) or <italic toggle=\"yes\">TRIM29</italic> (E-012409–00-0005, Horizon Discovery), respectively. The detailed process was described previously [##REF##30643195##3##]. Overexpression of FLAG-tagged TRIM29 in bladder cancer cells was carried out by using lentiviral transduction system described previously [##REF##30643195##3##].</p>", "<title>Modified 2D cell migration (Scratch) assay and phase-contrast microscopy</title>", "<p id=\"P11\">A coverglass-bottomed 4-well chamber (#155382 Nunc Lab-Tek II, Thermo Fisher Scientific) was coated with poly-L-lysine (#4832, Sigma-Aldrich, Burlington, MA) and collagen solution (3mg/ml, STEMCELL Technologies, Vancouver, Canada); a cell culture insert (#80209, Ibidi, Gräfelfing, Germany) was placed securely on the coverglass. Cells reaching 80% confluence were trypsinized and transferred into the cell culture insert (3.5 × 10<sup>4</sup> cells/insert chamber). Cells were cultured inside the insert overnight (or until the cells reach 80% or 90% confluence). The insert was removed to start the migration assay. 2D migration was observed and recorded by a LSM800 microscope (Zeiss, Oberkochen, Germany) equipped with time-lapse imaging ability and a climate control chamber. Images were taken at 10-min intervals and then analyzed by ZEN2 software (Zeiss). Cells on the leading edge were selected and tracked for calculating the velocity of migration.</p>", "<title>Immunoprecipitation</title>", "<p id=\"P12\">Cells cultured on plates reaching 90% confluence were lysed in buffer (25 mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM EDTA, 5% glycerol) for immunoprecipitation (IP). For conventional IP, the lysis buffer contained 0.1% NP40. Cell lysates were centrifuged at 3000 g for 10 min, and then the supernatants were collected. Magnetic beads (10015D, Thermo Fisher Scientific) were coated with TRIM29 antibody (B-2, Santa Cruz Biotechnology, Dallas, TX) for 6 h at 4°C before adding to cell lysates by following manufacturer’s instructions. Antibody-coated bead and cell lysates were mixed in 4°C for overnight. Beads were washed with cold PBS twice before adding protein sample loading buffer (#1610747, Bio-Rad, Hercules, CA) and heated at 95°C for 5 min. Immunoprecipitated samples were used to perform Western blot or mass spectrometry.</p>", "<title>Liquid Chromatography and Mass Spectrometry</title>", "<p id=\"P13\">The beads were resuspended in 50 μl of 0.1M ammonium bicarbonate buffer (pH ~ 8). Cysteines were reduced by adding 50 μl of 10 mM DTT and incubating at 45°C for 30 min. Samples were cooled to room temperature and alkylation of cysteines was achieved by incubating with 65 mM 2-Chloroacetamide under darkness for 30 min at room temperature. An overnight digestion with 1 μg sequencing grade, modified trypsin was carried out at 37°C with constant shaking in a thermomixer. Digestion was stopped by acidification and peptides were desalted using SepPak C18 cartridges using manufacturer’s protocol (Waters, Milford, MA). Samples were completely dried by using vacufuge. Resulting peptides were dissolved in 9 μl of 0.1% formic acid/2% acetonitrile solution and 2 μl of the peptide solution were resolved on a nano-capillary reverse phase column (Acclaim PepMap C18, 2 micron, 50 cm, Thermo Fisher Scientific) using a 0.1% formic acid/2% acetonitrile (Buffer A) and 0.1% formic acid/95% acetonitrile (Buffer B) gradient at 300 nl/min over a period of 180 min (2–25% buffer B in 110 min, 25–40% in 20 min, 40–90% in 5 min followed by holding at 90% buffer B for 10 min and equilibration with Buffer A for 30 min). Eluent was directly introduced into Q exactive HF mass spectrometer (Thermo Fisher Scientific) using an EasySpray source. MS1 scans were acquired at 60K resolution (AGC target = 3×106; max IT = 50 ms). Data dependent collision induced dissociation MS/MS spectra were acquired using Top speed method (3 seconds) following each MS1 scan (NCE ~ 28%; 15K resolution; AGC target 1×105; max IT 45 ms). Proteins were identified by searching the MS/MS Human Protein Database (20286 entries; reviewed; downloaded on 06/17/2020) and filtered for high confidence proteins using Proteome Discoverer (v2.4, Thermo Scientific). Search parameters included MS1 mass tolerance of 10 ppm and fragment tolerance of 0.2 Da; two missed cleavages were allowed; carbamidimethylation of cysteine was considered fixed modification and oxidation of methionine, deamidation of aspargine and glutamine were considered as potential modifications. False discovery rate (FDR) was determined using Percolator and proteins/peptides with a FDR of = 1% were retained for further analysis.</p>", "<title>Immunofluorescence staining and imaging</title>", "<p id=\"P14\">ls were seeded on poly-L-lysine- and collagen-coated coverglass. After designated treatment and time of incubation, cell samples were fixed by 4% paraformaldehyde in PBS for 10 min, then permeabilized with 0.5% Triton X-100 in PBS for 5 min. After thoroughly washing with PBS, samples were submerged in blocking solution (PBS containing 5% BSA) for 1 h at room temperature. After blocking, the samples were covered with primary antibody solution (designated primary antibody in PBS, 1:50 dilution) at room temperature for 16 h, followed by washing thoroughly with PBS. Then the samples were incubated in secondary antibody solution (1:300 dilution) for 1 h at room temperature and washed thoroughly with PBS before staining for nuclei with Hoechst 33342 solution for 5 min at room temperature. Samples were washed thoroughly again with PBS before mounted on glass slides with 30 μl mounting media. Images were obtained with confocal microscope Zeiss LSM800.</p>", "<title>Realtime Imaging of K14 + intermediate filaments during cell migration</title>", "<p id=\"P15\">UM-UC5 or UM-UC14 cells were transfected with mCherry-labeled K14 (#55066, Addgene). Cells were cultured on collagen type I-coated coverglass chamber slide within a culture insert. After removal of the insert, LSM800 confocal microscope (Zeiss) was used to visualize the area covered by the migrating cells. Time-lapse imaging was conducted at 3-minute intervals using a 63X oil objective.</p>", "<title>Quantification of the number and size of focal adhesion plaques</title>", "<p id=\"P16\">Confluent bladder cancer cells were trypsinized and cultured in ultra-low attachment 6-well culture plate (0.5 × 10<sup>6</sup> cells/well) for 24 h to form cancer spheroids. Spheroids were transferred to a 12-well plate with one poly-L-lysine- and collage type I-coated (3mg/ml, STEMCELL Technologies) coverglass placed in each well. Spheroids were allowed to attach and expand on coverglass for 48h at 37°C with 5% CO<sub>2</sub> supply. Samples were fixed and stained with anti-ZYX or anti-PXN antibodies according to immunofluorescence staining procedures described above. Images were taken by a LSM800 confocal microscope (Zeiss). The cells located on the leading edge of the expanded spheroids were selected manually by using ZEN2 software. The size and number of the ZYX or PXN + focal adhesion sites, were quantitated using ZEN2. Only focal adhesion sites ≥ 0.02 μm<sup>2</sup> were examined. Site number/cell was recorded.</p>", "<title>Realtime Analysis of focal adhesion dynamics</title>", "<p id=\"P17\">TRIM29 wildtype or KO bladder cancer cells (UM-UC5 and UM-UC14) were transfected with a plasmid expressing mCherry-tagged PXNn (#50526, Addgene) before culturing on collagen type I-coated coverglass chamber with culture inserts. The insert was removed to allow cells to migrate for 72 h, and the area of the migration was imaged with a LSM800 confocal microscope (Zeiss). Time-lapse imaging was carried out with 3-min intervals and seven slices of z stack (spanning height of 70 nm) by using 63X oil objective. The quantification of focal adhesion dynamics, including the rate of FA assembly (Ka) and disassembly (Kd), was performed according to the methods described in [##REF##24974036##12##].</p>", "<title>Data Availability</title>", "<p id=\"P18\">All data presented in the Results were generated by the authors and are available on request.</p>" ]	[ "<title>Results</title>", "<p id=\"P19\">Loss of TRIM29 blocks bladder cancer migration. The tripartite motif gene, <italic toggle=\"yes\">TRIM29</italic>, is required for invasion in bladder cancer [##REF##26471361##2##, ##REF##30643195##3##] and many other malignancies [##REF##27430345##13##, ##REF##32640423##14##]. Invasion is a complex process that involves degradation of extracellular matrix barriers, cellular detachment and reattachment, and increased motility [##REF##25415508##15##, ##REF##28187288##16##]. To determine which of these aspects of invasion were regulated by TRIM29 in bladder cancer, we examined invasion and migration using transwell, 3D collagen tumor spheroid invasion and modified scratch assays. <italic toggle=\"yes\">TRIM29</italic> was knocked down (TRIM29-KD) with shRNA in UM-UC13 or knocked out with CRISPR in UM-UC14 and UM-UC5 as previously described (##FIG##0##Fig. 1A##)[##REF##30643195##3##]. As expected, <italic toggle=\"yes\">TRIM29</italic> knockdown (<italic toggle=\"yes\">TRIM29</italic>-KD) in UM-UC13 and <italic toggle=\"yes\">TRIM29</italic> knockout (TKO) in UM-UC5 and UM-UC14 significantly reduced transwell invasion (##FIG##0##Fig. 1B##) and ##FIG##2##3D## tumor spheroid invasion (Supplemental Fig. 1). To determine whether TRIM29 was specifically required for cancer cell migration, we performed a modified scratch assay in which cells were cultured on collagen type I-coated cover glass, a scratch is created by insert removal, and individual cell migration velocity was quantified by time-lapse microscopy. <italic toggle=\"yes\">TRIM29</italic>-KO (UM-UC5, UM-UC14) or TRIM29-KD (UM-UC13) significantly reduced migration of individual cancer cells (##FIG##0##Fig. 1C## and ##FIG##0##1D##). Re-expression of TRIM29-FLAG in the <italic toggle=\"yes\">TRIM29</italic>-KO cells (UM-UC5 and UM-UC14) rescued the cell migration ability disrupted by knockout of <italic toggle=\"yes\">TRIM29</italic> (##FIG##0##Fig. 1D##, Supplemental Fig. 2). These results establish that <italic toggle=\"yes\">TRIM29</italic> is required for bladder cancer cell migration during invasion.</p>", "<p id=\"P20\">TRIM29 is part of a protein complex including intermediate filament, motor and focal adhesion proteins. TRIM29 has previously been demonstrated to exert cellular effects by binding and sequestering proteins and regulating ubiquitination and protein stability [##REF##26471361##2##, ##REF##19249679##17##–##REF##29038422##20##]. To comprehensively identify the interactome of TRIM29 in bladder cancer and identify the mechanism by which TRIM29 promotes bladder cancer migration and invasion, we performed immunoprecipitation (IP) of TRIM29 and liquid chromatography and mass spectrometry (LC/MS) in UM-UC5 and 9 bladder cancer cell lines to identify proteins present in the immunocomplex with TRIM29. UM-UC5 and UM-UC9 <italic toggle=\"yes\">TRIM29</italic>-KO cells which lack TRIM29 expression were subjected to TRIM29 IP and LC/MS to control for nonspecific pulldown and act as a negative control. We identified 1125 proteins in UM-UC5 and 270 proteins in UM-UC9 which were selectively immunoprecipitated in TRIM29 WT but not KO samples (Supplemental Table 1). 144 of these proteins were detected in both UM-UC5 and UM-UC9. As expected, TRIM29 was one of the most enriched proteins in both cell lines. To identify the functional classes of the 1125 and 270 proteins selectively co-IP’d with TRIM29 in UM-UC5 and UC9, we subjected each gene list to KEGG pathway enrichment analysis. For both UM-UC5 and UC9, there was striking enrichment in genes related to Regulation of Actin Cytoskeleton and Focal Adhesion in our TRIM29 co-IP protein complexes (Supplemental Table 2). Within these pathways, the proteins involved in regulation of focal adhesion and regulation of the actin cytoskeleton (MYH9, MYO1C) have previously been shown to regulate cell adhesion, migration and invasion [##UREF##3##21##]. Additionally, we found enrichment in numerous intermediate filament proteins (K5, K6A, K8, K9, K10, K18). These results suggested that TRIM29 forms protein complexes with focal adhesion, actin cytoskeleton, and intermediate filament proteins, suggesting a potential means whereby TRIM29 regulates cancer migration and invasion.</p>", "<p id=\"P21\">TRIM29 Regulates K14 + IF in Invasive and Migratory Cells. <italic toggle=\"yes\">KRT14</italic> is transcriptionally regulated by TP63 [##REF##17159913##22##] and is upregulated in invasive leader cells in breast cancer by TP63 [##REF##24332913##4##]. We have previously shown that TP63 regulates transcription of <italic toggle=\"yes\">TRIM29</italic> and <italic toggle=\"yes\">KRT14</italic> in basal bladder cancer, that TRIM29 is upstream of K14 and that both are required for bladder cancer invasion [##REF##30643195##3##]. Since TRIM29 forms a protein complex with IF proteins in bladder cancer cells in our LC/MS screen and regulates keratin distribution in squamous cell carcinoma [##REF##34657752##23##], we hypothesized that TRIM29 might specifically localize to K14-containing IF to regulate migration and invasion. To examine this, we generated bladder cancer spheroids in suspension conditions as previously described and embedded them in type I collagen on coverglass [##REF##30643195##3##]. Spheroids were cultured for 48 h, fixed and subjected to immunofluorescent staining for TRIM29, actin and K14. Both TRIM29 and K14 were selectively upregulated in the cells in the invasive component of the bladder cancer spheroids (##FIG##1##Fig. 2A##, region outside of dotted line). These results suggest that TRIM29 is selectively upregulated with K14 in the invading tumor cells.</p>", "<p id=\"P22\">TRIM29 localizes to filamentous structures and has previously been reported to interact with the IF, Vimentin [##REF##7644499##24##]. We observed that multiple keratins were part of the TRIM29 immunocomplex in bladder cancer cells (Supplemental Table 1), thus we hypothesized that TRIM29 might localize to IFs during invasion. To determine this, we performed immunofluorescent staining for TRIM29, K14, and actin in multiple bladder cancer cells. We chose K14 and not other keratins identified in LC/MS screen because of our prior data linking TRIM29 function to K14 [##REF##30643195##3##]. TRIM29 and K14 strongly co-localized to the IF structures observed in the invasive cells of multiple bladder cancer cell lines (colocalization between K14 and TRIM29 shown in white, ##FIG##1##Fig. 2B##). Interestingly, although TRIM29 and K14 were always present in contiguous IF structures throughout the cytoplasm, the peripheral, membrane proximal regions in lamellipodia showed the highest overlap (arrows, ##FIG##1##Fig. 2B##). Given that TRIM29 and K14 were selectively upregulated in migratory/invasive cells (##FIG##1##Fig. 2A##), these results suggested the TRIM29 and K14 might both be present in the same protein complex during migration.</p>", "<p id=\"P23\">To determine the role of TRIM29 in K14 filament dynamics in migratory bladder cancer cells, we transduced UM-UC5 and UM-UC14 cells with a K14-mCherry fusion protein (##FIG##1##Fig. 2C##). To determine if K14 and TRIM29 were part of the same protein complex in these cells, we performed co-immunoprecipitation (IP) using an anti-mCherry antibody. We found that IP of mCherry-K14 resulted in co-IP of TRIM29 in UM-UC5 and UM-UC14 cell lines but not in the control cells lacking K14-mCherry (##FIG##1##Fig. 2C##). Likewise, IP of TRIM29 also resulted in co-IP of K14-mCherry (Supplemental Fig. 3) establishing that TRIM29 and K14 are part of the same protein complex.</p>", "<p id=\"P24\">Next, to assess the role of TRIM29 in regulation of K14 dynamics during migration, we observed migrating WT and <italic toggle=\"yes\">TRIM29</italic>-KO UM-UC5 and UM-UC14 cells expressing K14-mCherry (##FIG##1##Fig. 2D##–##FIG##1##F## Supplemental Video 1–4). In TRIM29 WT cells, the migratory cells formed a rigid, symmetrical, and compact cell structure with filamentous K14 distributed evenly through the cytoplasm (##FIG##1##Fig. 2D##, Supplemental Video 1 and 3). In contrast, <italic toggle=\"yes\">TRIM29</italic>-KO cells displayed irregular elongated morphologies and K14 did not form regular filamentous structures (##FIG##1##Fig. 2D##, Supplemental Video 2 and 4). Further, examination of migration in <italic toggle=\"yes\">TRIM29</italic> WT and KO cells using time lapse imaging demonstrated that while <italic toggle=\"yes\">TRIM29</italic> WT cells showed well organized K14 + filaments and efficient cell migration, <italic toggle=\"yes\">TRIM29</italic>-KO cells lacked organized K14 filaments and demonstrated disordered migration (##FIG##1##Fig. 2E##–##FIG##1##F##, Supplemental Video 1–4). These results suggest that loss of TRIM29 destabilizes K14 + intermediate filaments, changes the morphology of invasive cells and impairs migratory ability.</p>", "<p id=\"P25\">Mechanism of TRIM29 regulation of K14. We next sought to determine the mechanism by which TRIM29 regulates K14 + IF during invasion. FAM83H has been proposed to bind to TRIM29 and K14 and to regulate K14 distribution in other types of cancer [##REF##34657752##23##]. We therefore hypothesized that TRIM29 regulation of K14 might involve interaction with FAM83H. Interestingly, while FAM83H was expressed in UM-UC5 and UM-UC14 cancer cells, it did not co-IP with K14 or TRIM29 suggesting that it was not part of the TRIM29-K14 complex in bladder cancer (##FIG##1##Fig. 2C##, data not shown).</p>", "<p id=\"P26\">TRIM29 has also been shown to facilitate ubiquitination and degradation of innate immune proteins during viral infections [##REF##29581886##19##, ##REF##31270148##25##]. To determine if K14 was a target of TRIM29-mediated ubiquitination, we treated WT and <italic toggle=\"yes\">TRIM29</italic>-KO UM-UC5 and UM-UC14 cells -with either vehicle or MG132 to block proteasomal degradation of ubiquitinated proteins. While we did observe significant differences in total ubiquitination in <italic toggle=\"yes\">TRIM29</italic> WT and KO cells, we did not observe either mono or poly-ubiquitinated K14 (Supplemental Fig. 4, data not shown) suggesting that TRIM29-mediated ubiquitination does not contribute to its regulation of K14.</p>", "<p id=\"P27\">K14-dependent disulfide bonds mediate some functions of K14 [##UREF##4##26##]. To determine if the TRIM29-K14 protein interaction depended on K14 disulfide bonds, we treated lysates with TCEP, a reducing agent which disrupts disulfide bonds, and performed IP of K14. We found that the TRIM29 interaction with K14 was reduced by TCEP treatment (##FIG##1##Fig. 2C##), suggesting that TRIM29 presence in the K14 protein complex was influenced by disulfide bond presence. Taken together, these results indicate that TRIM29 is part of a disulfide-dependent protein complex with K14.</p>", "<p id=\"P28\">TRIM29 and K14 Regulate Focal Adhesions During Invasion. Keratin + IF regulate focal adhesion stability and cellular migration [##UREF##3##21##] and proteins associated with focal adhesions were pulled down with TRIM29 in UM-UC9 and UM-UC5 cells. Based on these results, we hypothesized that the TRIM29-K14 interaction regulated migration via effects on focal adhesion formation or turnover. To examine this, we performed staining for TRIM29, PXN, zyxin (ZYX− a member of the focal adhesion complex) and actin in our invasive bladder cancer spheroids and found that TRIM29 + IF terminated in PXN + and ZYX + FA sites in the migratory bladder cancer cells (##FIG##2##Fig. 3A## – ##FIG##2##D##). These focal adhesions sites were concentrated in filopodia and lamellipodia (arrows) on the leading edge of migratory cancer cells. To determine if TRIM29 was required for the formation of these FAs during invasion, we examined staining in UM-UC5 and UM-UC14 <italic toggle=\"yes\">TRIM29</italic>-KO cells and found that <italic toggle=\"yes\">TRIM29</italic>-KO significantly reduced ZYX + and PXN + focal adhesions (##FIG##3##Fig. 4A## – ##FIG##3##E##, Supplemental Fig. 5). These results suggest that <italic toggle=\"yes\">TRIM29</italic> is involved in FA regulation during bladder cancer cell migration.</p>", "<p id=\"P29\">TRIM29 Regulates Focal Adhesion Stability During Cancer Migration. FA presence during cancer cell migration is dependent on the rate of FA formation and dissolution. Since K6 + IF are known to regulate FA formation and resolution [##UREF##3##21##] and since TRIM29 was found to be part of the focal adhesion protein complex, we hypothesized that TRIM29 might regulate focal adhesion stability during invasion and migration. To examine this, we measured focal adhesion dynamics in WT and <italic toggle=\"yes\">TRIM29</italic>-KO bladder cancer cells expressing a mCherry-tagged PXN construct in a migration assay. As expected, mCherry + FA were visible at the leading edge of invasive cells during time-lapse microscopy (##FIG##4##Fig. 5A##). In WT cells, the focal adhesion sites first appeared at the leading edge of cells and became larger as they moved gradually toward the posterior edge of the cells, but the foci in <italic toggle=\"yes\">TRIM29</italic>-KO were present for a shorter amount of time and dispersed more quickly (Supplemental video 5–8). To quantify this process, focal adhesion sites from the time lapse images were randomly selected, mCherry signal was quantified and analysis was performed as previously published [##UREF##3##21##]. By analyzing the rates of assembly (Ka) and disassembly (Kd) of each focal adhesion site, we found that the rate of disassembly of focal adhesion is higher in <italic toggle=\"yes\">TRIM29</italic>-KO cells, whereas the assembly rate was not different between <italic toggle=\"yes\">TRIM29</italic>-KO and WT (##FIG##4##Fig. 5B##). These results suggest that TRIM29 regulates FA stability during invasion and migration.</p>", "<p id=\"P30\">K14 is Required for TRIM29 Regulation of FA Stability and Promotion of Bladder Cancer Migration and Invasion. Based on the results that TRIM29 was required to stabilize K14 + IF and focal adhesions during bladder cancer migration and invasion, we hypothesized that TRIM29-mediated stabilization of FA required K14. To test this hypothesis, we knocked-down <italic toggle=\"yes\">KRT14</italic> in our <italic toggle=\"yes\">TRIM29</italic>-KO UM-UC14 cells with or without <italic toggle=\"yes\">TRIM29</italic> re-expression (Supplemental Fig. 2) and measured ZYX + and PXN + FA sites in migrating cells. <italic toggle=\"yes\">TRIM29</italic> re-expression allowed robust recovery of ZYX + and PXN + focal adhesion sites, but this effect was abrogated by <italic toggle=\"yes\">KRT14</italic> knock-down (##FIG##5##Fig. 6A## & ##FIG##5##B##). These results suggested that <italic toggle=\"yes\">TRIM29’</italic>s promigratory phenotype would require both <italic toggle=\"yes\">KRT14</italic> and <italic toggle=\"yes\">ZYX</italic>. To test this, we performed RNAi-based gene knock-down of <italic toggle=\"yes\">KRT14</italic> or <italic toggle=\"yes\">ZYX</italic> in UM-UC10 and UM-UC14 bladder cancer cell lines with or without <italic toggle=\"yes\">TRIM29</italic> expression. Cell migration was then measured by modified scratch assay and invasion was measured using a transwell assay. <italic toggle=\"yes\">TRIM29</italic> expression promoted increased cancer cell migration and invasion (##FIG##5##Fig. 6C## & ##FIG##5##D##) [##REF##24332913##4##]. Further, knockdown of <italic toggle=\"yes\">KRT14</italic> or <italic toggle=\"yes\">ZYX</italic> expression blocked <italic toggle=\"yes\">TRIM29</italic>-induced cell migration and transwell invasion (##FIG##5##Fig. 6C## & ##FIG##5##D##). Taken together, these results demonstrate K14 is required for TRIM29-mediated stabilization of FA and that both <italic toggle=\"yes\">KRT14</italic> and <italic toggle=\"yes\">ZYX</italic>, are required for <italic toggle=\"yes\">TRIM29</italic>-mediated migration and invasion.</p>" ]	[ "<title>Discussion</title>", "<p id=\"P31\">Invasive progression is the most important biological factor which determines bladder cancer clinical outcomes. We have previously shown that bladder cancer invasion is driven by TP63-mediated upregulation of <italic toggle=\"yes\">TRIM29</italic> and <italic toggle=\"yes\">KRT14</italic> [##REF##30643195##3##]. However, the mechanism whereby TRIM29 and K14 promote invasive progression and metastasis was unclear. In this study, we demonstrate that a primary function of <italic toggle=\"yes\">TRIM29</italic> during invasion is the regulation and promotion of tumor cell migration. Mechanistically, TRIM29 specifically regulates tumor migration by physical association with the K14 + intermediate filaments in invasive bladder cancer cells. Further, the physical association of TRIM29 with K14 and focal adhesion sites appears to stabilize these structures and alter cellular morphology, promoting a pro-invasive, pro-migratory phenotype (##FIG##6##Fig. 7##). These results establish a new role for TRIM29 in the regulation of cytoskeletal functions and focal adhesion interaction with the extracellular matrix, areas where TRIM29 has not been previously implicated.</p>", "<p id=\"P32\">The basal molecular subtype of bladder cancer is associated with worse survival and poorer outcomes for patients [##REF##24520177##27##, ##REF##24525232##28##]. Activation of a TP63-mediated basal gene program in tumor cells has been linked to tumor invasion and metastasis in breast and bladder cancers by our group as well as others [##REF##30643195##3##, ##REF##24332913##4##]. Here we demonstrate that this basal gene program which includes upregulation of <italic toggle=\"yes\">TRIM29</italic> and <italic toggle=\"yes\">KRT14</italic>, can occur selectively in invasive bladder cancer cells and specifically promotes cancer cell motility by altering the physical structure of the invasive cell and its attachments to ECM. These results establish novel mechanisms that contribute to the lethal phenotypes seen in basal subtype bladder cancer. They also suggest that treatments which disrupt focal adhesion functions may be an attractive approach for bladder cancer patients with basal subtype tumors which have poor outcomes and for which treatment options are limited.</p>", "<p id=\"P33\">The role of intermediate filaments and focal adhesion complex proteins in normal cell motility and in cancer cell invasion and metastasis is complex [##REF##25460777##5##, ##REF##12845599##29##–##REF##25820462##33##]. Intermediate filaments are known to interact directly with and regulate the focal adhesion complex [##REF##25460777##5##]. Likewise, the focal adhesion complex, which includes integrins, adaptor proteins such as PXN and ZYX, and kinases like FAK and c-Src, is a known subject to serine and tyrosine phosphorylation which regulate focal adhesion complex formation and dissolution during cell migration [##REF##11146675##9##, ##REF##28214467##34##]. Since we find that TRIM29 modulates focal adhesion dissolution, we hypothesize that it may do so by promoting PXN phosphorylation which has been shown to govern focal adhesion stability. Alternatively, TRIM29 has also been shown to harbor ubiquitin ligase function [##REF##29581886##19##, ##REF##29038422##20##] and it is conceivable that TRIM29 directly ubiquitinates K14 or one or multiple components of the focal adhesion complex leading the phenotypes observed in this study. Despite this notion, we were unable to detect ubiquitination of either K14, PXN or ZYX in multiple experiments suggesting that TRIM29 does not directly ubiquitinate K14, PXN or ZYX (Supplemental Fig. 4 and data not shown).</p>", "<p id=\"P34\">High levels of FAK expression often correlate with invasiveness in cancer cells [##REF##12562313##35##], and tumors with high c-Src activity also correlate with malignant potential [##REF##12020799##36##]. In bladder cancer, FAK and Src activity have been linked to survival, invasive progression and migration [##REF##26640543##37##–##REF##31938172##39##] and PTEN, a downstream target of TRIM29 [##REF##26471361##2##], also has been shown to impact FAK and AKT phosphorylation [##REF##26837847##40##]. Our results suggest that a key function of TRIM29 is to stabilize the focal adhesion complex and it is therefore likely that this activity also impacts FAK and c-Src signaling mediating its effect on tumor migration and invasion. Further, if true, this suggests that kinase inhibition of FAK or c-Src may be an attractive therapeutic strategy in patients with invasive basal subtype bladder cancers.</p>" ]	[]	[ "<p id=\"P1\">Bladder cancer is a common malignancy whose lethality is determined by invasive potential. We have previously shown that <italic toggle=\"yes\">TRIM29</italic>, also known as <italic toggle=\"yes\">ATDC</italic>, is transcriptionally regulated by TP63 in basal bladder cancers where it promotes invasive progression and metastasis, but the molecular events which promote invasion and metastasis downstream of <italic toggle=\"yes\">TRIM29</italic> remained poorly understood. Here we identify stimulation of bladder cancer migration as the specific role of TRIM29 during invasion. We show that TRIM29 physically interacts with K14 + intermediate filaments which in turn regulates focal adhesion stability. Further, we find that both K14 and the focal adhesion protein, ZYX are required for bladder cancer migration and invasion. Taken together, these results establish a role for TRIM29 in the regulation of cytoskeleton and focal adhesions during invasion and identify a pathway with therapeutic potential.</p>" ]	[]	[ "<title>Acknowledgments:</title>", "<p id=\"P35\">The authors would like to acknowledge Venkatesha Basrur and the Proteomics Resource Facility, Department of Pathology, University of Michigan for their assistance with the liquid chromatography and mass spectrometry experiments.</p>", "<title>Funding:</title>", "<p id=\"P36\">This work was funded by NIH R01 AR079418 (PAC), NIH R21 CA 259763 (MD), the Rogel Cancer Center Core Grant CA046592–26S3 (PLP, NAJ), NIH K08 CA201335–01A1 (PLP), NIH R37 CA273138–01 (PLP), BCAN YIA (PLP) and Damon Runyon Clinical Investigator Award (PLP).</p>" ]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1</label><caption><p id=\"P37\">TRIM29 regulates invasion and migration of bladder cancer cells. (A) Knockout (KO) or knockdown (KD) of TRIM29 expression assessed by immunoblot. (B) KO or KD of TRIM29 decreases invasion in a transwell invasion assay. WT: wildtype, TKO: <italic toggle=\"yes\">TRIM29</italic>-KO, TKD: <italic toggle=\"yes\">TRIM29</italic>-KD. n=6. <italic toggle=\"yes\">p</italic><0.001. (C) Timelapse images of 2D migration assay demonstrate that knockout (TKO) or knockdown of TRIM29 (TKD) decreases migration of human bladder cancer cells. White dashed lines indicate the leading edges at start time point. Scale bar = 100 μm. (D) Quantitative analysis of 2D migration assay. Data represent the mean ± STD. n=5. <italic toggle=\"yes\">p</italic><0.01, <italic toggle=\"yes\">p</italic><0.0001, p>0.1. KO = Knockout. EV = Empty Expression Vector. KD = Knockdown.</p></caption></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2</label><caption><p id=\"P38\">TRIM29 and K14 are upregulated in migratory cells during bladder cancer spheroid invasion. (A) Immunofluorescence images of UM-UC5 spheroids show enriched expression of TRIM29 and K14 as compared to noninvasive cells (center circle). Scale bar = 100 μm. (B) Colocalization (white) of filamentous TRIM29 and K14 in multiple human bladder cancer cell lines. Scale bar = 10 μm. (C) Co-immunoprecipitation of mCherry-tagged K14 and TRIM29 demonstrate a physical association between K14 and TRIM29. Protein loading for input blots: 20 μg/lane. (D) TRIM29 KO alters distribution of K14-containing IF and cell morphology or migrating cells. Scale bar = 25 μm (E-F) <italic toggle=\"yes\">TRIM29</italic>-KO in UM-UC5 and UM-UC14 results in altered cell morphology and disordered migration in a modified scratch assay. Scale bar = 50 μm.</p></caption></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3</label><caption><p id=\"P39\">TRIM29+ IFs terminate in PXN+ (A & C) and ZYX+ (B & D) focal adhesion sites in filipodia and lamelopodia in invasive UM-UC5 (A & B) and UM-UC14 (C & D) bladder cancer cells. Inset images show higher magnification view. Scale bar = 10 μm.</p></caption></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4</label><caption><p id=\"P40\">TRIM29 regulates focal adhesion. (A - D) TRIM29 KO reduces ZYX+ focal adhesion sites during UM-UC5 and UM-UC14 bladder cancer spheroid invasion. Scale bar = 10 μm. (E) Quantitative analysis of ZYX+ focal adhesions (UC5-WT, n=80; UC5-TKO, n=51; UC14-WT, n=33; UC14-TKO, n=18) or PXN+ focal adhesions (UC5-WT, n=168; UC5-TKO, n=194; UC14-WT, n=261; UC14-TKO, n=340). Data represent the mean ± STD. <italic toggle=\"yes\">p</italic><0.05.</p></caption></fig>", "<fig position=\"float\" id=\"F5\"><label>Figure 5</label><caption><p id=\"P41\">The expression of TRIM29 affects the turnover of focal adhesion sites during cell migration. (A) Timelapse images of UM-UC5 cells expressing mCherry-Paxillin during cell migration. Arrowhead indicates monitored focal adhesion site. Arrow shows the direction of cell movement. Scale bar = 20 μm. (B) TRIM29 KO had no effect on the rate of assembly (Ka) but increased the rate of disassembly (Kd) of focal adhesion sites in UM-UC5 and UM-UC14 bladder cancer cells. Data represent the mean ± STD. n = 21 for UM-UC5 cells, n = 24 for UM-UC14 cells. <italic toggle=\"yes\">p</italic><0.05</p></caption></fig>", "<fig position=\"float\" id=\"F6\"><label>Figure 6</label><caption><p id=\"P42\">K14 regulates TRIM29-induced focal adhesions and bladder cancer migration. (A - B) Re-expression of TRIM29 in UM-UC14 TRIM29 KO cell line allows recovery of ZYX and PXN+ focal adhesion sites, but this effect is abrogated by K14 KD. GFP used as vector control. NT: nontargeting siRNA control. K14KD: siRNA targeting K14. (C-D) K14 and ZYX are required for TRIM29-induced migration (C) and invasion (D). Top row: UM-UC10; Bottom row: UM-UC14. KD: siRNA mediated knockdown. Data represent the mean ± STD. <italic toggle=\"yes\">p</italic><0.05. ** p>0.05.</p></caption></fig>", "<fig position=\"float\" id=\"F7\"><label>Figure 7</label><caption><p id=\"P43\">Model of the role of TRIM29, K14 and focal adhesion complexes during bladder cancer migration and invasion.</p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[]	[]	[ "<graphic xlink:href=\"nihpp-rs3697712v1-f0001\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-rs3697712v1-f0002\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-rs3697712v1-f0003\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-rs3697712v1-f0004\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-rs3697712v1-f0005\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-rs3697712v1-f0006\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-rs3697712v1-f0007\" position=\"float\"/>" ]	[]	[{"label": ["1."], "surname": ["Islami", "Ward", "Sung", "Cronin", "Tangka", "Sherman"], "given-names": ["F", "EM", "H", "KA", "FKL", "RL"], "article-title": ["Annual Report to the Nation on the Status of Cancer, Part 1: National Cancer Statistics"], "source": ["J Natl Cancer Inst"], "year": ["2021"]}, {"label": ["8."], "surname": ["Revach", "Grosheva", "Geiger"], "given-names": ["OY", "I", "B"], "article-title": ["Biomechanical regulation of focal adhesion and invadopodia formation"], "source": ["J Cell Sci"], "year": ["2020"], "volume": ["133"]}, {"label": ["10."], "surname": ["Katoh"], "given-names": ["K."], "article-title": ["FAK-Dependent Cell Motility and Cell Elongation"], "source": ["Cells"], "year": ["2020"], "volume": ["9"]}, {"label": ["21."], "surname": ["Wang", "Chen", "Liu", "Parent", "Coulombe"], "given-names": ["F", "S", "HB", "CA", "PA"], "article-title": ["Keratin 6 regulates collective keratinocyte migration by altering cell-cell and cell-matrix adhesion"], "source": ["J Cell Biol"], "year": ["2018"]}, {"label": ["26."], "surname": ["Guo", "Redmond", "Leacock", "Brovkina", "Ji", "Jaskula-Ranga"], "given-names": ["Y", "CJ", "KA", "MV", "S", "V"], "article-title": ["Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14\u20133-3sigma and YAP1"], "source": ["Elife"], "year": ["2020"], "volume": ["9"]}]	{ "acronym": [], "definition": [] }	40	CC BY	no	2024-01-13 23:36:45	Res Sq. 2023 Dec 12;:rs.3.rs-3697712	oa_package/4d/0c/PMC10760242.tar.gz
PMC10765177	36779452	[ "<title>Introduction</title>", "<p>On 16 March 2012, an act of Parliament was passed and vascular surgery was designated a stand-alone surgical specialty of the General Medical Council (GMC).<sup>##UREF##0##1##,##UREF##1##2##</sup> The Joint Committee for Surgical Training (JCST) assembled a new Vascular surgery Specialty Advisory Committee (SAC) to design and deliver a new curriculum. In 2019, the training programme delivered its first cohort of fully trained vascular specialists who had completed the new curriculum.<sup>##UREF##2##3##</sup></p>", "<p>Quality assurance (QA) in training programmes is imperative to ensure the delivery of safe, competent, specialist doctors.<sup>##UREF##3##4##</sup> For vascular surgery in the UK, QA is the responsibility of the vascular SAC, through its QA Group, under the oversight of JCST. The vascular SAC comprises consultant vascular surgeons with an interest in medical education from across the UK and Ireland, along with a trainee representative. Each of the UK’s 13 deaneries and The Republic of Ireland has a committee member, known as the Liaison Member (LM), who acts as the link between the Deanery Training Programme Director (TPD) and the SAC.<sup>##UREF##4##5##</sup></p>", "<p>Historically, the SAC QA group collated annual reports on the vascular training programme in each Deanery. Information contributed by TPDs and LMs, together with the results of an annual end-of-year trainee survey conducted by the vascular trainee representative body (the Rouleaux Club), is used. Data from these three sources were collated and a formal specialty report compiled, outlining the Deanery-specific training programme quality based subjectively on the information provided with no guidance or scoring system.</p>", "<p>This QA process was subjective and susceptible to a lack of continuity, because the QA Lead changes regularly and the trainee representative demits every 2 years. As such, a more objective, transparent and reproducible measure of the quality of training programmes was needed.</p>", "<p>The JCST has a QA strategy, which it delivers and monitors via the SAC, and in 2018 the JCST committed to produce annual regional quality reports to improve the accessibility of QA information regarding local surgical training programmes. In order for the Vascular SAC to achieve this, specialty-specific quality indicators were needed. This study aimed to determine appropriate training programme quality indicator domains to inform future QA processes and the development of a scoring system to assess quality in the UK vascular surgery training programme.</p>" ]	[ "<title>Methods</title>", "<title>Study design and participants</title>", "<p>A three-stage modified Delphi consensus process was completed to establish general domains on which to assess the quality of a vascular training programme.</p>", "<title>Pre-Delphi: identify potential domains and experts</title>", "<p>Authors and members of the QA Group (SAC trainee representative, SAC chair and SAC QA lead) compiled a list of potential domains using all sources previously used in training programme QA. These included JCST quality indicators, JCST trainee survey, GMC survey, LM reports and TPD reports (##TAB##0##Table 1##).</p>", "<p>The same group identified stakeholders as experts suitable to invite to participate in the Delphi process. Stakeholders were defined as those directly involved in participating in, delivering or designing the training programme. The stakeholder groups were deemed to be trainees (The Rouleaux Club committee members were utilised, all elected roles voted for by trainees to represent them), training programme directors, members of the vascular SAC, Vascular Society (VS) education committee and VS executive committee (##FIG##0##Figure 1##). These were all appointed or elected roles.</p>", "<title>Delphi consensus</title>", "<p>Stage 1 – Participants were asked to rate how appropriate they perceived each domain to be for assessing the quality of a vascular training programme, using a nine-point Likert scale, ranging from one (inappropriate) to nine (extremely appropriate). Domain headings were given with a brief explanation of what would be included and assessed in that domain. In this stage, participants were invited to suggest additional domains not already presented in Stage 1.</p>", "<p>Stage 2 – All participants from Stage 1 were invited to participate in Stage 2. Descriptive statistics from the responses obtained in Stage 1 were included to allow participants to understand the initial degree of consensus. Domains were organised into four groups according to summary scores: ‘consensus appropriate’, ‘consensus inappropriate’, ‘disagreement’ and ‘equivocal’ (see <italic>Data analysis</italic>). No further response was solicited for ‘consensus inappropriate’ definitions.</p>", "<p>Stage 3 – All participants from Stage 1 were invited to participate in Stage 3. Descriptive statistics from the responses obtained in Stage 2 were presented (see <italic>Data analysis</italic>). Participants were asked to rate, on a nine-point Likert scale, how strongly they agreed that each of the ‘consensus appropriate’ domains should be used in the QA process and how strongly they agree that each of the ‘consensus inappropriate’ domains need not be used in the quality assessment of a training programme. Participants were also asked to prioritise the domains in order of importance (1 being the most important) for assessing the quality of the training programme.</p>", "<title>Data analysis</title>", "<title>Analysis of Delphi Stage 1</title>", "<p>Descriptive statistics were used to summarise the results of Stage 1, including the number of participants rating the outcome as either seven, eight or nine on the Likert scale (very appropriate/extremely appropriate). Domains rated seven, eight or nine on the Likert scale by at least 20 percent of participants were retained for the next stage. All other domains were discarded.</p>", "<title>Analysis of Delphi Stage 2</title>", "<p>For each domain presented in Stage 2 the proportion of participants scoring 1–3, 4–6 and 7–9 on the nine-point Likert scale was calculated. For the purpose of the Delphi process, ‘appropriate’ referred to appropriateness to assess the quality of the vascular training programme. ‘Consensus appropriate’ was defined as greater than 70 percent of items scoring 7–9 and less than 25 percent of participants scoring 1–3. ‘Consensus inappropriate’ was defined as greater than 70 percent of participants scoring 1–3 AND less than 25 percent of participants scoring 7–9. ‘Disagreement’ occurred when 33 percent or more scored 1–3 and 33 percent or more scored 7–9 for a particular domain. All other combinations were considered ‘Equivocal’. All domains were designated into one of these four categories. ‘Consensus appropriate’ items were brought forward for the third stage and ‘Consensus inappropriate’ and ‘Equivocal’ items were discarded.</p>", "<title>Analysis of Delphi Stage 3</title>", "<p>For each domain presented in Stage 3 the proportion of participants scoring 1–3, 4–6 and 7–9 on the nine-point Likert scale were calculated. The definitions of consensus described in round 2 was applied to these data.</p>", "<p>Domains designated ‘Consensus appropriate’ were defined in the final report as appropriate to assess the quality of the vascular training programme. Any remaining domains designated ‘Disagreement’ were discussed at the final consensus meeting of stakeholders. All other domains were discarded.</p>", "<title>Rationalisation of domains</title>", "<p>To confirm consensus and rationalise assessment to ten domains the average prioritisation score of each domain was calculated as well as the proportion of participants ranking each domain in the top ten most important.</p>" ]	[ "<title>Results</title>", "<p>A total of 54 vascular surgeons and vascular trainees were invited to participate in the Delphi consensus; 39 responded to stage 1 (25 consultants and 14 trainees). Of these, 15 were members of the SAC (1 trainee, 14 consultants), 11 were TPDs (5 of whom also sit on the SAC) and 10 were members of the VS executive committee or education committee (1 of whom was also a TPD, 3 were on the SAC and 1 was a trainee). Stages 2 and 3 received 37 and 36 responses, respectively (##FIG##0##Figure 1##).</p>", "<title>Stage 1</title>", "<p>In all, 20 domains were entered into the Delphi process (##TAB##0##Table 1##). The mean Likert score of all domains was 7.5 (standard deviation (SD) 0.58). All domains were deemed consensus appropriate. The mean Likert score for each domain ranged from 6.5 to 8.3 (SD 0.57–1.88). ##TAB##1##Table 2## summarises the domains accepted and rejected through each stage of the Delphi process; 16 additional domains were suggested by the experts, 9 of which were already encompassed within the existing domains and so were rejected by the QA group for Stage 2 (##TAB##2##Table 3##); 7 were included in Stage 2.</p>", "<title>Stage 2</title>", "<p>A total of 27 domains were entered into Stage 2; 16 were deemed consensus appropriate for stage 3 (mean Likert score range 6.6–8.6, SD 0.49–1.96). Domains with mean Likert scores of 4.9–6.8 were removed (11 domains). These included work-place based assessments (mean Likert score 6.6, SD 1.98), research opportunities (mean Likert score 6.6, SD 1.58), GMC survey (mean Likert score 5.7, SD 1.84), subspeciality training opportunities (mean Likert score 6.7, SD 1.31), and all the newly suggested domains from Stage 1. ##TAB##1##Table 2## shows the domains retained for Stage 3.</p>", "<title>Stage 3</title>", "<p>A total of 16 domains entered stage 3 of the Delphi process (##TAB##1##Table 2##); 10 were deemed consensus appropriate (mean Likert score range 6.6–8.3, SD 0.84–1.48). These domains were JCST survey results, clinical experience, educational programme, radiology support, timetable, regional support for trainees, trainer support for trainees, opportunities for professional development, trainee-rated quality of consultant teaching and training and trainee recommendation of the post. Six domains with mean Likert scores of 6.47–7.17 (SD 1.34–1.64) were discarded: access to and provision of simulation training (mean Likert score 6.7, SD 1.39), annual review of competence progression (ARCP) outcomes (mean Likert score 6.9, SD 1.64), training postinformation (mean Likert score 6.6, SD 1.36), quality of assigned educational supervisor (AES) feedback report (mean Likert score 6.8, SD 1.13), completion of checklists (mean Likert score 6.5, SD 1.55), and Fellowship of the Royal Colleges of Surgeons (FRCS) exam results (mean Likert score 7.2, SD 1.34). ##TAB##2##Table 3## shows the final domains deemed consensus appropriate.</p>", "<title>Rationalisation to ten priority domains</title>", "<p>Altogether, ten domains were deemed consensus appropriate. The prioritisation score of the domains was calculated according to the study protocol. All ten that were identified as suitable to use in programme QA were ranked in the top ten by more than 50% of Delphi participants, and had an average prioritisation score greater than or equal to nine.</p>" ]	[ "<title>Discussion</title>", "<p>Assessing quality involves making a comparison of one thing against other things of a similar kind. However, definitions of quality are ultimately ‘constructed in the minds of the definers’. <sup>##UREF##5##6##</sup></p>", "<p>The Delphi technique is a method for organising conflicting values and experiences, which facilitates the incorporation of multiple opinions into consensus decisions. It is used to combine expert opinion systematically to arrive at an informed group consensus on a complex problem.<sup>##UREF##6##7##</sup></p>", "<p>Surgical training programmes are complex and involve a broad spectrum of stakeholders, with varied backgrounds. This presents risk of variation in views and priorities or what constitutes ‘quality’ in a training programme, making Delphi methodology highly appropriate.<sup>##UREF##6##7##</sup></p>", "<p>The GMC defines QA and standards for the management and delivery of undergraduate and postgraduate medical education and training. The JCST also has clearly defined quality indicators for each surgical specialty training programme.<sup>##UREF##7##8##</sup> Quality processes follow these principles but, although carefully considered and extensive, they do not cover all aspects that trainees, TPDs and other parties involved in the delivery of the training programme consider as adding significant value to vascular surgical training.</p>", "<p>Using Delphi methodology, this study sought to identify the most important domains of vascular surgical training for inclusion in training programme quality assessment and QA. The principal finding was the prioritisation of ten domains deemed appropriate for programme assessment by key stakeholders. As far as the authors are aware this is the first time a Delphi process has been employed to establish consensus on the quality assessment of training programmes.</p>", "<p>The ten domains that were deemed consensus appropriate to assess the quality of a training programme are all considered existing markers of quality.</p>", "<title>Training programme survey</title>", "<p>The JCST survey has been a compulsory component of all UK surgical training programmes since 2011.<sup>##UREF##8##9##</sup> It was developed by JCST in conjunction with the various Schools of Surgery in the UK, in an attempt to limit the number of surveys required from trainees.<sup>##UREF##9##10##</sup> Its strengths include the achievement of this first objective, now representing the single compulsory training survey for most UK surgical trainees. It is also described as anonymous, although supervisors and various training body officials can access an individual’s responses, which presents a risk of under-reporting. It is placement-specific, meaning that answers relate to a training post, rather than a training centre, although this does mean completion might be required biannually. However, as each individual training post is usually undertaken by just one or two trainees per year, there is a risk that small numbers of responses may not accurately reflect the quality of the training post, or that individual circumstances may make responses nonrepresentative. There is, therefore, a need to consider multiple responses in the longitudinal assessment of any training post and, with a relatively small number of vascular surgery trainees in each Deanery, the same principle applies. An unclear range of factors also seems to substantially influence the responses to the JCST survey, as exemplified in a comparison of multiple training surveys in 2017,<sup>##UREF##8##9##</sup> which demonstrated very poor correlation between surveys, leading to widely varying quality ranking across centres, depending which survey was examined.</p>", "<title>Clinical experience</title>", "<p>The JCST Quality Indicators (QI) for vascular surgery<sup>##UREF##7##8##</sup> have four QIs relating to clinical exposure. Clinical exposure is required to achieve the competencies dictated by the curriculum<sup>##UREF##10##11##</sup> and completion of these competencies is required to obtain Certificate of Completion of Training (CCT) and recommendation to join the GMC specialist register. This is ultimately the entire purpose of the training programme; to deliver the curriculum to produce ‘competent doctors able to deliver excellent outcomes for patients as consultant vascular surgeons’.<sup>##UREF##10##11##</sup></p>", "<title>Educational programme</title>", "<p>Formal teaching is another QI from the JCST but is also an integral part to gaining knowledge and the evidence base for current practice. The ASPIRE (Annual SPecIalist Registrar Educational) programme is unique to Vascular Surgery and consists of specific educational days for each year of specialty training. Those who have attended the ASPIRE 7 course are historically more likely to pass the FRCS(Vasc) exam than those who have not. Both local and national educational programmes contribute to trainees gaining competencies and knowledge to enable them to pass the FRCS(Vasc) exam and achieve eligibility for completion of training.</p>", "<title>Radiology support</title>", "<p>Endovascular intervention is important for the management of multiple vascular pathologies and the curriculum strives to deliver surgeons who can perform hybrid revascularisation procedures and perform endovascular interventions in collaboration with interventional radiologists (IR). Cross-specialty training provides opportunities to optimise experience and exposure to a variety of techniques for both IR and vascular trainees. Collaboration between the specialities is fundamental to the successful delivery of the curriculum.</p>", "<title>Regional support for trainees</title>", "<p>The Junior Doctors Contract (2016) identified a range of factors that were having a significant impact on the quality of life of doctors in training. These included geographical limitations of training, limited opportunities for doctors to train flexibly, varying equity in study budget provision and inequality for those who take time out of training.<sup>##UREF##11##12##</sup> Consequently ‘Enhancing Junior Doctors’ Working Lives’ programme was established and, as part of this, the SuppoRTT (Supported Return to Training) programme was developed. The 2019 Rouleaux Club survey (submitted but not yet in print) investigated the reasons why trainees left vascular surgical training. Of trainees appointed to the national training programme between 2013 and 2019, 15.4% resigned (unpublished data). Support for trainees directly impacts on their health and wellbeing and their subsequent retention in the training programme. The JCST also recognises the need for supportive processes in its QI.</p>", "<title>Trainer support for trainees</title>", "<p>The JCST QIs clearly indicate that consultant supervision must be appropriate for trainees’ level of training and experience and supervised activities should include theatre, clinic, ward rounds and emergency activity.</p>", "<title>Opportunities for professional development</title>", "<p>Both the vascular curriculum and JCST QI feature aspects of professional development. Attendance at conferences is key to staying up to date as well as enhancing research and quality improvement. Attendance at courses allows for the acquisition of new skills and specialist knowledge that complements local training resources.</p>", "<title>Strengths and weaknesses</title>", "<p>Strengths of this study included the participation of key stakeholders in vascular surgical training, who are ideally placed to determine the areas of greatest importance. There was a good response rate (>70%) with wide UK geographical coverage, and effective trainee representation. The inherent strengths of electronic Delphi methodology, such as its low cost, flexibility and reflexivity, a degree of anonymity, convenience for distance participation, and ability to organise widespread and diverse group thinking, proved useful in this study.<sup>##UREF##6##7##</sup></p>", "<p>Potential limitations include those inherent to electronic Delphi methodology, such as an inability to control potential distractors during participation and possible technology difficulties, although no participant or invited stakeholder reported such difficulties. There was some participant attrition, although with just one participant from Stage 1 failing to complete Stage 3, this is unlikely to have changed the Delphi outcome substantially. As a self-selected group of educationalists, there is a risk that the expert participants held views that differed to the broader vascular surgery professional community.</p>", "<title>Next steps</title>", "<p>These domains will be used by the key stakeholders in conjunction with the JCST survey and JCST QIs to develop a scoring system to provide an objective measure of quality of the vascular training programmes across the UK. Data will be collected electronically from LMs, TPDs and trainees (JCST survey). This process will be piloted and evaluated prospectively to accurately establish a scoring system that is transparent, reliable and reproducible, allowing year-on-year comparison of the training programmes.</p>" ]	[ "<title>Conclusion</title>", "<p>This study has identified the most important domains of vascular surgical training for inclusion in training programme quality assessment. These data will permit the development of a scoring system for the formalisation of the annual assessment of vascular training programme quality in the UK, permitting a reliable and reproducible year-on-year comparison of programme performance. The methodology and results of this study are likely to be transferable to other training programmes beyond the UK. If used appropriately, this study might offer greater potential to flag up areas of underperformance and highlight the best performing training programmes to share best practice. Piloting and prospective evaluation will be necessary during implementation of the new system.</p>" ]	[ "<title>Introduction</title>", "<p>A robust and reproducible way of assessing training should optimise and standardise vascular surgical training. This study describes the methodology supporting the Vascular Surgery Specialty Advisory Committee regional quality assurance reports for vascular surgery training programmes in the UK.</p>", "<title>Methods</title>", "<p>A Delphi consensus exercise was performed to establish the domains of training that most appropriately assess the quality of a vascular surgery training programme. A total of 54 stakeholders were invited to participate, including trainees, training programme directors and members of the vascular speciality advisory committee (SAC), vascular society executive and education committees.</p>", "<title>Results</title>", "<p>A total of 39 stakeholders successfully completed the three-stage Delphi process over 15 weeks. The domains identified as most appropriate to assess the quality of a vascular training programme were: Joint Committee on Surgical Training (JCST) survey results, clinical experience, regional education programmes, radiology support, timetable, regional support for trainees, trainer support for trainees, opportunities for professional development, trainee-rated quality of consultant teaching and training, and trainee recommendation of the post.</p>", "<title>Conclusions</title>", "<p>This study describes a method to identify and prioritise domains that are appropriate to assess the quality of a vascular training programme. The domains that were identified as appropriate to assess quality are transferable internationally and the Delphi methodology could be used by other training schemes to ‘fine-tune’ their own domains to review and optimise the quality of their own training programmes.</p>" ]	[]	[]	[ "<fig position=\"float\" id=\"rcsann.2022.0146F1\" fig-type=\"figure\"><label>Figure 1<x xml:space=\"preserve\"> </x></label><caption><p>Participants in the three-stage Delphi process</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"rcsann.2022.0146TB1\"><label>Table 1<x xml:space=\"preserve\"> </x></label><caption><p>Possible domains</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><tbody><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Domain</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Factors to be considered in the domain</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">JCST survey results</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">GMC survey results</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">Clinical experience</td><td rowspan=\"1\" colspan=\"1\">Operative experience, outpatient sessions, MDT, ward rounds</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Subspecialty training opportunities</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">Educational programmes</td><td rowspan=\"1\" colspan=\"1\">Frequency and quality of local departmental teaching, Regional/ Deanery teaching, Journal club, X-ray meetings with educational component, MDTs with an educational component, Attendance at ASPIRE courses</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Trainer support of trainees</td><td rowspan=\"1\" colspan=\"1\">OOH supervision, clinic supervision, operative supervision</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Radiology support</td><td rowspan=\"1\" colspan=\"1\">Access to IR training lists, enthusiasm to train</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Opportunities for professional development</td><td rowspan=\"1\" colspan=\"1\">Access to study leave for courses and conferences, attendance at courses and conferences</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Access to and provision of simulation training</td><td rowspan=\"1\" colspan=\"1\">Attendance at ASPIRE courses, local provision of high-fidelity simulation, NOTSS and human factors training</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Research opportunities and output</td><td rowspan=\"1\" colspan=\"1\">Proportion of trainees with higher degrees, output</td></tr><tr><td rowspan=\"1\" colspan=\"1\">ARCP outcomes</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\"> Training post information and administration</td><td rowspan=\"1\" colspan=\"1\">Vascular only rota from ST5 onwards, number of trainees in a unit, relevant general surgical firms, geographical location of training post/size of deanery, administration of training programme and training posts, e.g. knowing placements/rotas in a timely fashion</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Regional support for trainees</td><td rowspan=\"1\" colspan=\"1\">Opportunity and support for LTFT if required; opportunity and support for parental leave; experienced episodes of being bullied, harassed or undermined; witnessed episodes of bullying, harassment or undermining; professional advice and support SuppoRTT programme for all those returning to training</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> FRCS (Vasc) exam results</td><td rowspan=\"1\" colspan=\"1\">Attempts and pass rate Part 1/Part 2</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> WBA</td><td rowspan=\"1\" colspan=\"1\">Number of WBA completed; length of time between performing WBA and it being entered on ISCP; support and engagement of trainers with ISCP</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Timetable</td><td rowspan=\"1\" colspan=\"1\">Sessions range and type; number of clinics; number of theatre lists; vascular only rota</td></tr><tr><td rowspan=\"1\" colspan=\"1\"> Completion of checklists</td><td rowspan=\"1\" colspan=\"1\">ST4/6/8</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Trainee recommendation of the post as per JCST survey</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">Trainee rated quality of consultant teaching and training as per JCST survey</td><td rowspan=\"1\" colspan=\"1\"/></tr><tr><td rowspan=\"1\" colspan=\"1\">Quality of AES feedback report</td><td rowspan=\"1\" colspan=\"1\"/></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0146TB2\"><label>Table 2<x xml:space=\"preserve\"> </x></label><caption><p>Delphi process results</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"center\" span=\"1\"/><col align=\"center\" span=\"1\"/><col align=\"center\" span=\"1\"/><col align=\"center\" span=\"1\"/></colgroup><tbody><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Original domains</bold>\n</td><td colspan=\"4\" rowspan=\"1\">\n<bold>Consensus appropriate<break/>mean Likert score</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\"/><td rowspan=\"1\" colspan=\"1\">\n<bold>Stage 1 (percentage Likert ≥7)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Stage 2 (percentage Likert ≥7)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Stage 3 (Percentage Likert ≥7)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Accepted prioritisation score (average prioritisation score)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">JCST survey</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6.8 (72%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6.6 (73%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6.6 (72%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7 (9)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">GMC survey</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6.5 (67%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 5.7 (43%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Clinical experience</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.7 (100%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.6 (97%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.3 (94%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 1 (1)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Subspecialty training opportunities</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.4 (82%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 6.7 (65%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Educational programmes</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.3 (97%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.2 (92%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.7 (92%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 3 (6)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Trainer support of trainees</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.3 (97%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.6 (100%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.9 (89%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7 (9)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Radiology support</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.1 (95%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.8 (92%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.3 (78%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7 (9)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Opportunities for professional development</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.7 (90%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.8 (95%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.2 (75%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6 (8)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Access to and provision of simulation training</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.7 (85%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.4 (75%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 6.7 (56%)</td><td rowspan=\"1\" colspan=\"1\">No 16 (11)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Research opportunities and output</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.0 (69%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 6.6 (64%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">ARCP outcomes</td><td rowspan=\"1\" colspan=\"1\"><bold>Yes 7.6 (87%</bold>)</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.8 (89%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 6.9 (69%)</td><td rowspan=\"1\" colspan=\"1\">No 11 (10)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Training post information and administration</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.5 (82%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.5 (92%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 6.6 (53%)</td><td rowspan=\"1\" colspan=\"1\">No 13 (12)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Regional support for trainees</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.9 (92%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 8.1 (89%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.4 (78%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes16 (11)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">WBAs</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6.7 (62%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 6.6. (69%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Timetable</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.5 (87%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.9 (97%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.6 (83%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7 (9)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Completion of checklists</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.1 (77%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6.6 (72%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 6.5 (56%)</td><td rowspan=\"1\" colspan=\"1\">No 13 (12)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">FRCS (Vasc) exam results</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.4 (72%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\"><bold>Yes 7.6 (86%</bold>)</td><td rowspan=\"1\" colspan=\"1\">No 7.2 (69%)</td><td rowspan=\"1\" colspan=\"1\">No 11 (10)</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Trainee recommendation of the post as per JCST survey</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.5 (90%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.8 (94%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.4 (83%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7 (9)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Trainee rated quality of consultant teaching and training as per JCST survey</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.6 (95%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.6 (97%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 7.5 (83%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 4 (7)</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Quality of AES feedback report</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6.8 (67%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Yes 6.6 (72%)</bold>\n</td><td rowspan=\"1\" colspan=\"1\">No 6.8 (56%)</td><td rowspan=\"1\" colspan=\"1\">No 13 (12)</td></tr><tr><td colspan=\"5\" rowspan=\"1\">\n<bold>Additional Suggested domains</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Joy at work</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">No 6.6 (64%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Whether trainers have designated time within their job plans to act as AES</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">No 6.8 (67%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Consultant jobs at the end of the programme. Need for specialist fellowship, e.g. endovascular</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">No 6.2 (53%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">NVR logged procedures</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">No 6.3 (64%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Dropout rate of trainees, particularly important at ST1 and 2 when they start</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">No 6.6 (58%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">The colleague test: i.e. would your colleagues let you operate on their relative. Would you be happy to have this person as a colleague? Do you think they can do the job?</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">No 6.3 (58%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Educational qualifications of consultants in the units</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">No 4.9 (22%)</td><td rowspan=\"1\" colspan=\"1\">–</td><td rowspan=\"1\" colspan=\"1\">–</td></tr></tbody></table></table-wrap>", "<table-wrap position=\"float\" id=\"rcsann.2022.0146TB3\"><label>Table 3<x xml:space=\"preserve\"> </x></label><caption><p>Suggested domains excluded as already incorporated into another domain</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" span=\"1\"/><col align=\"left\" span=\"1\"/></colgroup><tbody><tr><td rowspan=\"1\" colspan=\"1\">\n<bold>Suggested domain</bold>\n</td><td rowspan=\"1\" colspan=\"1\">\n<bold>Existing domain covering suggestion</bold>\n</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Mentorship opportunities, who to contact, what support offered</td><td rowspan=\"1\" colspan=\"1\">Regional support for trainees</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Access to regular interventional radiology lists</td><td rowspan=\"1\" colspan=\"1\">Radiology support</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Structured work schedules, LFG frequency and multidisciplinary unit attendance, IRMER compliance, access to peripheral angiography lists, team training</td><td rowspan=\"1\" colspan=\"1\">Timetable</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Split site working, i.e. at both arterial and nonarterial centres</td><td rowspan=\"1\" colspan=\"1\">Clinical experience</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Quality and frequency of regional teaching programme</td><td rowspan=\"1\" colspan=\"1\">Educational programme</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Number of index cases undertaken in each individual unit - it is impossible to train if the unit is not undertaking the cases</td><td rowspan=\"1\" colspan=\"1\">Clinical experience</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Leadership training</td><td rowspan=\"1\" colspan=\"1\">Access to simulation</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Time spent in each unit and how often rotations change</td><td rowspan=\"1\" colspan=\"1\">Training programme information</td></tr><tr><td rowspan=\"1\" colspan=\"1\">Destination for senior trainees – consultant jobs/need for fellowship</td><td rowspan=\"1\" colspan=\"1\">Suggested twice</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[]	[ "<table-wrap-foot><fn><p>AES = assigned educational supervisor; ARCP = annual review of competence progression; ASPIRE = Annual Specialist Registrar Educational; FRCS = Fellowship of the Royal Colleges of Surgeons; GMC = General Medical Council; IR = interventional radiologists; ISCP = Intercollegiate Surgical Curriculum Programme; JCST = Joint Committee for Surgical Training; LTFT = less than full time; MDT = multidisciplinary team; NOTSS = nontechnical skills for surgeons; OOH = out-of-hours; SuppoRTT = supported return to training; WBA = work based assessments</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>AES = assigned educational supervisor; ARCP = annual review of competence progression; FRCS = Fellowship of the Royal Colleges of Surgeons; GMC = General Medical Council; JCST = Joint Committee for Surgical Training; NVR = National Vascular Registry; WBA = work based assessments</p></fn></table-wrap-foot>", "<table-wrap-foot><fn><p>IRMER = ionising radiation (medical exposure) regulations; LFG = local faculty group</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"rcsann.2022.0146.01\" position=\"float\"/>" ]	[]	[{"label": ["1."], "collab": ["Vascular Society of Great Britain and Ireland"], "source": ["Yearbook 12"], "ext-link": ["https://www.vascularsociety.org.uk/_userfiles/pages/files/Document%20Library/AGM_Yearbook_2012_singlepages_4web.pdf"], "comment": ["(cited December 2023)"]}, {"label": ["2."], "collab": ["General Medical Council"], "source": ["GMC approved postgraduate curricula"], "ext-link": ["https://www.gmc-uk.org/education/standards-guidance-and-curricula/curricula"]}, {"label": ["3."], "collab": ["Vascular Society of Great Britain and Ireland"], "source": ["Yearbook 19"], "ext-link": ["https://www.vascularsociety.org.uk/_userfiles/pages/files/ASM%202019/-%20FINAL%20Yearbook%202019%20v2(1).pdf"], "comment": ["(cited December 2023)"]}, {"label": ["4."], "collab": ["Legislation.gov.UK"], "source": ["Medical Act 1983, UK General Public acts 1983 c.54"], "ext-link": ["https://www.legislation.gov.uk/ukpga/1983/54/contents"]}, {"label": ["5."], "collab": ["Joint Committee on Surgical Training"], "italic": ["The Gold Guide"]}, {"label": ["6."], "surname": ["Cameron", "Whetten", "Smart"], "given-names": ["K", "D", "JC"], "article-title": ["Organizational effectiveness and quality: the second generation"], "italic": ["Higher Education: Handbook of Theory and Research"], "volume": ["11"], "publisher-loc": ["New York", "NY"], "publisher-name": ["Agathon Press"], "year": ["1996"], "fpage": ["265"], "lpage": ["306"]}, {"label": ["7."], "surname": ["Donohoe", "Stellefson", "Tennant"], "given-names": ["H", "M", "B"], "article-title": ["Advantages and limitations of the e-Delphi technique: implications for health education researchers"], "italic": ["Am J Health Educ"], "year": ["2012"], "bold": ["43"], "fpage": ["38"], "lpage": ["46"]}, {"label": ["8."], "collab": ["Joint Committee on Surgical Training"], "source": ["JCST quality indicators"], "ext-link": ["https://www.jcst.org/quality-assurance/quality-indicators"], "comment": ["(cited December 2023)"]}, {"label": ["9."], "collab": ["Royal College of Surgeons of England"], "source": ["Online training surveys: not worth the paper they\u2019re written on"], "ext-link": ["https://publishing.rcseng.ac.uk/doi/full/10.1308/rcsbull.2018.32"], "comment": ["(cited December 2023)"]}, {"label": ["10."], "collab": ["Joint Committee on Surgical Training."], "source": ["The JCST trainee survey"], "ext-link": ["https://www.jcst.org/-/media/files/jcst/quality-assurance/trainee-survey/survey-faqs-v6.pdf"], "comment": ["(cited December 2023)"]}, {"label": ["11."], "collab": ["Intercollegiate Surgical Curriculum Programme."], "source": ["Vascular surgery curriculum"], "ext-link": ["https://www.iscp.ac.uk/media/1113/vascular-surgery-curriculum-aug-2021-approved-oct-20.pdf"], "comment": ["(cited December 2023)"]}, {"label": ["12."], "collab": ["Enhancing Junior Doctors Working Lives"], "source": ["Progress made since 2017\u2019s report"], "ext-link": ["https://www.hee.nhs.uk/sites/default/files/documents/EJDWL%20-%202018%20progress%20report.pdf"], "comment": ["(cited January 2023)"]}]	{ "acronym": [], "definition": [] }	12	CC BY	no	2024-01-13 23:40:16	Ann R Coll Surg Engl. 2024 Jan 13; 106(1):70-77	oa_package/b8/20/PMC10765177.tar.gz
PMC10769221	38187638	[ "<title>Introduction</title>", "<p id=\"P5\">The prefrontal cortex evolved to process a wide range of information in order to adaptively guide behaviors in complex environments<sup>##UREF##0##1##</sup>. For social animals, it has been hypothesized that the prefrontal cortex, and other brain regions, prioritize social information to successfully navigate volatile social environments involving multiple conspecifics in group settings<sup>##UREF##1##2##–##REF##33169032##5##</sup>. In many primate species, social gaze plays a pivotal role in conveying essential social information<sup>##UREF##2##6##</sup>, and several prefrontal brain regions are known to exhibit selective neural activity for social gaze interaction<sup>##REF##30017395##7##, ##REF##35545090##8##</sup>. While multiple subregions in the primate temporal and posterior parietal cortices, including the gaze-following patch, have been widely implicated in the perceptual aspects of social gaze<sup>##REF##1348133##9##–##REF##37211234##12##</sup>, the prefrontal subregions are theorized to play critical functions in integrating social, affective, and motivational information to enable appropriate social gaze processing<sup>##REF##19223221##13##</sup>.</p>", "<p id=\"P6\">The neural systems involved in social gaze interaction must distinguish social from non-social gaze events, and also mark significant interactive events such as mutual eye contact, in order to regulate social behaviors. This is likely facilitated by the continuous monitoring of one’s own gaze and other’s gaze over time. Recent research in pairs of rhesus macaques has demonstrated that a large proportion of individual neurons in the prefrontal cortex, including the orbitofrontal cortex (OFC), the dorsomedial prefrontal cortex (dmPFC), and the gyrus of anterior cingulate cortex (ACCg), exhibit robust neural representations for gaze fixations directed toward the eyes and the face of a conspecific partner and for context-specific mutual eye contact events<sup>##REF##35545090##8##</sup>. Importantly, a substantial proportion of cells in these areas were found to parametrically track the Euclidian distance of one’s own gaze fixations in space relative to a partner monkey’s eyes and the distance of the partner’s gaze fixations relative to one’s own eyes<sup>##REF##35545090##8##</sup>. Dynamic changes in these gaze distance variables provide information on the proximity of gaze fixations of interacting individuals to one another. This information becomes particularly valuable for computing interactive gaze events, such as mutual eye contact or joint attention, when gaze distance variables for self and other converge to specific values. Thus, this parametric representation of gaze-related distances in individual neurons is a noteworthy finding as it can provide a moment-by-moment index of social attention during an ongoing social interaction, possibly serving as a simple, yet elegant, mechanism of social gaze monitoring. This type of gaze-distance coding is not specific to social information processing, however. In OFC, it has been shown that a large proportion of neurons encode the gaze fixation distance from a value-predicting cue on the screen during free viewing<sup>##REF##27263972##14##</sup>, providing a potentially shared mechanism linking gaze position and reward valuation in both social and non-social contexts.</p>", "<p id=\"P7\">Nevertheless, a lingering question remains: do neural populations in OFC, dmPFC, or ACCg causally contribute to dynamic social attention? To address this question, here we applied weak, real-time, closed-loop microstimulations unilaterally to each of the three prefrontal areas upon the precise moment when the stimulated monkey fixated on partner monkey’s eyes. Compared to sham stimulations, microstimulations of the OFC facilitated social attention in the spatial dimension by decreasing the average distance of one’s own gaze fixations relative to partner’s eyes. Importantly, this effect was more pronounced for gaze fixations in the contralateral visual field and specific to attending to social stimuli. Moreover, microstimulations of the OFC also exerted an influence in the temporal dimension of social attention by reducing the inter-looking interval for attending to partner’s face as well as reducing the latency to reciprocate partner’s directed gaze. Thus, microstimulations of OFC had a dual impact on both spatial and temporal aspects of dynamic social attention by facilitating focal visual attention around another social agent and promoting reciprocal gaze exchanges. These findings highlight the primate OFC as a causal node in controlling dynamic social attention.</p>" ]	[ "<title>Methods</title>", "<title>Animals</title>", "<p id=\"P28\">Two adult male rhesus macaques (<italic toggle=\"yes\">Macaca mulatta</italic>) were involved as stimulated monkeys (M1; monkeys L and T; both aged 10 years, weighing 15.7 kg and 14.1 kg, respectively). For each M1, unrelated monkey E (female, aged 10 years, weighing 10.9 kg) served as a partner monkey (M2). M2 was previously housed in the same colony room with M1s and other rhesus macaques and later moved to an adjacent colony room. The focus of the current study was to investigate the causal functions of OFC, dmPFC, and ACCg in dynamic social attention and did not include the necessary number of pairs to examine the effects of social relationships. Our previous published work using the identical paradigm has provided a comprehensive examination of the effects of social relationship on social gaze interaction from unique 8 dominance-related, 20 familiarity-related, and 20 sex-related perspectives<sup>##REF##27486105##15##</sup>. In this study, all animals were kept on a 12-hr light/dark cycle with unrestricted access to food, but controlled access to fluid during testing. All procedures were approved by the Yale Institutional Animal Care and Use Committee and in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. No animals were excluded from our analyses.</p>", "<title>Experimental setup</title>", "<p id=\"P29\">On each day, M1 and M2 sat in primate chairs (Precision Engineering, Inc.) facing each other, 100 cm apart and the top of each monkey’s head 75 cm from the floor, with three monitors facing each monkey and the middle monitor 36 cm away from each monkey’s eyes (##FIG##0##Fig. 1a##). Two infrared eye-tracking cameras (EyeLink 1000, SR Research) simultaneously and continuously recorded the horizontal and vertical eye positions from both monkeys at 1,000 Hz. We conducted a two-step calibration procedure described in our previous work<sup>##REF##35545090##8##</sup>.</p>", "<p id=\"P30\">Each data collection day consisted of a total of alternating 10 <italic toggle=\"yes\">live social gaze</italic> sessions and 5 <italic toggle=\"yes\">non-social control</italic> sessions on average for monkey L (9–11 social and 4–8 control sessions across all days) and alternating 15 <italic toggle=\"yes\">live social gaze</italic> sessions and 5 <italic toggle=\"yes\">non-social control</italic> sessions on average for monkey T (14–15 social and 5 control sessions across all days). Each session lasted 300 sec. During <italic toggle=\"yes\">live social gaze</italic> sessions, pairs of monkeys were allowed to freely interact with each other using gaze (##FIG##0##Fig. 1a##, left). During <italic toggle=\"yes\">non-social control</italic> sessions, M1 was allowed to freely examine the space where a <italic toggle=\"yes\">random dot motion (RDM) stimulus</italic> was presented on a mini monitor positioned on M2’s primate chair directly in front of M2’s face (##FIG##0##Fig. 1a##, right). At the beginning of each <italic toggle=\"yes\">live social gaze</italic> session, the middle monitors were lowered down remotely so that the two monkeys could fully see each other (##FIG##0##Fig. 1a##, top). Before the beginning of each <italic toggle=\"yes\">non-social control</italic> session, the mini monitor was positioned by an experimenter in front of M2’s face (##FIG##0##Fig. 1a##, right) and the middle monitors were lowered down remotely once the experimenter left the testing room. The mini monitor was 38 cm × 21 cm (W × H) at a resolution of 1024 pixel × 768 pixel. <italic toggle=\"yes\">RDM stimulus</italic> was constructed using Variable Coherence Random Dot Motion MATLAB library (<ext-link xlink:href=\"https://shadlenlab.columbia.edu/resources/VCRDM.html\" ext-link-type=\"uri\">https://shadlenlab.columbia.edu/resources/VCRDM.html</ext-link>) and contained randomly moving dots within two circular apertures of 2.4 deg diameter each, with an inter-aperture horizontal distance of 1.6 deg equidistantly placed to the left and right of the center of M2’s <italic toggle=\"yes\">Eyes</italic> ROI. <italic toggle=\"yes\">RDM stimulus</italic> (white dots on a black background, with a density of 16.7 dots/deg<sup>2</sup> per second) generated apparent motion either upward or downward with a 100% coherence with a fixed velocity 2 deg/sec. Motion direction remained consistent within a session. At the end of each session, the middle monitors were raised up remotely and blocked the stimulated monkey’s visual access to the partner monkey or the <italic toggle=\"yes\">RDM stimulus</italic> during a 180-sec break.</p>", "<title>Surgery and anatomical localization</title>", "<p id=\"P31\">All animals received a surgically implanted headpost (Grey Matter Research) for restraining their head movement. A second surgery was performed on the two M1 animals to implant a custom chamber (Rogue Research Inc.) to permit recording and microstimulation in OFC (11 and 13), dmPFC (6 and 8), and ACCg (24a, 24b and 32)<sup>##UREF##7##52##</sup>. Placement of the chambers was guided by both structural magnetic resonance imaging (MRI, 3T Siemens) scans and stereotaxic coordinates. See ##FIG##0##Fig. 1b## for microstimulation sites on representative MR slices from both monkeys.</p>", "<title>Closed-loop microstimulation protocol</title>", "<p id=\"P32\">On each day before data collection, a guide tube was used to penetrate intact dura and to guide a microstimulation electrode (median impedance 50 kΩ) and a recording electrode (tungsten, FHC Inc), which were remotely lowered by using a motorized multi-electrode microdrive system (NaN Instruments) at the speed of 0.02 mm/sec. After the two electrodes reached target site, we ensured that we positioned the electrodes in the grey matter and waited 30 min for the tissue to settle for signal stability before starting experiment. The microstimulation site was usually positioned within 1mm from the recording electrode site on the chamber grid. Each closed-loop microstimulation (PlexStim system, Plexon Inc) was selectively triggered by M1 fixating within M2’s <italic toggle=\"yes\">Eyes</italic> region for at least 30 msec in the live social gaze condition or M1 fixating within the <italic toggle=\"yes\">RDM stimulus</italic> region (same location and size as <italic toggle=\"yes\">Eyes</italic> ROI in the live social gaze condition) for at least 30 msec in the non-social control condition, with a probability of 50%. For every four trials, two microstimulations and two shams were randomly assigned. Parameters of each microstimulation (cathode-leading bipolar with a phase duration of 200 μsec and an interphase duration of 100 μsec) were 75 μA in amplitude, 100 Hz in frequency, and 200 msec in duration. Because the gaze-contingency of a microstimulation or sham was computed and implemented on the same microcontroller (Arduino), there was a negligible (< 1 msec) delay between registering a gaze fixation and initiating a microstimulation or sham. To avoid overstimulation of brain tissue, any two consecutive trials (including both microstimulations and shams) had to be at least 5 sec apart (##FIG##0##Fig. 1c##–##FIG##0##d##; ##SUPPL##0##Fig. S1a##).</p>", "<title>Frequency of microstimulations and regions of interest for social and non-social gaze sessions</title>", "<p id=\"P33\">To quantify the frequency of microstimulations received by the stimulated monkeys, we calculated and compared the total number of microstimulations and shams per day across the three stimulated brain regions and two animals by using Wilcoxon rank sum test (##FIG##0##Fig. 1e##; ##SUPPL##0##Fig. S1b##). On each experiment day, we identified the following regions of interest (ROIs): <italic toggle=\"yes\">Eyes</italic> and <italic toggle=\"yes\">non-eye Face</italic> (the rest of the face excluding the <italic toggle=\"yes\">Eyes</italic> regions) in the live social gaze condition, and <italic toggle=\"yes\">RDM stimulus</italic> in the non-social control condition (same location and size as <italic toggle=\"yes\">Eyes</italic> ROI). In some analyses, we examined <italic toggle=\"yes\">whole Face</italic> which is the union of <italic toggle=\"yes\">Eyes</italic> and <italic toggle=\"yes\">non-eye Face</italic> ROIs. Based on each day’s calibration, <italic toggle=\"yes\">whole Face</italic> ROI was defined by the four corners of a monkey’s face and the <italic toggle=\"yes\">Eyes</italic> ROI was defined by adding a padding of to the center of each eye. Fixations were identified using EyeMMV toolbox in MATLAB<sup>##UREF##8##53##</sup>. We detected fixations based on spatial and duration parameters, using t1 = 1.18 and t2 = 0.59 degrees of visual angle for the spatial tolerances and a minimum duration of 70 msec. As this fixation detection procedure does not incorporate velocity, we did not consider eye movement speed when identifying fixations. For each of the ROIs, we calculated the total number of gaze fixations and the average duration per fixation of the stimulated monkey for each day. Wilcoxon signed rank test was used to compare each variable between <italic toggle=\"yes\">Eyes</italic> and <italic toggle=\"yes\">non-eye Face</italic>, as well as <italic toggle=\"yes\">Eyes</italic> and <italic toggle=\"yes\">RDM stimulus</italic>. Wilcoxon rank sum test was used to compare each variable of each ROI between any pair of stimulated brain regions (##SUPPL##0##Fig. S1c##).</p>", "<title>Fixation density map</title>", "<p id=\"P34\">To construct a fixation density map, we examined the gaze positions of all M1’s fixations in space during the post-gaze epoch (within 1.5 sec after the onset of a microstimulation or sham) and assigned each fixation to a one-visual degree grid-square in a big spatial grid spanning 40 deg in both horizontal and vertical dimensions centered on partner’s <italic toggle=\"yes\">Eyes</italic> ROI. Total number of fixations per day was calculated by summing across such fixations in each grid-square for microstimulation trials and sham trials separately and were z-scored. Difference in such fixation density between microstimulation and sham trial types was averaged across days for each stimulated brain region and plotted as heatmaps aligned to the center of partner’s <italic toggle=\"yes\">Eyes</italic> (##FIG##1##Fig. 2a##, monkey T’s heatmaps were flipped horizontally as his chamber was implanted on the different hemisphere as monkey L; see ##SUPPL##0##Fig. S2a## for individual stimulated animals). We focused on the post-gaze epoch as 1.5 sec was the common time window for both animals where we observed the reported stimulation effects (microstimulations of OFC in monkey L lasted for 3 sec after trial onset).</p>", "<title>Gaze distance analyses</title>", "<p id=\"P35\">In the live social gaze condition, for each trial, we examined all M1’s fixations during post-gaze epoch and calculated the Euclidean distance between each fixation and the center of partner’s <italic toggle=\"yes\">Eyes</italic> ROI projected onto the same plane. Such distance was first averaged across all fixations after each trial and then averaged for each trial type for each day (##FIG##1##Fig. 2b##). Wilcoxon signed rank test was used to compare social gaze distance between microstimulation and sham trial types (##FIG##1##Fig. 2c##). Fixations were further categorized into those on the <italic toggle=\"yes\">contralateral</italic> hemifield (opposite visual field of the stimulated brain hemisphere; ##FIG##1##Fig. 2d##) and <italic toggle=\"yes\">ipsilateral</italic> hemifield (same visual field as the stimulated brain hemisphere) for each M1 separately. The microstimulation effect on social gaze distance was examined for fixations in the <italic toggle=\"yes\">contralateral</italic> and <italic toggle=\"yes\">ipsilateral</italic> hemifield separately (##FIG##1##Fig. 2e##). Wilcoxon signed rank test was used to compare microstimulation effect on social gaze distance for each hemifield separately and between hemifields. The same analysis was applied for the non-social control condition (##FIG##1##Fig. 2f##–##FIG##1##h##) by calculating the Euclidean distance between M1’s fixations and the center of <italic toggle=\"yes\">RDM stimulus</italic>.</p>", "<title>Gaze latency analyses</title>", "<p id=\"P36\">To examine dynamic social attention in the temporal dimension, we examined two measurements, <italic toggle=\"yes\">inter-looking interval</italic> and <italic toggle=\"yes\">reciprocation latency</italic>. Specifically, we focused on the <italic toggle=\"yes\">whole Face</italic> ROI and combined events when only M1 fixated on the <italic toggle=\"yes\">whole Face</italic> of M2 and the events when both monkeys’ gaze positions were within each other’s <italic toggle=\"yes\">whole Face</italic>. First, we examined <italic toggle=\"yes\">inter-looking interval</italic>, the latency for M1 to look back at M2’s <italic toggle=\"yes\">whole Face</italic> within 5 sec after the onset of a microstimulation or sham (##FIG##2##Fig. 3a##). <italic toggle=\"yes\">Inter-looking interval</italic> was calculated for each trial and averaged across all microstimulation trials and sham trials separately for each day (##FIG##2##Fig. 3b##). Wilcoxon signed rank test was used to compare such interval between microstimulation and sham trial types. Same analysis was applied for the non-social control condition by using the corresponding <italic toggle=\"yes\">whole Face</italic> ROI. We also performed a trial-level analysis given that there was a relative low number of relevant gaze events by collapsing all microstimulation trials and all sham trials separately across all days for each stimulated brain region (##SUPPL##0##Fig. S2b##). Wilcoxon rank sum test was used to compare <italic toggle=\"yes\">inter-looking interval</italic> between microstimulation and sham trial types on the trial level.</p>", "<p id=\"P37\">We next examined <italic toggle=\"yes\">reciprocation latency</italic>, the latency for M1 to look back at M2’s <italic toggle=\"yes\">whole Face</italic> after M2 looked at M1’s <italic toggle=\"yes\">whole Face</italic> within 5 sec after the onset of a microstimulation or sham (##FIG##2##Fig. 3c##). <italic toggle=\"yes\">Reciprocation latency</italic> was calculated for each trial and averaged across all microstimulation trials and sham trials separately for each day (##SUPPL##0##Fig. S2c##). Wilcoxon signed rank test was used to compare such latency between microstimulation and sham trial types. Again, due to the scarcity of relevant gaze events, we collapsed all microstimulation trials and all sham trials separately across all days for each stimulated brain region (##FIG##2##Fig. 3d##). Wilcoxon rank sum test was used to compare such latency between microstimulation and sham trial types. This analysis can only be applied in the live social gaze condition because there was no information about M2’s gaze in the non-social control condition given that M2’s visual access to M1 was blocked by the mini monitor placed in front of her.</p>", "<title>Saccade kinematics</title>", "<p id=\"P38\">To inspect if microstimulations resulted in any change in the current gaze event or saccade kinematics in the live social gaze condition, we first examined the average duration of current looking at partner’s <italic toggle=\"yes\">Eyes</italic> that triggered a microstimulation or sham, as well as the total number of microsaccades and macrosaccades (##SUPPL##0##Fig. S3a##–##SUPPL##0##c##). These measurements were calculated for each day and Wilcoxon signed rank test was used to compare them between microstimulation and sham trial types for each stimulated brain region. We identified saccades using an unsupervised clustering method<sup>##UREF##9##54##</sup> that captured both canonical microsaccades (small deviations in position within an epoch in which the eye is mostly steady) and macrosaccades (a more explicit saccade to a new spatial location). We thus separated microsaccades and macrosaccades in the following way: for each detected saccade event, if the event occurred strictly within an interval that was separately identified as a fixation<sup>##UREF##8##53##</sup>, we classified the event as a microsaccade; otherwise, we classified the event as a macrosaccade. We then examined macrosaccade kinematics. We looked at M1’s macrosaccades during the post-gaze epoch for each microstimulation or sham and calculated peak velocity (deg/sec) and amplitude (deg) for the first macrosaccade. For each day, we then fit a linear regression between peak velocity and amplitude of all such saccades for microstimulation trials and sham trials separately and calculated the slope difference between the two trial types (##SUPPL##0##Fig. S3d##). Wilcoxon signed rank test was used to compare such slope difference to zero. Within each day, we also created a shuffled null distribution of such slope differences by shuffling trial type label 1,000 times and compared the real median slope difference to the 1,000 medians of slope difference from the shuffled null distribution (##SUPPL##0##Fig. S3e##; permutation test). Furthermore, we categorized these macrosaccades into four groups depending on their direction (‘II’: saccades going from ipsilateral [I] hemifield to ipsilateral [I] hemifield; ‘IC’: saccades going from ipsilateral hemifield to contralateral [C] hemifield; also ‘CI’; ‘CC’). Wilcoxon signed rank test was used to test microstimulation effect on saccade kinematics against zero for each group separately.</p>", "<title>Inter-individual gaze dynamics analyses</title>", "<p id=\"P39\">In addition to M1’s gaze behaviors, we also examined how the two monkeys in a pair interacted with each other and their gaze directionality. By using moment-by-moment social gaze distance during the post-gaze epoch from each monkey (distance between one’s gaze positions and the center of the other monkey’s <italic toggle=\"yes\">Eyes</italic>), we applied causal decomposition analysis<sup>##UREF##3##17##</sup> and calculated the average relative causal strength across all intrinsic mode functions (IMFs) for each trial. A relative causal strength value closer to 1 means stronger directionality from M1 (stimulated monkey) to M2 (partner monkey) and a value closer to 0 means stronger directionality from M2 to M1 (##FIG##3##Fig. 4a##–##FIG##3##b##). Because the causal decomposition analysis required continuous data, we smoothed gaze data to fill in the gaps between fixations and excluded a trial if more than 1 sec continuous eye tracking samples of either monkey were ‘NaN’ or the start and end points of either monkey’s smoothed portion were more than 20 visual degrees apart. Wilcoxon signed rank test was used to compare the relative causal strength between microstimulation and sham trial types (##SUPPL##0##Fig. S4a##). Again, this analysis can only be applied in the live social gaze condition as there was no information about M2’s gaze in the non-social control condition.</p>", "<p id=\"P40\">To further investigate microstimulation effect on a longer timescale, we divided microstimulations into early epoch (the first 45 stimulations) and late epoch (the next 45 stimulations) for each day. 76 out of 81 days had at least 90 stimulations. The 5 days excluded from further analysis were 1 day from monkey L with OFC microstimulations, 1 day from monkey T OFC, 2 days from monkey T dmPFC, and 1 day from monkey T ACCg. Wilcoxon signed rank test was used to compare the relative causal strength for different combinations of microstimulation trial types and time epochs (##SUPPL##0##Fig. S4b##). Then, for each day, we fitted a linear regression between social gaze distance and relative gaze causal strength. This analysis was conducted by using social gaze distance in both hemifields combined, contralateral hemifield, and ipsilateral hemifield. Wilcoxon signed rank test was used to compare the slope of this fitted line between late epoch and early epoch separately for OFC, dmPFC, and ACCg (##SUPPL##0##Fig. S4c##; ##FIG##3##Fig. 4c##; ##SUPPL##0##Fig. S4d##). Lastly, to make sure the observed results were robust, we calculated the real median slope difference between late epoch and early epoch for each stimulated region and compared it to the null distribution of slope difference medians by shuffling the temporal order of the 90 microstimulations for 1,000 times for each day (##SUPPL##0##Fig. S4e##; ##FIG##3##Fig. 4d##; ##SUPPL##0##Fig. S4f##; permutation test).</p>" ]	[ "<title>Results</title>", "<p id=\"P8\">Two unique pairs of rhesus macaques (M1: stimulated monkey or ‘self’, monkeys L and T; M2: partner monkey or ‘other’, monkey E) engaged in spontaneous face-to-face social gaze interaction<sup>##REF##35545090##8##, ##REF##27486105##15##</sup> while the gaze positions of both monkeys were continuously and simultaneously tracked at high temporal and spatial resolution. To examine the causal moment-by-moment contributions of different prefrontal areas in live social gaze interaction, we applied weak, real-time, closed-loop microstimulations (75 μA, 100 Hz, 200 msec; <xref rid=\"S10\" ref-type=\"sec\">Methods</xref>) with a probability of 50% (half microstimulation trials and half sham trials) contingently upon the moment when the stimulated monkey fixated on the partner monkey’s eyes in the live social gaze condition (##FIG##0##Fig. 1a##, left; <xref rid=\"S10\" ref-type=\"sec\">Methods</xref>) or on a random dot motion (RDM) stimulus (presented on a mini monitor positioned in front of M2’s face) in the non-social control condition (##FIG##0##Fig. 1a##, right). RDM stimulus was chosen as a non-social control since it has no behavioral meaning (i.e. no intrinsic value) to monkeys. On each experimental day, microstimulations were applied to one of the three prefrontal areas: OFC, dmPFC, or ACCg (##FIG##0##Fig. 1b##–##FIG##0##d##; ##SUPPL##0##Fig. S1a##; <xref rid=\"S10\" ref-type=\"sec\">Methods</xref>).</p>", "<p id=\"P9\">The total number of microstimulations (and shams) received per day was comparable across the three stimulated regions and comparable between the two animals both in the social gaze and non-social control conditions (##FIG##0##Fig. 1e##, live social gaze condition, all p > 0.90, Wilcoxon rank sum, two-sided, FDR-corrected; ##SUPPL##0##Fig. S1b##, non-social control condition, all p > 0.10). Further, we quantified spontaneously occurring gaze behaviors of the stimulated monkeys in the following regions of interest (ROIs): <italic toggle=\"yes\">Eyes</italic> and <italic toggle=\"yes\">non-eye Face</italic> (the rest of the face excluding the <italic toggle=\"yes\">Eyes</italic> region) of the partner monkey in the live social gaze condition, and the <italic toggle=\"yes\">RDM stimulus</italic> (same location and size as <italic toggle=\"yes\">Eyes</italic> ROI) in the non-social gaze control condition. The total number of fixations on partner’s <italic toggle=\"yes\">Eyes</italic> per day was significantly higher than fixations on <italic toggle=\"yes\">non-eye Face</italic> for all three stimulated brain regions (##SUPPL##0##Fig. S1c##, top, all p < 10<sup>−4</sup>, Wilcoxon signed rank, two-sided, FDR-corrected), suggesting the significance of gaze directed to eyes that has been shown in previous studies in both humans and non-human primates<sup>##REF##35545090##8##, ##REF##27486105##15##, ##REF##29474416##16##</sup>. In addition, the total number of fixations on partner’s <italic toggle=\"yes\">Eyes</italic> per day was comparable to fixations on the <italic toggle=\"yes\">RDM stimulus</italic> for days involving the three stimulated regions (##SUPPL##0##Fig. S1c##, top, all p > 0.30), making it reasonable for us to compare the two conditions when examining microstimulation effect.</p>", "<title>Closed-loop microstimulations of OFC facilitate dynamic social attention in the spatial dimension</title>", "<p id=\"P10\">In our prior research, we elucidated a single-cell mechanism of social gaze monitoring in OFC, dmPFC, and ACCg. Notably, a significant proportion of neurons in these areas exhibited continuous and parametric tracking of where an individual is looking in space relative to another social agent or where the other agent is looking relative to oneself. This finding provides insight into a potential neural mechanism of social gaze monitoring involving these prefrontal regions<sup>##REF##35545090##8##</sup>. The current study investigated whether these prefrontal regions causally regulate such social gaze tracking.</p>", "<p id=\"P11\">To address this question, we first constructed a fixation density map for each trial considering all fixations during the analyzed post-gaze epoch (within 1.5 sec after the onset of a microstimulation or sham; <xref rid=\"S10\" ref-type=\"sec\">Methods</xref>) in the visual space surrounding the <italic toggle=\"yes\">Eyes</italic> and <italic toggle=\"yes\">whole Face</italic> (union of <italic toggle=\"yes\">Eyes</italic> and <italic toggle=\"yes\">non-eye Face</italic>) of the partner monkey. Differences in such fixation density maps between microstimulation and sham trial types revealed a potential role of OFC in modulating momentary dynamic social attention. Specifically, microstimulations of OFC led to more clustered subsequent gaze fixations around the partner monkey (##FIG##1##Fig. 2a##; see ##SUPPL##0##Fig. S2a## for the results from individual stimulated monkeys). To quantify this effect, for each microstimulation or sham, we calculated the average Euclidean distance between each of the stimulated monkey’s gaze fixations during the post-gaze epoch and the center of partner’s <italic toggle=\"yes\">Eyes</italic> in the live social gaze condition (##FIG##1##Fig. 2b##, left, social gaze distance; <xref rid=\"S10\" ref-type=\"sec\">Methods</xref>) or the center of <italic toggle=\"yes\">RDM stimulus</italic> in the non-social gaze control condition (##FIG##1##Fig. 2b##, right, non-social gaze distance). We then compared the average of these gaze distances per day between microstimulation and sham trial types for each stimulated brain region.</p>", "<p id=\"P12\">As the fixation density maps show, microstimulations of OFC significantly decreased the average distance of one’s own gaze positions in space relative to partner’s <italic toggle=\"yes\">Eyes</italic> during the post-gaze epoch, compared to shams (##FIG##1##Fig. 2c##, p < 0.001, Wilcoxon signed rank, two-sided). This suggests a facilitation of social attention in the spatial dimension by promoting gaze fixations around another social agent following OFC microstimulation. By contrast, we did not observe such stimulation effect on social gaze distance for dmPFC (##FIG##1##Fig. 2c##, p = 0.361) or ACCg (##FIG##1##Fig. 2c##, p = 0.374). Notably, the observed stimulation effect of OFC was more pronounced for gaze fixations in the contralateral visual field of the stimulated brain hemisphere (##FIG##1##Fig. 2d##–##FIG##1##e##; contralateral: p < 0.001; ipsilateral: p = 0.068; contralateral vs. ipsilateral: p = 0.026; Wilcoxon signed rank, two-sided). Again, no such effect was observed in either hemifield for dmPFC (##FIG##1##Fig. 2e##, contralateral: p = 0.501; ipsilateral: p = 0.149; contralateral vs. ipsilateral: p = 0.230) or ACCg (##FIG##1##Fig. 2e##, p = 0.442; p = 0.517; p = 0.564).</p>", "<p id=\"P13\">Crucially, these stimulation effects of OFC were exclusively observed in the live social gaze condition (i.e., microstimulations triggered by looking at partner’s <italic toggle=\"yes\">Eyes</italic>) and not in the non-social gaze control condition using the <italic toggle=\"yes\">RDM stimulus</italic> with no behavioral meaning to monkeys (##FIG##1##Fig. 2f##, OFC: p = 0.118; dmPFC: p = 0.719, ACCg: p = 0.302). The absence of stimulation effect for the <italic toggle=\"yes\">RDM stimulus</italic> was also found when gaze fixation locations were split by hemifield for OFC (##FIG##1##Fig. 2g##–##FIG##1##h##; contralateral: p = 0.097; ipsilateral: p = 0.249; contralateral vs. ipsilateral: p = 0.442), dmPFC (p = 0.374; p = 0.517; p = 0.773) or ACCg (p = 0.532; p = 0.943; p = 0.171), supporting that the observed effects of OFC microstimulations in the spatial dimension were selective to social gaze interaction or when the stimulus had a behavioral meaning.</p>", "<title>Microstimulations of OFC also promote dynamic social attention in the temporal dimension</title>", "<title>Inter-looking interval</title>", "<p id=\"P14\">In addition to the spatial dimension, the temporal aspect of social attention plays a crucial role in guiding social gaze interaction. Specifically, the time elapsed between individual instances of looking at another agent could serve as an index of social attention, with shorter durations between such gaze events indicating increased social attention. In this context, we sought to determine whether OFC microstimulations contributed to a reduction in the interval between social gaze events, in addition to the observed enhancement of social attention in the spatial dimension. Specifically, we examined the latency of M1 to look back at M2’s <italic toggle=\"yes\">whole Face</italic> (i.e., the first <italic toggle=\"yes\">whole Face</italic> event within 5 sec after the onset of a microstimulation or sham that was triggered by fixation to partner’s <italic toggle=\"yes\">Eyes</italic> in the live social gaze condition, <italic toggle=\"yes\">inter-looking interval</italic>; ##FIG##2##Fig. 3a##; <xref rid=\"S10\" ref-type=\"sec\">Methods</xref>). Microstimulations of OFC decreased this inter-looking interval (##FIG##2##Fig. 3b##, p = 0.035, Wilcoxon signed rank, two-sided). However, we did not observe such stimulation effect for dmPFC (##FIG##2##Fig. 3b##, p = 0.792) or ACCg (##FIG##2##Fig. 3b##, p = 0.291). Further, this reduction of inter-looking interval from OFC microstimulations was specific to social attention as no effect was observed in the non-social gaze condition (OFC: p = 0.773; dmPFC: p = 0.080; ACCg: p = 0.943). It is worth noting that this analysis had a relative low number of relevant gaze events compared to social gaze distance data from the spatial dimension analysis (i.e., the stimulated monkey did not look back at the partner’s <italic toggle=\"yes\">whole Face</italic> during the examined time window on 41% of microstimulation and sham trials per day on average). Nevertheless, when we combined all trials for each stimulated region, we still observed similar results to the day-level analysis above (##SUPPL##0##Fig. S2b##, OFC: p = 0.010; dmPFC: p = 0.301; ACCg: p = 0.602; Wilcoxon rank sum, two-sided). Microstimulations of OFC therefore tended to lead monkeys to look back at another social agent faster, which may facilitate social gaze monitoring and dynamic social attention.</p>", "<title>Reciprocation latency</title>", "<p id=\"P15\">We next examined a more explicitly interactive aspect of social gaze dynamics. Specifically, we inspected the average latency of M1 to reciprocate gaze back at M2’s <italic toggle=\"yes\">whole Face</italic> after M2 looked at M1’s <italic toggle=\"yes\">whole Face</italic> within 5 sec after the onset of a microstimulation or sham that was triggered by fixation to partner’s <italic toggle=\"yes\">Eyes</italic> (<italic toggle=\"yes\">reciprocation latency</italic>; ##FIG##2##Fig. 3c##; <xref rid=\"S10\" ref-type=\"sec\">Methods</xref>). On the day level, microstimulations did not seem to greatly reduce such reciprocation latency (##SUPPL##0##Fig. S2c##, OFC: p = 0.130; dmPFC: p = 0.701; ACCg: p = 0.400; Wilcoxon signed rank, two-sided). However, this is likely due to a low number of relevant gaze events (i.e., there was no sequence of M2 looking at M1 and then M1 looking back at M2 during the examined time window on 86% of microstimulation and sham trials per day on average). When combining all trials for each stimulated region, we observed that microstimulations of OFC decreased reciprocation latency (##FIG##2##Fig. 3d##, p = 0.011, Wilcoxon rank sum, two-sided). We again did not observe such stimulation effect for dmPFC (##FIG##2##Fig. 3d##, p = 0.777) or ACCg (##FIG##2##Fig. 3d##, p = 0.368). Microstimulations of OFC therefore tended to lead monkeys to reciprocate another social agent’s gaze faster.</p>", "<p id=\"P16\">Thus, during spontaneous real-life social gaze interaction, closed-loop microstimulations of the OFC, following specific social gaze events, effectively enhanced momentary dynamic social attention in both spatial and temporal dimensions. In the spatial dimension, the subsequent gaze fixations were more clustered around another social agent, an effect more pronounced in the contralateral hemifield. In the temporal dimension, the inter-looking interval and reciprocation latency were shortened. Crucially, these effects were specific to social attention and were not observed for the <italic toggle=\"yes\">RDM stimulus</italic>.</p>", "<title>Microstimulation effects of OFC are not driven by low-level properties of saccades</title>", "<p id=\"P17\">Importantly, the observed microstimulation effects of OFC were not driven by any change in the duration of the current gaze fixation to partner’s <italic toggle=\"yes\">Eyes</italic> that itself triggered a microstimulation or sham (##SUPPL##0##Fig. S3a##, p = 0.302, Wilcoxon signed rank, two-sided), number of microsaccades (##SUPPL##0##Fig. S3b##, p = 0.456), number of macrosaccades (##SUPPL##0##Fig. S3c##, p = 0.055), macrosaccade kinematics indexed by saccade peak velocity over amplitude (##SUPPL##0##Fig. S3d##, p = 0.665, Wilcoxon signed rank, two-sided; ##SUPPL##0##Fig. S3e##, p = 0.515, permutation test), or macrosaccade kinematics when considering saccade direction (##SUPPL##0##Fig. S3f##, ‘II’: macrosaccades from ipsilateral hemifield to ipsilateral hemifield; ‘IC’: macrosaccades from ipsilateral hemifield to contralateral hemifield; ‘CI’; ‘CC’; all p > 0.47, Wilcoxon signed rank, two-sided). Therefore, microstimulation effects of OFC were not associated with low-level changes in eye movements.</p>", "<title>Do microstimulations of OFC also lead to longer timescale modulation of social gaze exchanges?</title>", "<p id=\"P18\">The results reported above have shown that microstimulations of OFC enhance momentary dynamic social attention. Do these microstimulations also modulate social gaze exchanges on a longer timescale? To examine this, we analyzed inter-individual gaze dynamics between the stimulated monkey and the partner monkey. First, we applied a causal decomposition analysis<sup>##UREF##3##17##</sup> using moment-by-moment social gaze distance from each monkey (distance between one’s gaze positions and the center of the other monkey’s <italic toggle=\"yes\">Eyes</italic>) during the post-gaze epoch (within 1.5 sec after the onset of a microstimulation or sham) and controlled for saccades (##FIG##3##Fig. 4a##–##FIG##3##b##; <xref rid=\"S10\" ref-type=\"sec\">Methods</xref>). This allowed us to calculate a relative causal strength index that showed how much the gaze behaviors of one monkey in a pair was influenced by the gaze behaviors of the other monkey. To investigate stimulation effect on a longer timescale, we compared the first 45 stimulations (early epoch) to the next 45 stimulations (late epoch) from each day (<xref rid=\"S10\" ref-type=\"sec\">Methods</xref>). While microstimulations of OFC enhanced momentary dynamic social attention as shown in the previous sections, they did not seem to impact gaze directionality indexed by the magnitude of relative causal strength for both time epochs combined (##SUPPL##0##Fig. S4a##, p = 0.239, Wilcoxon signed rank, two-sided) and for each epoch separately (##SUPPL##0##Fig. S4b##, all p > 0.16). Further, to examine whether inter-individual gaze dynamics were modulated by where oneself was looking in space, we correlated social gaze distance and relative causal strength (<xref rid=\"S10\" ref-type=\"sec\">Methods</xref>) and found the slope of this fitted correlation comparable between early and late epochs for OFC (##SUPPL##0##Fig. S4c##, both hemifields combined: p = 0.757; ##FIG##3##Fig. 4c##, contralateral: p = 0.882; ##SUPPL##0##Fig. S4d##, ipsilateral: p = 0.098).</p>", "<p id=\"P19\">However, the slope of this fitted correlation for dmPFC was stronger for the late epoch than early epoch, specifically for gaze fixations in the contralateral hemifield (##FIG##3##Fig. 4d##; p = 0.015, permutation test; ##SUPPL##0##Fig. S4e##, both hemifields combined: p = 0.131; ##SUPPL##0##Fig. S4f##, ipsilateral: p = 0.455). These results suggested that microstimulations of dmPFC, but not OFC or ACCg, altered how social gaze exchanges were modulated by the location of the stimulated monkey’s gaze fixations in space on a longer timescale. Specifically, the slope of this examined correlation on average was positive in both early and late epochs for gaze fixations in both hemifields for dmPFC, indicating that as the stimulated monkey fixated closer around the partner monkey (smaller social gaze distance), his gaze behaviors were more likely to be led by the partner (lower relative causal strength). Intriguingly, as the number of dmPFC microstimulations accumulated within an experiment day, this effect became larger (greater slope for late epoch compared to early epoch). Microstimulations of dmPFC therefore altered how social gaze exchanges were modulated by the location of one’s gaze fixations on a relatively long timescale. These effects were also not driven by low-level properties of saccades (##SUPPL##0##Fig. S3##, all p > 0.16).</p>" ]	[ "<title>Discussion</title>", "<p id=\"P20\">In primates, the gaze serves a critical function as they navigate through their social environment. Our previous electrophysiological work revealed that interactive social gaze variables are widely represented in the primate prefrontal-amygdala networks. In addition to the amygdala, a substantial proportion of neurons in OFC, dmPFC, and ACCg represent key signatures of social gaze interaction. Notably, spiking activity of many neurons in these prefrontal regions parametrically tracks one’s own gaze relative to another agent (‘social gaze distance’ also examined in the current paper) as well as other agent’s gaze relative to oneself<sup>##REF##35545090##8##</sup>. Here, we report that weak, real-time, closed-loop microstimulations of OFC modulate dynamic social attention. In the spatial dimension, these microstimulations resulted in clustered subsequent gaze fixations around another agent (reduced social gaze distance), an effect more pronounced for gaze fixations in the contralateral hemifield. In the temporal dimension, these microstimulations reduced the inter-looking interval for attending to another agent and the latency to reciprocate other’s directed gaze. These effects were found to be occurring on a relatively short timescale as OFC microstimulations did not change how long-term social gaze exchanges were modulated by the location of one’s own gaze fixations, unlike what we found with dmPFC microstimulations.</p>", "<p id=\"P21\">Widespread representations of social gaze variables in OFC, dmPFC, and ACCg neurons<sup>##REF##35545090##8##</sup> are likely shaped by their common anatomical connectivity patterns with other brain regions in the social brain<sup>##REF##33169032##5##</sup>. The three prefrontal regions, albeit to different degrees, are bidirectionally connected to the amygdala<sup>##REF##3624555##18##–##REF##8847421##20##</sup>, often referred to as the hub of social cognition<sup>##REF##25152530##21##</sup> and implicated in both face and gaze processing<sup>##REF##35545090##8##, ##REF##17093126##22##–##REF##30012600##24##</sup>. Moreover, the orbitofrontal and medial prefrontal cortices, including the regions examined in this study, receive innervation from subregions in the inferior temporal cortex (IT) and the superior temporal sulcus (STS)<sup>##REF##2925903##25##, ##REF##2792241##26##</sup>. These anatomical connections are likely to be functionally important for social gaze processing. The primate IT contains multiple face patches<sup>##UREF##4##27##, ##REF##35263138##28##</sup> and the middle STS is believed to be a potential macaque homolog of the human temporal parietal junction, implicated in mentalizing in humans<sup>##REF##12689373##29##</sup>, based on both functional connectivity<sup>##UREF##5##30##</sup> and neural recoding<sup>##REF##33230321##31##</sup>. Face processing and mentalizing functions might be closely intertwined with the representations of social gaze variables. In this notion, it is possible that the interactive social gaze signals in OFC, dmPFC, and ACCg are subserving more abstract social cognitive functions that are functionally shared with social gaze processing.</p>", "<p id=\"P22\">During social gaze interaction, individuals constantly evaluate objects and other individuals in the environment and make momentary decisions to look toward or away from them. OFC neurons encode a wide range of outcome-related variables, such as expected value, choice value, reward prediction error, and choice and outcome history<sup>##REF##16633341##32##–##REF##33139951##34##</sup> that dynamically contribute to value and decision computations in OFC populations<sup>##REF##27273768##35##–##REF##37932464##37##</sup>. These decision computations in OFC might facilitate the encoding of moment-to-moment value associated with other’s gaze and looking at other’s eyes for guiding adaptive behaviors. Indeed, value coding in OFC neurons is known to be modulated by gaze location. When monkeys freely viewed reward-predicting cues presented on a monitor, value signals in many OFC cells associated with the cues increased when monkeys fixated closer to the cues<sup>##REF##27263972##14##</sup>, suggesting a crucial role of OFC in both valuation and attention, two components foundational also to social gaze interaction. It has also been shown that in the OFC, weak microstimulations, similar to the ones used here, enhanced value computations during decision-making<sup>##REF##33139951##34##</sup>. Taken together, this might suggest a possible mechanism for the observed effects of OFC microstimulations. We hypothesize that weak, closed-loop microstimulations of OFC would increase the value signals associated with certain social gaze events and therefore enhance subsequent social attention.</p>", "<p id=\"P23\">It has been long theorized that looking at the face or the eyes of a conspecific has adaptive value<sup>##REF##10940436##38##</sup>. Indeed, value and social gaze variables have been shown to be representationally shared in the primate amygdala<sup>##REF##32968281##39##</sup>, which is strongly reciprocally connected to OFC<sup>##REF##8847421##20##</sup>. Our findings might reflect a synergistic effect of intrinsic value of social stimuli and microstimulation. Face and eyes are highly valued and readily capture attention. Weak microstimulations could further amplify the value signals in OFC<sup>##REF##33139951##34##</sup> associated with looking at a social agent, thereby driving monkeys to fixate closer to and attend faster to the agent. Importantly, the effects of OFC microstimulations we observed were specific to the social context and not observed in the non-social control condition. This is likely because the <italic toggle=\"yes\">RDM stimulus</italic> does not have any intrinsic or adaptive value in our experimental context, although it is visually salient and captures attention. We anticipate that OFC microstimulations would also enhance attention to certain non-social objects especially when they hold adaptive value, such as bananas, or learned cues that predict reward<sup>##REF##27263972##14##</sup> or that guide gaze-following<sup>##REF##31964825##11##</sup>.</p>", "<p id=\"P24\">Studies that have causally manipulated activity in the primate brain have provided critical insights into brain functions. Microstimulations of the face patches in IT revealed their interconnectivity and distorted face perception<sup>##REF##28288127##40##</sup>. Microstimulations of a gaze-following patch in the posterior STS impaired gaze-following behaviors when monkeys viewed images with different gaze directions<sup>##REF##31964825##11##, ##REF##37211234##12##</sup>. In the decision-making literature, microstimulations of OFC were shown to bias choices<sup>##REF##33139951##34##</sup>. Further, closed-loop microstimulations of OFC delivered contingently upon theta frequency oscillation were shown to disrupt this synchronization and impair reward-guided learning<sup>##REF##32160515##41##</sup>. In the current work, closed-loop microstimulations of OFC delivered upon specific social gaze events enhanced dynamic social attention.</p>", "<p id=\"P25\">Intriguingly, we found that microstimulations of dmPFC altered how social gaze exchanges were modulated by the location of one’s gaze fixations on a longer timescale. The closer the stimulated monkey looked near the partner monkey, the more likely his gaze behaviors were led by the partner. Based on the hypothesized role of dmPFC in mentalizing and representing social information about self and other<sup>##REF##22864610##42##–##REF##34672743##44##</sup>, this finding is consistent with the possibility that dmPFC microstimulations might have modulated the computations for understanding the intention of other’s gaze, which likely requires building an internal model of a social agent over multiple interactive bouts on a longer timescale. On the other hand, we observed neither short-term nor long-term microstimulation effect in ACCg. Given that social gaze signals are widely found in OFC, dmPFC, and ACCg<sup>##REF##35545090##8##</sup>, such dissociated functional consequences among the three areas from our closed-loop microstimulation protocol suggest potential differentiations on how neuromodulations affect different prefrontal populations. However, the current study cannot rule out if evoking behavioral changes in different neural tissues may require tailored stimulation protocols.</p>", "<p id=\"P26\">Future studies applying different stimulation protocols (non-closed-loop or closed-loop stimulations contingently upon a different gaze behavior of the stimulated monkey or specific gaze behavior of the social partner) might further reveal new insights into how the prefrontal cortex is involved in social gaze interaction. It is also critical to explore the stimulation parameter space as positive effects of different brain areas could depend on the choice of parameters<sup>##REF##33139951##34##</sup>. Moreover, in the current study, we used the same partner monkey who was familiar to the two stimulated monkeys. Social gaze dynamics have been shown to be influenced by dominance and familiarity<sup>##REF##27486105##15##</sup>. Further, the orbitofrontal and medial prefrontal networks are differentially connected to a specific region in the temporal pole<sup>##REF##12975812##45##</sup> that processes personally familiar faces<sup>##REF##28798130##46##</sup>. Therefore, it would be informative to test if the observed effects of OFC microstimulations are modulated by social context.</p>", "<p id=\"P27\">During ongoing gaze exchanges, it is critical to dynamically increase or decrease attention to another social agent following specific social gaze events. Such behavioral contingency or adaptability is essential in guiding social interaction. Moreover, given the importance of social gaze in multitudes of social behaviors in primate species, social gaze representations in the brain may be tightly coupled to action or outcome related information about other social agents that are critical for observational learning and social decision-making<sup>##REF##22864610##42##, ##REF##30224807##43##, ##UREF##6##47##, ##REF##23263442##48##</sup>. Importantly, atypical visual attention and social gaze patterns are frequently associated with social disorders, such as autism spectrum disorder (ASD)<sup>##REF##12215080##49##–##REF##26593094##51##</sup>. Our findings also have a therapeutic implication for using closed-loop microstimulation protocols – a ‘social brain interface’ – to modulate atypical social attention and social gaze behaviors in ASD. Stimulating OFC during an eye looking training session may help improve social attention, and stimulating dmPFC could potentially enhance responsiveness in social gaze exchanges on a longer timescale. Future investigations utilizing a noninvasive closed-loop stimulation protocol will help develop therapies to mitigate atypical social gaze behaviors.</p>" ]	[]	[ "<p id=\"P1\">Contributed equally</p>", "<p id=\"P2\">Author Contributions</p>", "<p id=\"P3\">S.W.C.C., S.F., and O.D.M. designed the study and wrote the paper. S.F., A.R.N., and O.D.M. performed the experiments. S.F., N.A.F., O.D.M., and S.W.C.C. analyzed the data.</p>", "<p id=\"P4\">The prefrontal cortex is extensively involved in social exchange. During dyadic gaze interaction, multiple prefrontal areas exhibit neuronal encoding of social gaze events and context-specific mutual eye contact, supported by a widespread neural mechanism of social gaze monitoring. To explore causal manipulation of real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events to three prefrontal areas in monkeys. Microstimulations of orbitofrontal cortex (OFC), but not dorsomedial prefrontal or anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing distance of one’s gaze fixations relative to partner monkey’s eyes. In the temporal dimension, microstimulations of OFC reduced the inter-looking interval for attending to another agent and the latency to reciprocate other’s directed gaze. These findings demonstrate that primate OFC serves as a functionally accessible node in controlling dynamic social attention and suggest its potential for a therapeutic brain interface.</p>" ]	[ "<title>Supplementary Material</title>" ]	[ "<title>Acknowledgments</title>", "<p id=\"P42\">This work was supported by the National Institute of Mental Health (R01MH110750; R01MH120081; R01 MH128190).</p>", "<title>Data availability</title>", "<p id=\"P41\">Behavioral and neural data presented in this paper will be available at the DANDI archive (changlabneuro).</p>" ]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1.</label><caption><title>Experimental setup and microstimulation design.</title><p id=\"P47\">(<bold>a</bold>) Experimental paradigm for studying the functional role of the primate prefrontal cortex in naturalistic social gaze interaction. Left, live social gaze condition where each real-time microstimulation was selectively triggered by M1 fixating on M2’s <italic toggle=\"yes\">Eyes</italic> for at least 30 msec with a probability of 50% (half microstimulation trials and half sham trials). Right, non-social gaze control condition where each real-time microstimulation was selectively triggered by M1 fixating for at least 30 msec on the <italic toggle=\"yes\">random dot motion (RDM) stimulus</italic> (same location and size as <italic toggle=\"yes\">Eyes</italic> ROI in the live social gaze condition) presented on a mini monitor placed in front of M2’s face. (<bold>b</bold>) Anatomical localizations of microstimulation sites in OFC, dmPFC, and ACCg from monkey L (n = 15 sites per area) and monkey T (n = 12 sites per area). (<bold>c</bold>) Diagram of the closed-loop microstimulation design. To avoid overstimulation of brain tissue, any two consecutive trials (including both microstimulations and shams) had to be at least 5 sec apart, and for every four trials, two microstimulations and two shams were randomly assigned. (<bold>d</bold>) Three examples of 30-sec experiment segments from the live social gaze condition. Each example, from top to bottom, shows M1’s <italic toggle=\"yes\">Eyes</italic> (blue) and <italic toggle=\"yes\">non-eye Face</italic> (pink) events (other fixations in space are not shown here), shams (gray) and microstimulations (red) triggered by looking at partner’s <italic toggle=\"yes\">Eyes</italic>, raw signals recorded, and multi-unit activity. (<bold>e</bold>) Total number of microstimulations (red) and shams (gray) received per day in the live social gaze condition for monkey L (left) and monkey T (right). Data points connected with lines indicate measurements from the same day. The total number of microstimulations and shams per day was comparable across the three stimulated regions and comparable between the two animals (all p > 0.90). n.s., not significant, Wilcoxon rank sum, two-sided, FDR-corrected. Statistics for shams are not shown in the figure; none of the comparisons is significant.</p></caption></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2.</label><caption><title>Microstimulation effects on dynamic social attention in the spatial dimension.</title><p id=\"P48\">(<bold>a</bold>) Microstimulation effect (difference between microstimulation and sham trial types) on the fixation density map of space surrounding partner monkey’s <italic toggle=\"yes\">Eyes</italic> (blue rectangle) and <italic toggle=\"yes\">whole Face</italic> (pink rectangle) for OFC, dmPFC, and ACCg (n = 27 sites per area). (<bold>b</bold>) Diagrams illustrating social and non-social gaze distances. For each microstimulation or sham, we calculated the average distance of all M1 fixations in space during the analyzed post-gaze epoch (within 1.5 sec after the onset of a microstimulation or sham) relative to M2’s <italic toggle=\"yes\">Eyes</italic> in the live social gaze condition (social gaze distance, left) and relative to <italic toggle=\"yes\">RDM stimulus</italic> in the non-social gaze control condition (non-social gaze distance, right). (<bold>c</bold>) Average social gaze distance per day (in visual degrees) for sham and microstimulation trial types separately for OFC, dmPFC, and ACCg. Data points in the same color connected with lines indicate measurements from the same day. Compared to shams, microstimulations of OFC significantly decreased social gaze distance during the post-gaze epoch (p < 0.001 for both monkeys combined; this effect was also present and significant in each monkey: p = 0.008 for monkey L and p = 0.002 for monkey T). *** p < 0.001, n.s., not significant, Wilcoxon signed rank, two-sided. (<bold>d</bold>) Diagrams illustrating the <italic toggle=\"yes\">contralateral</italic> hemifield (opposite visual field of the stimulated brain hemisphere) and the <italic toggle=\"yes\">ipsilateral</italic> hemifield (same visual field as the stimulated brain hemisphere) in the live social gaze condition. (<bold>e</bold>) Microstimulation effect on social gaze distance for fixations in the <italic toggle=\"yes\">contralateral</italic> hemifield and <italic toggle=\"yes\">ipsilateral</italic> hemifield separately for OFC, dmPFC, and ACCg. A negative value here (difference between microstimulation and sham trial types) indicates that microstimulations, compared to shams, resulted in more clustered subsequent gaze fixations around partner monkey’s <italic toggle=\"yes\">Eyes</italic>. Data points in the same color connected with lines indicate measurements from the same day. The observed stimulation effect of OFC was more pronounced for gaze fixations in the contralateral visual field of the stimulated hemisphere (contralateral: p < 0.001 for both monkeys combined; p = 0.015 for monkey L and p = 0.012 for monkey T; ipsilateral: p = 0.068 for both combined; p = 0.208 for L and p = 0.233 for T; both hemifields combined: p < 0.001 for both combined; p = 0.008 for L and p = 0.002. for T). * p < 0.05, *** p < 0.001, n.s., not significant, Wilcoxon signed rank, two-sided. (<bold>f–h</bold>) Same format as (<bold>c–e</bold>) but for the non-social gaze control condition. n.s., not significant, Wilcoxon signed rank, two-sided.</p></caption></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3.</label><caption><title>Microstimulation effects on dynamic social attention in the temporal dimension.</title><p id=\"P49\">(<bold>a</bold>) Diagram illustrating inter-looking interval, the latency of M1 to look back at M2’s <italic toggle=\"yes\">whole Face</italic> during 5 sec after the onset of a microstimulation or sham. (<bold>b</bold>) Average inter-looking interval per day for sham and microstimulation trial types separately for OFC, dmPFC, and ACCg. Data points in the same color connected with lines indicate measurements from the same day. Microstimulations of OFC decreased inter-looking interval (p = 0.035 for both monkeys combined; p = 0.188 for monkey L and p = 0.092 for monkey T). * p < 0.05, n.s., not significant, Wilcoxon signed rank, two-sided. (<bold>c</bold>) Diagram illustrating reciprocation latency, the latency of M1 to gaze back at M2’s <italic toggle=\"yes\">whole Face</italic> after M2 looked at M1’s <italic toggle=\"yes\">whole Face</italic> during 5 sec after the onset of a microstimulation or sham. (<bold>d</bold>) Distribution of reciprocation latency for sham (gray) and microstimulation (red) trial types separately for OFC, dmPFC, and ACCg. Trial-level data were collapsed across all days for each stimulated brain region. Microstimulations of OFC decreased reciprocation latency (p = 0.011 for both combined; p = 0.074 for L and p = 0.079 for T). * p < 0.05, n.s., not significant, Wilcoxon rank sum, two-sided.</p></caption></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4.</label><caption><title>Longer timescale microstimulation effects on social gaze exchanges.</title><p id=\"P50\">(<bold>a</bold>) Diagram for M1 to M2 social gaze directionality when relative causal strength was greater than 0.5. (<bold>b</bold>) Diagram for M2 to M1 social gaze directionality when relative causal strength was less than 0.5. (<bold>c</bold>) Slope of correlation between social gaze distance in the contralateral hemifield and relative causal strength for microstimulations in the early epoch and late epoch separately for OFC, dmPFC, and ACCg. Data points in the same color connected with lines indicate measurements from the same day. For dmPFC, the slope of this fitted correlation was stronger for the late epoch than early epoch (p = 0.054 for both monkeys combined; p = 0.048 for monkey L and p = 0.625 for monkey T). * p » 0.05, n.s., not significant, Wilcoxon signed rank, two-sided. (<bold>d</bold>) Microstimulation effect (difference between late and early time epochs) on the slope of examined correlation in (<bold>c</bold>). Red lines show the real median slope difference between late epoch and early epoch, whereas gray bars show the shuffled null distribution of slope difference medians (shuffling time epoch label 1,000 times for each day). The slope of this fitted correlation was stronger for the late epoch than early epoch for dmPFC when using gaze fixations in the contralateral hemifield (p = 0.015 for both combined; p = 0.038 for L and p = 0.068 for T). * p < 0.05, n.s., not significant, permutation test.</p></caption></fig>" ]	[]	[ "<inline-formula><mml:math id=\"M1\" display=\"inline\"><mml:mrow><mml:mfrac><mml:mn>7</mml:mn><mml:mrow><mml:mn>24</mml:mn></mml:mrow></mml:mfrac><mml:mo>×</mml:mo><mml:mo stretchy=\"false\">(</mml:mo><mml:mtext>width of the face</mml:mtext><mml:mo>−</mml:mo><mml:mtext>distance between the two eyes</mml:mtext><mml:mo stretchy=\"false\">)</mml:mo></mml:mrow></mml:math></inline-formula>" ]	[]	[]	[]	[]	[ "<supplementary-material id=\"SD1\" position=\"float\" content-type=\"local-data\"><label>1</label></supplementary-material>" ]	[ "<fn-group><fn fn-type=\"COI-statement\" id=\"FN3\"><p id=\"P43\">Declaration of Interests</p><p id=\"P44\">The authors declare no competing interests.</p></fn><fn id=\"FN4\"><p id=\"P45\">Code availability</p><p id=\"P46\">Behavioral and neural data analysis codes central to this paper are available at <ext-link xlink:href=\"https://github.com/changlabneuro/TBD\" ext-link-type=\"uri\">https://github.com/changlabneuro/TBD</ext-link>.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"nihpp-2023.12.18.572176v1-f0001\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.18.572176v1-f0002\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.18.572176v1-f0003\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.18.572176v1-f0004\" position=\"float\"/>" ]	[ "<media xlink:href=\"NIHPP2023.12.18.572176V1-supplement-1.pdf\" id=\"d64e1150\" position=\"anchor\"/>" ]	[{"label": ["1"], "surname": ["Passingham", "Wise"], "given-names": ["R.E.", "S.P."], "source": ["The Neurobiology of the Prefrontal Cortex: Anatomy, Evolution, and the Origin of Insight"], "publisher-name": ["Oxford University Press"], "year": ["2012"]}, {"label": ["2"], "surname": ["Chang"], "given-names": ["S.W.C."], "article-title": ["Neuroethology of primate social behavior"], "source": ["Proceedings of the National Academy of Sciences"], "volume": ["110"], "comment": ["10387210394"], "year": ["2013"]}, {"label": ["6"], "surname": ["Mitani", "Call", "Kappeler", "Palombit", "Silk"], "given-names": ["J.C.", "J.", "P.M.", "R.A.", "J.B."], "source": ["The evolution of primate societies"], "publisher-name": ["University of Chicago Press"], "year": ["2012"]}, {"label": ["17"], "surname": ["Yang", "Peng", "Huang"], "given-names": ["A.C.", "C.-K.", "N.E."], "article-title": ["Causal decomposition in the mutual causation system"], "source": ["Nature Communications"], "volume": ["9"], "fpage": ["3378"], "year": ["2018"]}, {"label": ["27"], "surname": ["Tsao", "Moeller", "Freiwald"], "given-names": ["D.Y.", "S.", "W.A."], "article-title": ["Comparing face patch systems in macaques and humans"], "source": ["Proceedings of the National Academy of Sciences"], "volume": ["105"], "fpage": ["19514"], "lpage": ["19519"], "year": ["2008"]}, {"label": ["30"], "surname": ["Mars", "Sallet", "Neubert", "Rushworth"], "given-names": ["R.B.", "J.", "F.-X.", "M.F.S."], "article-title": ["Connectivity profiles reveal the relationship between brain areas for social cognition in human and monkey temporoparietal cortex"], "source": ["Proceedings of the National Academy of Sciences"], "volume": ["110"], "fpage": ["10806"], "lpage": ["10811"], "year": ["2013"]}, {"label": ["47"], "surname": ["Azzi", "Sirigu", "Duhamel"], "given-names": ["J.C.B.", "A.", "J.-R."], "article-title": ["Modulation of value representation by social context in the primate orbitofrontal cortex"], "source": ["Proceedings of the National Academy of Sciences"], "volume": ["109"], "fpage": ["2126"], "lpage": ["2131"], "year": ["2012"]}, {"label": ["52"], "surname": ["Paxinos", "Huang", "Toga"], "given-names": ["G.", "X.-F.", "A."], "article-title": ["The Rhesus Monkey Brain in Stereotaxic Coordinates"], "source": ["Sat Lake City, Academic Press, USA"], "volume": ["1"], "year": ["2000"]}, {"label": ["53"], "surname": ["Krassanakis", "Filippakopoulou", "Nakos"], "given-names": ["V.", "V.", "B."], "article-title": ["EyeMMV toolbox: An eye movement post-analysis tool based on a two-step spatial dispersion threshold for fixation identification"], "source": ["Journal of Eye Movement Research"], "volume": ["7"], "year": ["2014"]}, {"label": ["54"], "surname": ["Otero-Millan", "Castro", "Macknik", "Martinez-Conde"], "given-names": ["J.", "J.L.A.", "S.L.", "S."], "article-title": ["Unsupervised clustering method to detect microsaccades"], "source": ["Journal of Vision"], "volume": ["14"], "fpage": ["18"], "lpage": ["18"], "year": ["2014"]}]	{ "acronym": [], "definition": [] }	54	CC BY-ND	no	2024-01-13 00:14:49	bioRxiv. 2023 Dec 18;:2023.12.18.572176	oa_package/cb/08/PMC10769221.tar.gz
PMC10769225	38187585	[]	[ "<title>Materials and methods</title>", "<title>Yeast strains, plasmids, and growth conditions</title>", "<p id=\"P34\">All <italic toggle=\"yes\">Saccharomyces cerevisiae</italic> strains and plasmids used herein are listed in ##SUPPL##0##Supplementary Tables S2## and ##SUPPL##0##S3## respectively. <italic toggle=\"yes\">S. cerevisiae</italic> cells were grown in either liquid YPD (2% glucose, 2% peptone, 1% yeast extract), YPGly (2% glycerol, 2% peptone, 1% yeast extract), synthetic complete medium (SC) [2% glucose, 0.7% yeast nitrogen base (YNB) and Drop-Out complete (Kaiser, Formedium)] or SGal (2% galactose, 0.7% YNB and Drop-Out complete).</p>", "<p id=\"P35\">For protein visualization under the microscope, a PCR-based genomic tagging technique was employed to tag the genomic full length <italic toggle=\"yes\">TIM50</italic>, <italic toggle=\"yes\">TOM70</italic>, <italic toggle=\"yes\">CYC1</italic>, <italic toggle=\"yes\">YTA12</italic>, <italic toggle=\"yes\">ILV2</italic> and <italic toggle=\"yes\">PDR5</italic> ORFs with GFP or the <italic toggle=\"yes\">HSP104</italic> ORF with RFP. The plasmids pFA6a-GFP-HIS3MX (##REF##9717241##61##) and pYM43-Redstar2-clonNAT were used as a template for PCR reaction using primers listed in ##SUPPL##0##Table S4##. The plasmid pFA6a-3HA-HIS3MX (Longtine et al, 1998) was used to tag the genomic full length <italic toggle=\"yes\">TIM50</italic> using primers listed in ##SUPPL##0##Table S4##. The resulting cassettes were transformed in the corresponding strains following the lithium acetate-based method (##REF##1561104##62##). All the integrations were confirmed by genomic DNA conventional PCR.</p>", "<p id=\"P36\">Plasmid pRS406-GPDp-Su9-mCherry-URA3 was integrated in the corresponding strains for expression of Su9 (subunit 9 of the F0 ATPase) fused to mCherry and subsequent visualization of mitochondrial network. To constitutively visualize <italic toggle=\"yes\">TIM50</italic> single mRNAs, plasmids pRS405-CYC1p-MS2–4xGFP-LEU2 and plasmid pRS403-TIM50p-TIM50-flagiRFP-TIM50ter-MS2tag-HIS3MX (##REF##32762840##10##) were integrated in wild-type and <italic toggle=\"yes\">tif51A-1</italic> strains.</p>", "<p id=\"P37\">Plasmid pGAL-FLAG-TIM50-GFP-URA3 was constructed from the plasmid pYES2-pGAL-FLAG-htt25QP-GFP-URA3 (##REF##28900136##63##). First, the yeast <italic toggle=\"yes\">TIM50</italic> ORF was obtained by PCR using primers listed in ##SUPPL##0##Table S4##. Then, plasmid pYES2-pGAL-FLAG-htt25QP-GFP-URA3 was linearized by restriction enzyme XagI (Thermo Fisher Scientific) to replace huntingtin (htt) gene by <italic toggle=\"yes\">TIM50</italic> gene by homologous recombination. The resulting plasmid was transformed in the corresponding strains and transformants were selected in SC medium lacking uracil. To generate the strains harbouring the deletion of the seven consecutive prolines from the <italic toggle=\"yes\">TIM50</italic> gene sequence (Tim50Pro), the C-terminal TIM50-GFP sequence was amplified from genomic DNA of the strain PAY1078 using primers listed in ##SUPPL##0##Table S4##. The use of these primers resulted in the deletion of nucleotides 541–561 in <italic toggle=\"yes\">TIM50</italic>, which encode for the 7 prolines stretch of the Tim50 protein. The resulting PCR product was transformed in wild-type and <italic toggle=\"yes\">tif51A-1</italic> strains as previously described. All the integrations and deletions were confirmed by genomic DNA conventional PCR.</p>", "<p id=\"P38\">Nanoluciferase reporter constructs expressing different versions of the <italic toggle=\"yes\">TIM50</italic> gene or other mitoproteins under the control of a tetracycline-inducible operon (tetO7) were generated by cloning the corresponding ORF in the plasmid ZP446, derived from pAG306 vector. ZP446 backbone was amplified by PCR using oligos listed in ##SUPPL##0##Table S4##. Parental plasmid was digested by restriction enzyme DpnI (New England Biolabs) and linearized plasmid was isolated by gel purification (Zymo Research). The CDS fragments for cloning were amplified by conventional PCR from wild-type genomic DNA using oligos listed in ##SUPPL##0##Table S4##. After PCR product purification (Zymo Research), the fragments of interest were inserted into linearized ZP446 using Gibson Assembly. The resulting nanoluciferase constructs were linearized by restriction enzyme NotI (New England Biolabs) and integrated into the genome of the wild-type and <italic toggle=\"yes\">TIM50</italic> cells by homologous recombination. All the Tim50-nLuc plasmids used in this study are listed in ##SUPPL##0##Table S3##.</p>", "<p id=\"P39\">Experimental assays were performed with cells exponentially grown for at least four generations until required OD600 at the corresponding temperature. Temperature-sensitive strains were grown at the permissive temperature of 25°C until required OD600 and transferred to the non-permissive temperature of 37°C or 41°C for 4 h for complete depletion of eIF5A.</p>", "<title>Proteomic analysis</title>", "<p id=\"P40\">For the proteomic analysis three independent cultures of wild-type (BY4741), <italic toggle=\"yes\">tif51A-1</italic> and <italic toggle=\"yes\">tif51A-3</italic> were grown exponentially in YPD at 25°C and then incubated at 41°C for 4h. Proteins were extracted as previously described (##REF##24923804##38##) and analysed in the SCSIE (Servei Central de Suport a la Investigació Experimental; Universitat de València). Protein samples (about 20 µg of protein) were digested with 500 ng of trypsin (Promega) and peptides were analysed by an Ekspert nanoLC 42 nanoflow system (Eksigent Technologies, ABSCIEX) coupled to a nanoESI qQTOF MS (6600plus TripleTOF, ABSCIEX). The tripleTOF was operated in SWATH mode. 5 µl of each sample were loaded onto a trap column (3 µ C18-CL 120 ˘Α, 350 µm x 0.5 mm; Eksigent) and desalted with 0.1% TFA at 5 µl/min during 5 min. The peptides were loaded onto an analytical column (3 µ C18-CL 120 ˘Α, 0.075 × 150 mm; Eksigent) equilibrated in 5% acetonitrile 0.1% FA (formic acid). Peptide elution was carried out with a linear gradient of 7 to 40% B in 45 min (A: 0.1% FA; B: ACN, 0.1% FA) for at a flow rate of 300 nl/min. Peptides were analysed in a mass spectrometer nanoESI qQTOF (6600plus TripleTOF, ABSCIEX) using positive electrospray ionization (ESI) at an ion source temperature of 200°C. The tripleTOF was operated in swath mode, in which a 0.050-s TOF MS scan from 350–1250 m/z was performed, followed by 0.080-s product ion scans from 350–1250 m/z. 100 variable windows from 400 to 1250 m/z were acquired throughout the experiment. The total cycle time was 2.79 secs.</p>", "<p id=\"P41\">The processing settings used for the peptide selection were: detect at least 20 peptides per protein, 6 or more transitions per peptide, 95% peptide confidence threshold and 1% false discovery rate threshold; modified peptides were excluded. Only proteins that met these criteria and were detected in all strains were analysed in this study.</p>", "<p id=\"P42\">To analyse the proteomic data, protein areas were normalized by the total sum of the areas of all the quantified proteins. To obtain the GO terms overrepresented in the different groups of proteins, the ratio 41°C/25°C was calculated for each replicate and strain. Then each 41°C/25°C ratio of each temperature-sensitive mutant was divided by the ratio 41°C/25°C of wild-type strain, so that those with a value greater than 1 are up-regulated in the temperature-sensitive mutant with respect to wild-type, while those with a value less than 1 are down-regulated. Statistical significance was measured by Student’s t-test; only statistically significant proteins (p-value Student’s t-test < 0.05) were analysed.</p>", "<title>Nanoluciferase reporter assays</title>", "<p id=\"P43\">Nanoluciferase synthesis assays were performed as detailed in (##REF##35491906##64##). Briefly, cells were grown at 25°C in YPD media to an exponential OD600 0.4 and then transferred to 37°C for 4 h. Doxycycline was added to a final concentration of 10 µg/mL to induce the expression of the nanoluciferase reporter of the pAG306 series vectors and pre-incubated for 5 min at room temperature. The nanoluciferase activity was measured using furimazine as the nanoluciferase highly specific substrate. A 90 µl volume of each culture and 10 µl of the furimazine (1 in 200 dilution; Promega) were incubated in a Cellstar non-transparent white 96-well microplate for one h and the bioluminescence intensity was monitored with a Tecan Infinite 200 PRO plate reader every 30 s. All the bioluminescence measurements were acquired at 460 nm, the peak emission wavelength of nanoluciferase. Obtained data were linearized using Schleif plots to estimate the minimum reaction time required for complete translation (##REF##4577756##50##). The reaction time of the nLuc reporter alone was subtracted from the reaction time of the corresponding Tim50-nLuc fusion to calculate the time required for translating the different Tim50 sequence versions. At least five biological replicates of each Tim50-nLuc construct were analysed.</p>", "<title>RT-qPCR analysis</title>", "<p id=\"P44\">For the analysis of the mRNA levels, total RNAs were isolated from yeast cells following the phenol:chloroform protocol. Briefly, a volume of an exponential phase culture corresponding to 10 OD600 units was harvested and flash frozen. Cells were resuspended in 500 µL of cold LETS buffer (LiCl 0.1 M, EDTA pH 8.0 10 mM, Tris-HCl pH 7.4 10 mM, SDS 0.2%) and transferred into a screw-cap tube already containing 500 µL of sterile glass beads and 500 µL of phenol:chloroform (5:1). Then, cells were broken using the Precellys 24 tissue homogenizer (Bertin Technologies) and centrifugated. The supernatant was transferred into a new tube containing 500 µL of phenol:chloroform (5:1) and then to a tube containing 500 µL of chloroform:isoamyl alcohol (25:1). RNA from the top phase was precipitated and finally dissolved in water for later quantification and quality control with Nanodrop device (Thermo Fisher Scientific).</p>", "<p id=\"P45\">The reverse transcription and quantitative PCR reactions were performed as detailed in (##REF##23620734##65##). Briefly, 2.5 µg of the total DNAse-I (Roche) treated RNA were retrotranscribed using an oligo d(T)18 with Maxima Reverse Transcriptase (Thermo Fisher Scientific). cDNA was labelled with SYBR Pre-mix Ex Taq (Tli RNase H Plus, Takara) and the Cq values were obtained from the CFX96 TouchTM Real-Time PCR Detection System (BioRad). Endogenous <italic toggle=\"yes\">ACT1</italic> mRNA levels were used for normalization. At least three biological replicates of each sample were analysed, and the specific primers designed to amplify gene fragments of interest are listed in ##SUPPL##0##Table S4##.</p>", "<title>Western blotting</title>", "<p id=\"P46\">For yeast protein content analysis by western blotting we followed the protocol described in (##UREF##13##66##). Briefly, a cell culture volume corresponding to 10 OD600 units was harvested by centrifugation. For protein extraction, cell pellets were washed and resuspended in 200 µL of NaOH 0.2M and incubated at room temperature for 5 min for subsequent centrifugation at 12000 rpm for 1 min. Samples were then resuspended in 100 µL of 2X-SDS protein loading buffer (24 mM Tris-HCl pH 6.8, 10% glycerol, 0.8% SDS, 5.76 mM β-mercaptoethanol, 0.04% bromophenol blue) and boiled at 95°C for 5 min. Next, lysates were centrifuged at 3000 rpm for 10 min at 4°C to remove cell debris and insoluble proteins, and supernatants were transferred into new tubes and stored at −20°C. Total protein content in the extract was quantified by an OD280 estimation in a Nanodrop device (Thermo Fisher Scientific) to load equal protein amounts per sample into the SDS-PAGE gel. The acrylamide percentage of the used SDS-PAGE depended on the molecular weight of the protein of interest. SDS-PAGE and Western blotting were performed using standard procedures (BioRad). Blotting membranes were blocked with 5% skimmed milk in TBS-T (150 mM NaCl, 20 mM Tris, 0.1% Tween20, pH 7.6) for 1 h at room temperature and incubated with primary antibodies overnight at 4°C against either HA (1:5000, Roche 12013819001), FLAG (1:1000, Sigma F1804), Por1 (1:1000, Abcam ab110326), Hsp60 (1:1000, QED-BIOSCIENCE 11101) or glyceraldehyde-6-phosphate dehydrogenase (rabbit polyclonal anti-G6PDH antibody, 1:10000, Sigma A9521). Bound antibodies were detected using the appropriate horseradish peroxidase-conjugated secondary antibodies (1:10000, Promega). Chemiluminiscent signals were detected with an ECL Prime Western blotting detection kit (GE Healthcare) and digitally analysed using ImageQuant LAS 4000 software (GE Healthcare). Intensity of bands was normalized against G6PDH bands. At least three biological replicates of each sample were analysed.</p>", "<title>Fluorescence microscopy and analysis</title>", "<p id=\"P47\">Yeast cells were grown to a post-diauxic phase in SGal medium, centrifugated, washed and subjected to standard fluorescence and phase contrast microscopy. For mitochondrial protein localization experiments, cells were imaged using an Eclipse Ti-E microscope (Nikon) with an oil-immersion x63 objective. Imaging was controlled using NIS-Elements software (Nikon). For mitochondrial aggregates co-localization experiments and mitochondrial membrane potential measurements, fluorescence images were acquired using an Axio Imager Z1 fluorescence motorized microscope equipped with a Plan Apochratic x63/1.4 oil-immersion objective and a 100W mercury lamp (Carl Zeiss, Germany). Images were recorded with an AxioCam MRm digital camera (Carl Zeiss, Germany). The following excitation and emission wavelengths were used: DAPI (excitation 359 nm; emission 457 nm), GFP (excitation 475 nm; emission 509 nm), MitoTracker Red (excitation 578 nm; emission 600 nm), RFP (excitation 555 nm; emission 583 nm), mCherry (excitation 587 nm; emission 610 nm) and Nile Red (excitation 460 nm; emission 582 nm). The same exposure times were used to acquire all images. All the imaging analysis was performed on Image J software.</p>", "<p id=\"P48\">To analyse mitochondrial membrane potential, cells were incubated with 0.5 µM MitoTracker Red CMXRos (Thermo Fisher Scientific) for 30 min, washed and subjected to microscope. To analyse Pdr5 activity, cells were incubated with 3.5 µM Nile Red (Thermo Fisher Scientific) for 15 min, washed and subjected to microscope. To study nuclei localization, cells were incubated with 1 µg/mL 4,6-Diamidino-2-phenylindole dihydrochloride (DAPI, Thermo Fisher Scientific) for 20 min in the dark, washed and subjected to microscope.</p>", "<p id=\"P49\">For single molecule mRNA visualization with mitochondria, cells were imaged by an Eclipse Ti2-E Spinning Disk Confocal with Yokogawa CSU-X1 (Yokogawa) with 50 µm pinholes, located at the Nikon Imaging Center UC San Diego. Imaging was performed using SR HP APO TIRF 100 × 1.49 NA oil objective with the correction collar set manually for each experiment (pixel size 0.074 mm). Z-stacks (300 nm steps) were acquired by a Prime 95B sCMOS camera (Photometrics). Imaging was controlled using NIS-Elements software (Nikon).</p>", "<title>Polyribosome profile analysis</title>", "<p id=\"P50\">For polysome fractioning, cells were grown at 25°C to post-diauxic phase in SGal medium and transferred to 37°C for 4 h for the experiments requiring temperature-sensitive strains. Cell extractions and polysome gradients were performed as described by (##REF##22072789##67##). Briefly, a culture volume corresponding to an OD<sub>600</sub> of 100 was chilled for 5 min on ice in the presence of 0.1 mg/mL CHX. Cells were centrifuged at 4400 rpm for 3 min at 4°C and washed twice with 2 mL of lysis buffer (20 mM Tris-HCl pH 8, 140 mM KCl, 5 mM MgCl<sub>2</sub>, 0.5 mM DTT, 1% Triton X-100, 0.1 mg/mL CHX, and 0.5 mg/mL heparin). Cells were resuspended in 700 µL of lysis buffer and added to a tube already containing 500 µL of glass beads. Cells were mechanically disrupted by vortexing 8 times for 30 s with 30 s of incubation on ice in between. Then, lysates were cleared by centrifugation at 5000 rpm for 5 min at 4°C, and the supernatant was recovered. After centrifugation at 8000 rpm for 5 min at 4°C, the RNA was recovered, and its concentration was estimated using a Nanodrop device (Thermo Fisher Scientific). Glycerol was added to all the samples to a final concentration of 5%, and extracts were flash-frozen and stored at −80°C. Samples of 10 A<sub>260</sub>nm units were loaded onto 5–50% sucrose gradients and separated by ultracentrifugation for 2 h 40 min at 3500 rpm in a Beckman SW41Ti rotor at 4°C. Then, gradients were fractionated by isotonic pumping of 60% sucrose from the bottom, and twenty-two 0.5 mL samples were recovered. The polysome profiles were monitored by UV detection at 260 nm using a density gradient fractionation system (Teledyne Isco, Lincoln, NE). RNAs were extracted using SpeedTools Total RNA Extraction kit (Biotools B&M Labs) with the rD-NAse treatment after the RNA elution step. Specific mRNAs were analyzed by RT-qPCR using specific primers (listed in ##SUPPL##0##Table S4##) and represented as a percentage of total. Three biological replicates were performed for each polyribosome profile, and a representative profile is shown.</p>", "<title>Proteomic data accession</title>", "<p id=\"P51\">The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (##REF##36370099##68##) via the PRIDE (##REF##34723319##69##) partner repository with the dataset identifier PXD043905.</p>" ]	[ "<title>Results</title>", "<title>Depletion of eIF5A results in the down-regulation of many mitochondrial proteins including components of OXPHOS, TCA and mitochondrial membrane transporters</title>", "<p id=\"P10\">We and others have found that eIF5A is necessary to maintain high mitochondrial activity; additionally, several mitoproteins whose levels drop in the absence of functional eIF5A have been identified in yeast and mammalian cells (##UREF##6##26##, ##REF##35490374##27##, ##REF##31130465##35##, ##REF##35613595##36##). In order to expand our knowledge on the role of eIF5A in mitochondria, we performed a proteomic experiment in which a wild-type and two eIF5A temperature-sensitive mutant yeast strains, <italic toggle=\"yes\">tif51A-1</italic> carrying a single point mutation (Pro83 to Ser) and <italic toggle=\"yes\">tif51A-3</italic> carrying a double point mutation (Cys39 to Tyr, Gly118 to Asp) (##UREF##7##37##, ##REF##24923804##38##), were exponentially grown in YPD media at 25°C and then incubated at 41°C for 4 h to deplete eIF5A. Data from the three replicates shown in the MDS-plot indicated that eIF5A mutants are already different in their proteome with respect to the wild-type at permissive temperature, and this difference is exacerbated at restrictive temperature (##SUPPL##0##Fig EV1A##). We also confirmed the response of wild-type to heat stress conferred by incubation at 41°C as there was an enrichment in the functional categories (GOs) of ‘Cellular response to stress’ in its up-regulated proteins (##SUPPL##0##Fig EV1B##). We calculated the 41°C/25°C fold change of protein levels and then, the ratios between this fold change for each mutant respect to the wild-type. Out of the 1358 proteins detected in the three strains, 292 were significantly down-regulated and 135 up-regulated in at least one mutant respect to the wild-type (138 down- and 38 up-regulated in both eIF5A mutants). Down-regulated proteins were enriched in several functional categories related to mitochondria (##SUPPL##0##Fig EV1C## and ##SUPPL##0##Table S1##), including OXPHOS proteins and TCA enzymes (##FIG##0##Figs 1A##,##FIG##0##B## and ##SUPPL##0##Table S1##). We observed that several mitochondrial membrane transporters were also down-regulated, as the phosphate (<italic toggle=\"yes\">Mir1</italic>) and the ADP/ATP (<italic toggle=\"yes\">Pet9</italic>) MIM carrier proteins and members of the TOM translocase of the MOM (<italic toggle=\"yes\">Tom20</italic>, <italic toggle=\"yes\">Tom70</italic>) (##FIG##0##Figs 1A##,##FIG##0##B##, ##SUPPL##0##EV1C## and ##SUPPL##0##Table S1##). To independently corroborate the proteomic results, we confirmed the reduction in the levels of two of the most down-regulated mitoproteins, the <italic toggle=\"yes\">Por1</italic> porin of the MOM and the <italic toggle=\"yes\">Hsp60</italic> chaperone, in both <italic toggle=\"yes\">tif51A-1</italic> and <italic toggle=\"yes\">tif51A-3</italic> mutants at restrictive temperature (##FIG##0##Figs 1C##-##FIG##0##E##). On the other hand, proteins of functional categories related to cytoplasmic translation were up-regulated in eIF5A mutants with respect to wild-type due to a lower decrease in the 41°C/25°C fold change in the eIF5A mutants (##FIG##0##Figs 1A##,##FIG##0##B## and ##SUPPL##0##EV1C##). Proteins of the category ‘drug membrane transport’ (<italic toggle=\"yes\">Snq2</italic>, <italic toggle=\"yes\">Yor1</italic>, <italic toggle=\"yes\">Qdr2</italic>, <italic toggle=\"yes\">Pdr5</italic>) were also up-regulated in the eIF5A mutants at 41°C (##FIG##0##Figs 1A##, ##SUPPL##0##EV1C## and ##SUPPL##0##Table S1##). In sum, the proteomic results indicated, among other effects, the requirement of eIF5A to maintain adequate protein levels of a wide range of mitoproteins.</p>", "<p id=\"P11\">An important outcome of our proteomic analysis was that, among the down-regulated mitoproteins upon eIF5A depletion, most of them do not contain consecutive prolines nor a high number of other eIF5A-dependent motifs in their sequences (##REF##28549188##22##, ##REF##28392174##23##) (##SUPPL##0##Table S1##). This finding had been previously observed in yeast and mammalian cells (##REF##31130465##35##, ##REF##35613595##36##) and suggests a general down-regulation of mitochondrial proteins levels in the absence of eIF5A and, thus, a role for eIF5A different to that well-described and direct one on translating problematic amino acids for peptide bond formation.</p>", "<title>eIF5A depletion causes a down-regulation of mitochondrial proteins translation</title>", "<p id=\"P12\">The specific decrease in the levels of mitoproteins upon eIF5A depletion could be explained by decreased translation of the corresponding mRNAs, as it is suggested by similar or even higher mRNA levels of the down-regulated proteins Por1 and Hsp60 in <italic toggle=\"yes\">tif51A-1</italic> and <italic toggle=\"yes\">tif51A-3</italic> mutants (##FIG##0##Fig 1E##). To further investigate if the general down-regulation of mitoproteins was occurring at the translational level, we obtained polysome profiles for wild-type and <italic toggle=\"yes\">tif51A-1</italic> strains in galactose media to promote respiration at both permissive (25°C) and restrictive (37°C) temperatures and determined the distribution of specific mRNAs among the different polysomal fractions. Importantly, polysomes were maintained in both strains at both temperatures, indicating that global translation was not significantly affected (##FIG##1##Figs 2A##,##FIG##1##B##). To analyse the distribution of short length-RNAs along the fractions, we divided the polysome profiles in three different sections corresponding to the monosomal fractions (M), fractions occupied by mRNAs with 2 or 3 ribosomes (2n-3n) and the rest of the polysomal fractions (P). For long length-RNAs we used the sections corresponding to the monosomal fractions (M), fractions with 2 to 8 ribosomes (2n-8n) and the rest of the polysomal fractions (P) (##SUPPL##0##Fig EV2A##). In agreement with unaffected global translation, we found no differences in the ratios P/2n-3n and P/2n-8n between the two strains at both permissive and restrictive temperatures (##SUPPL##0##Figs EV2B##,##SUPPL##0##C##).</p>", "<p id=\"P13\">Next, we investigated the distribution of mRNAs encoding for mitoproteins with different biological function and intra-mitochondrial localization. We calculated the fold change between the mRNA abundance found at heavy and low polysomal fractions. Significant lower ratios were observed for <italic toggle=\"yes\">PET9</italic>, <italic toggle=\"yes\">TOM20</italic> and <italic toggle=\"yes\">TOM70</italic> mRNAs encoding mitochondrial transporters at the MIM and MOM in the <italic toggle=\"yes\">tif51A-1</italic> strain at restrictive temperature (##FIG##1##Figs 2C## and ##SUPPL##0##EV2D##) with no significant differences at permissive temperature (##SUPPL##0##Fig EV2G##). These results indicated that the mRNA abundance was shifted to earlier fractions and translation was reduced. Similar results were observed for the <italic toggle=\"yes\">ATP1</italic>, <italic toggle=\"yes\">CYC1</italic> and <italic toggle=\"yes\">COX5A</italic> mRNAs encoding OXPHOS components at the MIM and IMS (##FIG##1##Figs 2C## and ##SUPPL##0##EV2E##,##SUPPL##0##H##). The reported lower ribosome association with the mitochondrial mRNAs upon eIF5A depletion was in agreement with our proteomic analyses, since 7 out of the 8 tested mRNAs encoding for mitoproteins were detected in the proteomic study and showed down-regulation of the protein levels in the two eIF5A mutants at restrictive temperature (##SUPPL##0##Table S1##).</p>", "<p id=\"P14\">We also studied the translation of the constitutively expressed <italic toggle=\"yes\">ACT1</italic>, <italic toggle=\"yes\">RPP2B</italic> and <italic toggle=\"yes\">EFT2</italic> mRNAs encoding actin, a ribosomal protein and translation elongation factor, respectively, localized in the cytosol. Similar ratios were found between the wild-type and <italic toggle=\"yes\">tif51A-1</italic> strains at both temperatures, indicating that the translation of these mRNAs remained unaffected in the absence of eIF5A (##FIG##1##Figs 2C## and ##SUPPL##0##EV2F##,##SUPPL##0##I##), which agrees with the finding that global translation is not affected in the <italic toggle=\"yes\">tif51A-1</italic> mutant (##SUPPL##0##Figs EV2B##,##SUPPL##0##C##).</p>", "<p id=\"P15\">To specifically address whether the synthesis of mitoproteins by translation is down-regulated upon eIF5A depletion, we used a reporter construct integrated in the <italic toggle=\"yes\">URA3</italic> locus, consisting of a <italic toggle=\"yes\">tetO7</italic> inducible promoter and a nanoluciferase (nLuc) reporter ORF for measuring kinetics of protein synthesis. This system was recently used to quantify protein levels and translation stall duration from reporter mRNAs in yeast (##UREF##8##39##). We generated fusions of the OXPHOS genes <italic toggle=\"yes\">CYC1</italic> and <italic toggle=\"yes\">COX5A</italic>, and the TCA enzyme <italic toggle=\"yes\">SDH2</italic> to the nLuc reporter gene. After inducing expression, we analysed the protein synthesis by incubating for 1 h in anhydrotetracycline-supplemented media. We did not find significant differences in protein synthesis between the <italic toggle=\"yes\">tif51A-1</italic> mutant and the wild-type strain at restrictive temperature for the nLuc reporter alone, which targets the cytosol (##FIG##1##Fig 2D##). However, the synthesis of Cyc1, Cox5a and Sdh2 luciferase fusions was significantly affected at restrictive temperature in the <italic toggle=\"yes\">tif51A-1</italic> strain (##FIG##1##Fig 2D##). The obtained results point towards a specific mechanism connected to eIF5A to coordinately reduce the synthesis of mitoproteins at the translation level and, therefore, mitochondrial protein levels. However, this mechanism seems to not be connected to the presence of peptides requiring eIF5A for their synthesis during translation as none of the investigated mitochondrial mRNAs encode for polyprolines nor a high number of other eIF5A-dependent motifs.</p>", "<title>eIF5A depletion induces the mitochondrial protein import stress mitoCPR and MitoStores</title>", "<p id=\"P16\">The “drug membrane transport” functional group, which includes the ATP-binding cassette (ABC) transporters Pdr5, Snq2 and Yor1, was found among the few GOs up-regulated in the eIF5A mutant in our proteomic study (##FIG##0##Figs 1A##, ##SUPPL##0##EV1C## and ##SUPPL##0##DATA##). The evolutionarily conserved transporter <italic toggle=\"yes\">PDR5</italic> has been shown to be induced during the mitochondrial stress response called mitoCPR (mitochondrial compromised protein import response) (##UREF##4##18##). mitoCPR is induced upon defects in the translocation and import of mitoproteins to increase the activity of the proteasome in the cytosol, remove accumulated precursors from the TOM complex and stabilize homeostasis. This response relies on the Pdr3-mediated transcriptional activation of different genes related to the multidrug resistance (MDR) response, such as <italic toggle=\"yes\">PDR5</italic>, which is involved in lipid metabolism and transport. The Pdr3-induced expression of Cis1, among others, recruits the AAA-protease Msp1 to the TOM translocase of the MOM to mediate the removal of accumulated mitoproteins upon import failure (##UREF##4##18##). To investigate if the mitoCPR response was induced upon eIF5A depletion, we analysed the mRNA expression of <italic toggle=\"yes\">PDR3</italic> and the Pdr3-responsive genes <italic toggle=\"yes\">MSP1</italic>, <italic toggle=\"yes\">GRE2</italic>, <italic toggle=\"yes\">PDR1</italic>, <italic toggle=\"yes\">PDR3</italic>, <italic toggle=\"yes\">PDR5</italic> and <italic toggle=\"yes\">CIS1</italic> in the <italic toggle=\"yes\">tif51A-1</italic> mutant at restrictive temperature. The <italic toggle=\"yes\">tif51A-1</italic> mutant, but not the wild-type, showed a significant up-regulation of all genes except <italic toggle=\"yes\">MSP1</italic>, with <italic toggle=\"yes\">CIS1</italic> and <italic toggle=\"yes\">PDR5</italic> the most induced mRNAs (##FIG##2##Fig 3A##).</p>", "<p id=\"P17\">When induced by Pdr3, the Pdr5 ABC membrane transporter is observed in the plasmatic membrane, where it mediates the efflux of xenobiotics, as well as in the vacuole, where it is degraded (<bold>?</bold> ). We fused the Pdr5 ORF to GFP and analysed its cellular localization by fluorescence microscopy. We found that the levels of Pdr5 were almost non-detectable in the wild-type strain at both temperatures as well as in the <italic toggle=\"yes\">tif51A-1</italic> strain at permissive temperature. However, at restrictive temperature, Pdr5 protein levels were significantly induced in the <italic toggle=\"yes\">tif51A-1</italic> strain and could be observed at their expected cellular locations (##FIG##2##Figs 3B##,##FIG##2##C##). Then, we added Nile Red, a Pdr5 specific substrate which stains lipid granules, to the cell cultures. We observed red fluorescent signal inside the cells in all the tested conditions except for the <italic toggle=\"yes\">tif51A-1</italic> mutant at restrictive temperature, indicating that high Pdr5 pumping activity excludes the Nile Red from these cells (##SUPPL##0##Figs EV3A##,##SUPPL##0##B##).</p>", "<p id=\"P18\">Along with a transcriptional response, it has been found that mitoproteins can aggregate in the cytosol upon induction of mitochondrial import stress (##REF##34292154##40##, ##REF##36704946##41##). To explore the potential mislocalization of mitoproteins targeted to different locations within the mitochondria following eIF5A depletion, we investigated their distribution relative to a Su9-mCherry marker, which served to visualize the overall mitochondrial network. Tom70 is part of the TOM complex, placed in the MOM. Cytochrome c isoform 1 (Cyc1) is involved in the transfer of electrons during cellular respiration and targets the IMS. Yta12 is an m-AAA protease component required for the degradation of misfolded or unassembled proteins and targets the MIM. Ilv2 is an acetolactate synthase involved in the synthesis of isoleucine and valine and targets the MM. We found that the outer membrane protein Tom70 shows no difference between the wild-type and <italic toggle=\"yes\">tif51A-1</italic> mutant at permissive and restrictive temperatures (##FIG##2##Figs 3D## and ##SUPPL##0##EV3C##). ##FIG##2##Figs 3E##-##FIG##2##G## show that at restrictive temperature Yta12, Cyc1 and Ilv2 are localized in the mitochondria in the wild-type strain but, in the <italic toggle=\"yes\">tif51A-1</italic> mutant they also form foci, which do not co-localize to the mitochondria. On the contrary, no foci were observed at permissive temperature (##SUPPL##0##Figs EV3D##-##SUPPL##0##F##). Although Ilv2 has been described to accumulate as one big aggregate in the nucleus upon protein import failure (##REF##33734083##42##), we found that in the absence of eIF5A, this protein accumulates in multiple and distributed foci, similarly to the misslocalized protein aggregates of Cyc1 and Yta12.</p>", "<p id=\"P19\">Next, we asked about the intracellular localization and composition of these eIF5A-dependent mitoprotein foci. Different cellular destinations for mitoproteins aggregates have been described including the cytosol, endoplasmic reticulum and nucleus (##REF##33734083##42##). DAPI staining of the nucleus of the cells indicated that Cyc1 aggregates were not co-localizing in the nucleus and thus, seemed to be part of the cytosol (##FIG##2##Fig 3H##). To gain insight into the accumulation of non-imported mitochondrial precursors in cytosolic granules upon eIF5A depletion, we investigated whether chaperones such Hsp104 could be controlling this process. Hsp104 is a disaggregase that binds to aggregated or misfolded proteins and disentangles them in an ATP-dependent manner (##UREF##9##43##–##REF##28193623##45##). Recently it was found that induction of mitochondrial import stress can cause cytosolic accumulation and co-localization of mitochondrial matrix-destined precursor proteins with Hsp104 granules. We fused Hsp104 ORF to RFP in a strain already expressing Cyc1-GFP and analysed its cellular localization. We found that a high percentage (>80%) of Hsp104 foci co-localize with Cyc1 aggregates (##FIG##2##Fig 3I##).</p>", "<p id=\"P20\">Altogether, these results suggest that depletion of eIF5A compromises mitochondrial protein import, as the induction of the Pdr3-mediated mitoCPR response and the cytosolic Hsp104 aggregation of precursor mitoproteins into Mito-Stores have been described as mechanisms to reduce toxicity from accumulated mitoprotein precursors and to restore cellular homeostasis upon import failure.</p>", "<title>eIF5A alleviates ribosome stalling of TIM50 mRNA encoding the mitochondrial inner membrane receptor</title>", "<p id=\"P21\">Given the elevated mitochondrial protein import stress response found upon eIF5A depletion, we sought to explore the mechanism by which eIF5A impacts the mitochondrial protein import. Tim50 protein is a receptor component of the MIM translocase complex TIM23 which recognizes the N-terminal MTS-containing proteins after emerging from the TOM complex and mediates their import to the mitochondrial inner membrane and matrix ((##UREF##10##46##), see review (##UREF##11##47##)). Interestingly, Tim50 contains a 10 proline residues in a 14 amino acid region in the first half of the protein with 7 of them consecutive (##FIG##3##Fig 4A##) and, therefore, is a proposed putative eIF5A-target (##REF##35490374##27##). In addition, <italic toggle=\"yes\">TIM50</italic> overexpression has previously been found to induce mitochondrial protein import defects (##UREF##4##18##). We therefore sought to investigate the possible role of eIF5A in <italic toggle=\"yes\">TIM50</italic> mRNA translation. First, we genomically attached an HA tag to Tim50 to quantify the impact of eIF5A depletion on endogenous Tim50 expression. We found a significant drop in Tim50 protein levels upon eIF5A depletion with no decrease in its mRNA levels (##SUPPL##0##Fig EV4A##). Moreover, expressing a <italic toggle=\"yes\">FLAG-TIM50-GFP</italic> version under a <italic toggle=\"yes\">GAL</italic> inducible system, we detected a reduction in Tim50 protein synthesis in the two eIF5A mutants, that was not due to lower levels of the corresponding mRNA, further suggesting a role of eIF5A in the translation of <italic toggle=\"yes\">TIM50</italic> mRNA (##SUPPL##0##Fig EV4B##).</p>", "<p id=\"P22\">Tim50 protein half-life is approximately 9.6 h (##REF##25466257##48##), which makes it more difficult to measure large differences in new protein synthesis. Therefore, to accurately test and quantify the eIF5A-dependency for <italic toggle=\"yes\">TIM50</italic> mRNA translation, we fused two different versions of the <italic toggle=\"yes\">TIM50</italic> DNA sequence to a TetO7-inducible nLuc reporter: the first one expressing the wild-type <italic toggle=\"yes\">TIM50</italic> sequence and the second one expressing <italic toggle=\"yes\">TIM50</italic> with a deletion of the 7 consecutive prolines (Tim507Pro) (##FIG##3##Fig 4B##). After inducing expression, we analysed the protein synthesis by incubating for 1 h in anhydrotetracycline-supplemented media the wild-type and mutant cells. After analysing the protein synthesis, it was observed that the <italic toggle=\"yes\">tif51A-1</italic> mutant showed a 3-fold reduction in the synthesis of Tim50 at restrictive temperature compared to the wild-type strain, further suggesting Tim50 as an eIF5A target for translation elongation (##FIG##3##Fig 4C##). Considering that final protein abundance is determined by both mRNA levels and translation, we confirmed that the lower protein levels were not attributed to <italic toggle=\"yes\">TIM50</italic> transcription, since the mRNA levels were even slightly higher in the <italic toggle=\"yes\">tif51A-1</italic> mutant at restrictive temperature compared to wild-type (##SUPPL##0##Fig EV5A##). To test if the decrease in protein synthesis was due to the presence of a high number of prolines in the Tim50 sequence, we analysed the Tim50 version containing deletions of the 7 consecutive prolines. Results indicated that after removing the proline-rich region of Tim50, protein synthesis is rescued in the <italic toggle=\"yes\">tif51A-1</italic> mutant at 37°C and reaches similar protein levels to the wild-type strain (##FIG##3##Fig 4D##).</p>", "<p id=\"P23\">Inducible reporter assays enabled us to calculate both the overall expression levels as well as the time needed for translation elongation through the region upstream of the nLuc reporter gene (##UREF##8##39##, ##REF##26860732##49##). By using the Schleif plotting technique (##REF##4577756##50##, ##REF##27903884##51##), we compared the amount of time needed to detect luciferase signal from a reporter only expressing nLuc and the two Tim50 reporters. Then, we obtained the time required for ribosomes to translate each of the Tim50 versions. We found that the time required for translating a wild-type <italic toggle=\"yes\">TIM50</italic> mRNA was significantly increased in the <italic toggle=\"yes\">tif51A-1</italic> mutant at restrictive temperature. If a cell needs approximately 2 minutes to generate one full Tim50 polypeptide, upon eIF5A depletion, the ribosomes need almost 4 minutes to achieve the complete translation of this mRNA. However, the synthesis time required for translating TIM507Pro mRNAs were almost identical to those in the corresponding wild-type strain (##FIG##3##Fig 4E##). This extended translation duration was indicative of a ribosome stall at the polyprolines. To further confirm ribosome stalling, we analysed the ribosome density across the TIM50 transcript in control and an eIF5A degron strain (##REF##28392174##23##). We found a precipitous drop-off in ribosome density exactly where the stretch of polyprolines is located in Tim50 (540–561bp) upon eIF5A depletion but not in the control strain (##FIG##3##Fig 4F##). This absence of ribosomes after the stretch of polyprolines is indicative of ribosome stalling and the induction of ribosome quality control at the polyproline residues.</p>", "<p id=\"P24\"><italic toggle=\"yes\">TIM50</italic> mRNA is constitutively localized to the vicinity of the mitochondrial surface and the import of Tim50 protein to mitochondria occurs co-translationally (##UREF##2##9##, ##REF##32762840##10##). To confirm that ribosome stalling along <italic toggle=\"yes\">TIM50</italic> mRNA upon eIF5A depletion was mitochondrially localized, we visualized mitochondria using the marker Su9-mCherry and <italic toggle=\"yes\">TIM50</italic> mRNAs with the MS2 tag system (##REF##32762840##10##) in both wild-type and <italic toggle=\"yes\">tif51A-1</italic> strains at restrictive temperature. We observed <italic toggle=\"yes\">TIM50</italic> mRNA to be strongly associated with the mitochondrial surface in both strains (##SUPPL##0##Fig EV5B##). This result indicates that eIF5A depletion does not affect the localization of <italic toggle=\"yes\">TIM50</italic> mRNA molecules and that Tim50 ribosome stalling occurs adjacent to the mitochondrial surface.</p>", "<p id=\"P25\">Finally, we asked if ribosome stalling along <italic toggle=\"yes\">TIM50</italic> mRNA upon eIF5A depletion could affect its protein localization. We observed that Tim50 strongly localizes to the mitochondria in the wild-type strain. However, we found the presence of Tim50 foci which do not co-localize to the mitochondria in the <italic toggle=\"yes\">tif51A-1</italic> mutant whereas no aggregates were observed at permissive temperature (##FIG##3##Figs 4G## and ##SUPPL##0##EV5C##). The number of cells containing more than one of these Tim50 aggregates was found to be significantly increased in the <italic toggle=\"yes\">tif51A-1</italic> mutant at restrictive temperature (##FIG##3##Fig 4H##). DAPI staining of the nucleus of the cells indicated that Tim50 aggregates were not co-localizing in the nucleus and thus, seemed to be part of the cytosol (##FIG##3##Fig 4I##). To gain insight into the accumulation of Tim50 into Mitostores, as previously seen for Cyc1, we fused Hsp104 ORF to RFP in a strain already expressing Tim50-GFP and found that a high percentage (>70%) of Hsp104 foci co-localize with Tim50 aggregates (##FIG##3##Figs 4J## and ##SUPPL##0##EV5D##). Together, these results indicated that Tim50 down-regulation in the <italic toggle=\"yes\">tif51A-1</italic> mutant was due to a decrease in translation because ribosomes stall along the proline-rich region of its sequence. Thus, these data strongly suggest that <italic toggle=\"yes\">TIM50</italic> mRNA translation is directly dependent on eIF5A and its deficiency generates ribosome stalling on the mitochondrial surface and precursor protein accumulation in the cytosol.</p>", "<title>Deletion of Tim50 proline stretch in eIF5A mutant restores mitochondrial protein import without rescuing mitochondrial respiration</title>", "<p id=\"P26\">Herein, we have demonstrated how upon eIF5A depletion, Tim50 translation occurring at the mitochondrial surface stalls in the polyproline stretch and its protein synthesis is decreased. This generates specific import defects for mitoproteins, which accumulate and aggregate in the cytosol. Therefore, we asked if a reduction in Tim50 stalling and rescuing of Tim50 protein levels would alleviate the import collapse and its derived effects associated with eIF5A loss of function. To test this, we generated two strains expressing the endogenous Tim50 protein without the region containing the 7 consecutive prolines of its sequence (Tim50Pro) fused to GFP, the first one in a wild-type (BY4741) background and the second one in a <italic toggle=\"yes\">tif51A-1</italic> mutant background. In these strains, the endogenous <italic toggle=\"yes\">TIM50</italic> gene is mutated so that the only source of Tim50 protein for the cell is the eIF5A-independent version Tim50Pro. Here, translational stalling of <italic toggle=\"yes\">TIM50</italic> mRNA occurring at the mitochondrial surface is no longer present and Tim50 reporter levels are rescued upon eIF5A depletion (##FIG##3##Figs 4C##-##FIG##3##E##). Surprisingly, the functionality of the Tim50Pro version was shown to be almost unaffected. We observed no obvious growth differences in glycerol media between the wild-type strain containing full Tim50 or Tim50Pro (##FIG##4##Fig 5A##), although the proline-rich region is found in the presequence-binding groove of the Tim50 IMS domain, which functions in receiving the proteins in the TIM23 complex (##REF##26323300##52##). Therefore, the proline-rich region is not essential for cell viability under the respiratory conditions tested and thus, for the proper mitochondrial import.</p>", "<p id=\"P27\">We first tested the effect of substituting the endogenous Tim50 by Tim50Pro, whose translation is eIF5A-independent, on mitochondrial function and growth on respiratory media in eIF5A mutant cells. Expression of Tim50Pro did not rescue the growth of the <italic toggle=\"yes\">tif51A-1</italic> mutant under glycerol at semi-permissive temperature (##FIG##4##Fig 5A##). This result points to the idea that Tim50 is not the only mechanism linking eIF5A to mitochondrial function. In addition, when we checked the accumulation of the membrane potential-dependent dye mitotracker red, we observed a slight increase in the membrane potential at permissive and restrictive temperatures in the <italic toggle=\"yes\">tif51A-1</italic> Tim50Pro mutant respect to <italic toggle=\"yes\">tif51A-1</italic> mutant cells expressing wild-type Tim50 (##FIG##4##Figs 5B##,##FIG##4##C##).</p>", "<p id=\"P28\">We then tested whether rescue of Tim50 translational stalling and protein levels would rescue the mitochondrial import phenotypes we observed in the eIF5A depletion. We found a reduction in Tim50 cytosolic protein aggregates upon removal of the stretch of prolines, indicating proper protein import (##FIG##4##Figs 5D##,##FIG##4##E##). Furthermore, we found that the mRNA levels of the most induced mitoCPR genes (<italic toggle=\"yes\">PDR3</italic>, <italic toggle=\"yes\">PDR5</italic> and <italic toggle=\"yes\">CIS1</italic>) were significantly decreased in the <italic toggle=\"yes\">tif51A-1</italic> Tim50Pro mutant (##FIG##4##Fig 5F##). As Tim50Pro rescued both the mitoCPR effect and protein import of Tim50, we next tested whether this may influence the translation of oxidative phosphorylation reporters that have reduced expression upon eIF5A depletion in cells expressing wild-type Tim50. We observed that eIF5A depletion does not significantly affect the synthesis of Cyc1 and Cox5A reporters if the translational stalling along <italic toggle=\"yes\">TIM50</italic> is rescued by removing the prolines (##FIG##4##Fig 5G##). This suggests that the translational defects observed upon eIF5A depletion are secondary effects driven by a mitochondrial import stress.</p>" ]	[ "<title>Discussion</title>", "<p id=\"P29\">In this study we have expanded our knowledge on the effects of eIF5A depletion on the mitochondrial function and identified one of the possible molecular mechanisms by which eIF5A is required to maintain mitochondrial activity. We have shown that eIF5A is necessary for the translation of the proline-rich region of Tim50 protein, which is part of the TIM23 complex and essential for the recognition and sorting of mitoproteins into the mitochondrial inner membrane and matrix. Tim50 and Tim23 proteins expose conserved soluble domains into the IMS that interact with each other, and this interaction is essential for protein translocation by the complex (##REF##19017642##53##). Through the alleviation of ribosome stalling of <italic toggle=\"yes\">TIM50</italic> mRNA on the mitochondrial surface and thus, modulation of Tim50 protein levels, eIF5A specifically impacts mitochondrial import. Upon eIF5A depletion, the mitochondrial import of many inner mitoproteins is compromised. We have seen that non-imported mitoproteins aggregate in the cytosol as a consequence of the import stress response provoked by the lack of eIF5A. Interestingly, it has been recently demonstrated that decreased mitoprotein uptake with CCCP causes the stall of translocating proteins in the outer membrane (##REF##34847359##54##). A response for the clearance of stalled proteins in the mitochondrial surface has been shown to be mediated by the mitoCPR response, which induces, through the transcription factor Pdr3, the coordinated action of Cis1 and Msp1 to promote the degradation of arrested precursor proteins (##UREF##4##18##). Altogether, our results demonstrate that low levels of eIF5A causes mitochondrial stress by inducing <italic toggle=\"yes\">TIM50</italic> ribosome stalling and reducing Tim50 expression (##FIG##5##Fig 6##).</p>", "<p id=\"P30\">Our results also indicate that the accumulation of non-imported precursors in specific deposits in the cytosol is buffered by cytosolic chaperones, mainly Hsp104, to relieve the proteotoxic stress. These results are in line with the recent description of the cytosol as a place with capacity to store mitochondrial precursor proteins in dedicated storage granules that are controlled by the cytosolic chaperone system, with Hsp104 binding the N-terminal presequences of mitoproteins (##REF##36704946##41##). Similarly, the observed Pdr5 induction upon eIF5A depletion seems indicative of a cellular detoxification effort to eliminate toxic substrates accumulating in the cytosol in a context of protein aggregates accumulation.</p>", "<p id=\"P31\">Upon prolonged mitochondrial dysfunction, the stress response is usually accompanied by cytosolic translation attenuation to reduce the synthesis of precursors and the protein load to translocases. General translation is known to be down-regulated upon treatment with multiple mitochondrial stressors such as defective mitochondrial biogenesis (##REF##26245374##16##), clogger expression (##REF##30886345##17##), oxidative stress (<bold>?</bold> ) and mitochondrial depolarization with high CCCP doses (##REF##34847359##54##). Herein, we have found that eIF5A depletion specifically down-regulates the expression of most mitoproteins. We observed that while general cytosolic translation remained unaffected, translation of proteins targeting mitochondria was found to be uniformly affected, suggesting a connection between the import status and the translation of mitoproteins that need to be translocated. In the last years it has been proposed that eIF5A is necessary for the translation of specific mitoproteins with that specificity residing in the amino acid sequences at their N-terminal/MTS sequences, especially those ones with weak interactions with the peptide exit tunnel, yet it was unclear if this was a direct effect (##REF##31130465##35##, ##REF##35613595##36##). The fact that Tim50Pro alleviated the translational repression of Cyc1 and Cox5A even upon eIF5A depletion suggests that some aspects of this translational regulation may result indirectly from eIF5A depletion. This could potentially be linked to the mitochondrial import stress response rather than being directly regulated by eIF5A. Nevertheless, more work will be needed to further decipher the specific molecular changes linking eIF5A, general translation of mitochondrial proteins and overall mitochondrial function.</p>", "<p id=\"P32\">The presented results herein highlight the idea that multiple mechanisms, besides Tim50 regulation, link eIF5A to the mitochondrial function. While we found the recovery of Tim50 function with the Tim50Pro to rescue the mitochondrial import stress response after 4 hours of eIF5A depletion, this was not sufficient to fully recover the MIM potential nor to rescue the growth on respiratory media for longer times at semi-permissive temperature. This could be explained by the fact that over sustained periods at semi-permissive temperatures, eIF5A becomes further depleted and causes other mitochondrial mRNAs that are less sensitive to eIF5A levels to become stalled and to drive similar mitochondrial stress responses. Therefore, it is of interest to explore other putative mitochondrial targets with eIF5A-dependent motifs in their sequences.</p>", "<p id=\"P33\">Human Tim50 sequence contains 27 prolines, but these are found scattered throughout the sequence rather than accumulated in a specific region as in <italic toggle=\"yes\">S. cerevisiae’s</italic> Tim50. In future studies, it would be of interest to examine if Tim50 is a true eIF5A-target for its translation in higher eukaryotes. In humans, Tim50 down-regulation and derived import failure is associated with neurodegeneration and several genetic disorders (##REF##17435247##55##, ##REF##27573165##56##) whereas Tim50 overexpression has been observed in some cancer cell lines. The up-regulation of Tim50 activity may increase protein import and mitochondrial function, promoting cell growth and metastasis (##REF##21621504##57##–##UREF##12##59##). Furthermore, clogging of translocases and cytosolic deposition of mitochondrial precursors have been implicated with some neurodegenerative disorders. Aggregation of mitoproteins in the cytosol increases misfolding of α-synuclein and amyloid precursor proteins, which are involved in Parkinson’s and Alzheimer’s diseases, as they can co-aggregate together, engage translocases and further increase the clogging hazard (##REF##34292154##40##, ##REF##27630262##60##). The specific eIF5A-mediated mechanism of Tim50 translational stalling alleviation and therefore, mitochondrial protein import regulation, might be important for understanding the molecular basis of pathologies where mitochondrial protein uptake fails. Importantly, data shown herein points to a novel and more likely mitochondrial stress generated by lack or defects in eIF5A protein that could be found in nature and raise as one of the underlying causes of impaired protein uptake in disease contexts. Thereby, eIF5A and its well-characterized hypusination precursor spermidine, could be considered as potential candidates to potentiate the activity of mitochondrial import machineries in compromised cells.</p>" ]	[]	[ "<p id=\"P1\">Author contributions</p>", "<p id=\"P2\">PA, BMZ and MB-A conceived and supervised the study. PA, BMZ and MB-A designed the experiments. MB-A, VB and CR performed the experiments. MB-A PA and BMZ wrote and revised the manuscript.</p>", "<p id=\"P3\">The efficient import of nuclear-encoded proteins into mitochondria is crucial for proper mitochondrial function. The conserved translation factor eIF5A is primarily known as an elongation factor which binds ribosomes to alleviate ribosome stalling at sequences encoding polyprolines or combinations of proline with glycine and charged amino acids. eIF5A is known to impact the mitochondrial function across a variety of species although the precise molecular mechanism underlying this impact remains unclear. We found that depletion of eIF5A in yeast drives reduced translation and levels of TCA cycle and oxidative phosphorylation proteins. We further found that loss of eIF5A leads to the accumulation of mitoprotein precursors in the cytosol as well as to the induction of a mitochondrial import stress response. Here we identify an essential polyproline-containing protein as a direct eIF5A target for translation: the mitochondrial inner membrane protein Tim50, which is the receptor subunit of the TIM23 translocase complex. We show how eIF5A directly controls mitochondrial protein import through the alleviation of ribosome stalling along <italic toggle=\"yes\">TIM50</italic> mRNA at the mitochondrial surface. Removal of the polyprolines from Tim50 rescues the mitochondrial import stress response, as well as the translation of oxidative phosphorylation reporter genes in an eIF5A loss of function. Overall, our findings elucidate how eIF5A impacts the mitochondrial function by reducing ribosome stalling and facilitating protein translation, thereby positively impacting the mitochondrial import process.</p>" ]	[ "<p id=\"P4\">Mitochondria are complex eukaryotic organelles with endosymbiotic origin (##UREF##0##1##). In eukaryotes, mitochondria are essential for energy production and macromolecular synthesis as they house key metabolic processes such as oxidative phosphorylation (OXPHOS), electron transport chain (ETC) or TCA cycle, and lipid, amino acids, heme, and Fe-S clusters synthesis. Besides, mitochondria also participate in other cellular processes including Ca<sup>2+</sup> homeostasis and apoptosis. Given its cellular essentiality, mitochondrial function is critical in health and disease and is a pivotal hallmark of ageing-related disorders (##REF##15734681##2##, ##REF##28432755##3##).</p>", "<p id=\"P5\">The mitochondrial proteome comprises about 1000 proteins in budding yeast (##REF##20729931##4##). While the mitochondrial genome encodes 1% of them, the other 99% are encoded in the nuclear genome (##UREF##1##5##). Therefore, these nuclear-encoded mitochondrial proteins, herein termed mitoproteins, need to be transported into the mitochondria to fulfill their biological function. Mitoprotein import is therefore a key process for optimal mitochondrial function (##REF##32409196##6##). Mitoproteins are imported into the mitochondria through both post- and co-translational mechanisms. In the first case, cytosolic chaperones bind to and keep mitoproteins in an unfolded import-competent conformation until delivered to receptors at the mitochondrial surface (##REF##30868341##7##). Co-translational translocation implies the coupling of synthesis and import, with mRNA localization to the mitochondrial surface (##REF##4629740##8##–##REF##32762840##10##).</p>", "<p id=\"P6\">Protein translocases in the mitochondrial outer and inner membrane (MOM and MIM) mediate the import and sorting of proteins into mitochondria. Mitoproteins initially enter the organelle through the general translocase of the outer membrane (TOM complex), known as the universal entry gate. Most mitoproteins are recognized by their N-terminal positively charged presequences, the most common mitochondrial targeting sequences (MTS) (##REF##19837041##11##). Usually, mitoproteins contact the central receptor Tom20 and cross to the intermembrane space (IMS) through Tom40, the β-barrel poreforming subunit. Mitoproteins targeting the MIM or the mitochondrial matrix (MM) are then recognized by the major translocase of the inner membrane (TIM23 complex) with Tim23 as the central subunit and translocase pore and Tim50 as the receptor protein that specifically recognizes the MTS. TIM translocation is energetically driven by the MIM membrane potential and the action of the mtHsp70 motor system. Once reaching their destination, the MTS sequence is cleaved, and the protein is folded. Mitoproteins with no MTS show unclear targeting signals and their import is mediated by other translocases (see reviews (##REF##28301740##12##–##REF##36768800##14##)).</p>", "<p id=\"P7\">Import failure of mitoproteins leads to proteotoxic effects inside and outside the mitochondria, as unfolded precursors accumulate on the translocases and in the cytosol, which is detrimental to cellular fitness and is associated with various diseases. However, yeast cells are equipped with several stress responses which include a transcriptional and translational reprogramming, reducing the protein synthesis and increasing proteasomal activity to remove accumulated precursors from translocases and cytosol (##UREF##3##15##–##REF##31118508##19##).</p>", "<p id=\"P8\">Eukaryotic translation initiation factor 5A (eIF5A) is an essential and highly conserved protein across eukaryotes and archaea (##REF##1903841##20##). eIF5A promotes the translation elongation between amino acids known to be poor substrates for the formation of peptide bonds that may stall translation, such as polyproline motifs but also combinations of proline, glycine, and charged amino acids (##REF##23727016##21##–##REF##28392174##23##). eIF5A is the only known cellular protein containing the post-translational and essential modification hypusine, and in most eukaryotes, it is codified by two highly homologous isoforms, TIF51A and TIF51B in yeast (##REF##11161802##24##, ##UREF##5##25##). eIF5A expression is regulated according to the metabolic demands of the cell. In yeast, TIF51A gene is up-regulated under respiratory conditions by the transcription (activator/repressor) factor Hap1 (##UREF##6##26##, ##REF##35490374##27##), which responds to changes in oxygen and heme levels to activate the transcription of many respiratory genes (##REF##11212295##28##). However, under hypoxic/non-respiratory conditions, Hap1 represses TIF51A expression (##UREF##6##26##, ##REF##35490374##27##).</p>", "<p id=\"P9\">The cellular adaptation of eIF5A expression according to the energetic status of the cell highlights the essential role of eIF5A in mitochondrial function. Thus, a reduction in eIF5A protein triggers a decrease in the mitochondrial respiration rate and its membrane potential (##UREF##6##26##, ##REF##35490374##27##, ##REF##35163207##29##–##REF##32400964##31##). In addition, mitochondrial localization of eIF5A has been reported (##REF##22221319##32##–##REF##27414022##34##). Until now, two alternative but related mechanisms to explain the eIF5A role in mitochondrial function have been described. First, eIF5A was reported to control the synthesis and activity of many mitoproteins of macrophage cells. The mitochondrial targeting sequences (MTSs) of some of them were sufficient to confer hypusinated eIF5A-dependent translation efficiency, suggesting that eIF5A might regulate mitochondrial activity by promoting, directly or indirectly, the translation of MTSs of some mitoproteins, which are rich in charged amino acids (##REF##31130465##35##). In connection with this, Zhang et al. (##REF##35613595##36##) reported how eIF5A promotes the translation of some yeast respiratory proteins in response to oxygen levels and suggested that eIF5A and its hypusine would favor a suitable interaction between the amino acids from the MTS regions and the peptide exit tunnel. Here, we describe an alternative molecular mechanism by which eIF5A promotes mitochondrial activity. This mechanism relies on the eIF5A-dependent translation of Tim50, the receptor subunit of the TIM23 complex, impacting the mitochondrial import process. Through the alleviation of ribosome stalling of TIM50 mRNA and thus, modulation of Tim50 protein levels, eIF5A specifically controls the import and translocation of mitochondrial proteins. Hence, the loss of eIF5A drives the accumulation of precursors in the cytosol, activates the mitochondrial import stress response while secondarily reduces the translation and levels of many mitochondrial proteins.</p>", "<title>Supplementary Material</title>" ]	[ "<title>Acknowledgements</title>", "<p id=\"P52\">We thank Oreto Antúnez and M. Luz Valero from the Proteomics Service SCSIE (Universitat de València). Grant PID2020-120066RB-I00 funded by MCIN/AEI/10.13039/501100011033 to PA. This work was supported, in part, by the National Institutes of Health R35GM128798 to BMZ. This research was also funded by Generalitat Valenciana (AICO/2020/086 and CIAICO/2022/237) to PA. MB-A. is a recipient of a predoctoral fellowship (FPU2017/03542) funded by MCIN/AEI/10.13039/501100011033 and by ESF Investing in your future. Authors acknowledge support by all members of GFL lab.</p>" ]	[ "<fig position=\"float\" id=\"F1\"><label>Fig. 1.</label><caption><title>Proteomic analysis of eIF5A deletion shows down-regulation of mitochondrial proteins.</title><p id=\"P53\">(A) Volcano plot showing the log2 fold change values of 1358 detected proteins plotted against their associated log10 p-values. Dots representing individual proteins were divided in five different groups: p-value > 0.05 (black); p-value < 0.05 (grey); OXPHOS/TCA proteins (red); mitochondrial transport proteins (orange); translation proteins (blue) and drug membrane transport proteins (magenta). (B) Cumulative distributions of log2 fold changes of all proteins detected (grey), OXPHOS/TCA (red) and ribosomal proteins (blue). (C,D) Wild-type, <italic toggle=\"yes\">tif51A-1</italic> and <italic toggle=\"yes\">tif51A-3</italic> strains were cultured in YPD at 25°C until early exponential phase and transferred to 25°C or 41°C for 4 h. eIF5A, Por1 and Hsp60 protein levels were determined by western blotting (C) and quantified (D). G6PDH levels were used as loading control. A representative image is shown. (E) <italic toggle=\"yes\">POR1</italic> and <italic toggle=\"yes\">HSP60</italic> mRNA relative levels were determined by RT-qPCR. Data information: In (D,E) Results are presented as mean ± SD from three independent experiments. The statistical significance was measured by using a two-tailed paired Student t-test relative to 25°C. p < 0.05, p < 0.01, *p < 0.001.</p></caption></fig>", "<fig position=\"float\" id=\"F2\"><label>Fig. 2.</label><caption><title>The levels of mitochondrial proteins are post-transcriptionally affected upon eIF5A depletion.</title><p id=\"P54\">(A,B) Polysome profiles were obtained for wild-type and <italic toggle=\"yes\">tif51A-1</italic> strains cultured in SGal at 25°C (A) or 37°C (B) for 4 h. (C) The RNA from individual fractions of the polysomes profiles was extracted and the mRNA levels were analyzed by RT-qPCR using gene specific primers in the corresponding sections at restrictive temperature. Fold change between the heavy and the low polysomal sections are presented. (D) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing nLuc, Cyc1-nLuc, Cox5a-nLuc or Sdh2-nLuc (from left to right) reporters were cultured in YPD until early exponential phase and then transferred to 25°C or 37°C for 4 h. After addition of doxycycline to induce luciferase expression, the luminescence levels generated by the nanoluciferase 60 mins after the addition of the furimazine substrate were measured. Data information: In (C,D) Results are presented as average ± SD from three independent experiments. The statistical significance was measured by Student t-test relative to wild-type strain or to 25°C. p < 0.05, p < 0.001, p < 0.001.</p></caption></fig>", "<fig position=\"float\" id=\"F3\"><label>Fig. 3.</label><caption><title>eIF5A deficiency generates mitoCPR stress and mislocalization of mitoproteins.</title><p id=\"P55\">(A) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> were cultured in SGal medium at 25°C until reaching post-diauxic phase and then transferred to 25°C or 37°C for 4 h. mRNA relative levels from mitoCPR genes were determined by RT-qPCR. (B) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing Pdr5-GFP were cultured as in (A) and then subjected to fluorescence microscopy. (C) Quantification of Pdr5-GFP fluorescent signal from at least 150 cells. (D-G) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing Tom70-GFP (D), Yta12-GFP (E), Cyc1-GFP (F) or Ilv2-GFP (G) and Su9-mCherry were cultured as in (A) and subjected to fluorescence microscopy. (H) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing Cyc1-GFP and Su9-mCherry were cultured as in (A) and incubated for 30 mins with DAPI prior microscopy to stain the nuclei. (I) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing Cyc1-GFP and Hsp104-RFP were cultured as in (A). (B,D-I) A representative image is shown from three independent experiments. Data information: In (A,C) Results are presented as mean ± SD from three independent experiments. The statistical significance was measured by using a two-tailed paired Student t-test relative to 25°C. p < 0.05, **p < 0.001.</p></caption></fig>", "<fig position=\"float\" id=\"F4\"><label>Fig. 4.</label><caption><title>eIF5A depletion causes TIM50 polyproline ribosome stalling, decreased Tim50 protein levels and mislocalization.</title><p id=\"P56\">(A) Scheme showing Tim50 protein sequence. (B) Scheme showing the two different nLuc versions used in this study. Proline numbers are shown in magenta. (C,D) Wild-type strain (left) and <italic toggle=\"yes\">tif51A-1</italic> (middle) expressing the wild-type Tim50 (B) or Tim507Pro (C) were cultured in YPD until early exponential phase and then transferred to 25°C or 37°C for 4 h. After addition of doxycycline to induce luciferase expression, the luminescence levels generated by the nLuc after the addition of the furimazine substrate were measured along time. A representative experiment is shown. Quantification of the Tim50 protein levels is shown in the right. (E) Full protein synthesis time was calculated for wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing the wild-type Tim50 (left) or Tim507Pro (right). (F) Fraction of ribosome reads of various lengths along TIM50 transcript in (##REF##28392174##23##) ribosome profiling libraries. (G) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing Tim50-GFP and Su9-mCherry were cultured in SGal medium at 25°C until reaching post-diauxic phase, transferred to 37°C for 4 h and subjected to fluorescence microscopy. (H) Quantification of cells with Tim50 aggregates at 37°C is shown. (I) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing Tim50-GFP and Su9-mCherry were cultured as in (G) and incubated for 30 mins with DAPI prior microscopy to stain the nuclei. (J) Wild-type strain and <italic toggle=\"yes\">tif51A-1</italic> expressing Tim50-GFP and Hsp104-RFP were cultured as in (G). (G-I,J) A representative image is shown from three independent experiments. Data information: In (C-E,H) Results are presented as mean ± SD from three independent experiments. Statistical significance was measured using a two-tailed paired Student t-test relative to 25°C. p < 0.05, **p < 0.001.</p></caption></fig>", "<fig position=\"float\" id=\"F5\"><label>Fig. 5.</label><caption><title>Deletion of the Tim50 polyproline stretch in the eIF5A mutant does not rescue mitochondrial respiration but cancels the mitoCPR response induction.</title><p id=\"P57\">(A) Growth of the wild-type, <italic toggle=\"yes\">tif51A-1</italic>, wild-type Tim50Pro and <italic toggle=\"yes\">tif51A-1</italic> Tim50Pro was tested in YPGly and YPD media at the indicated temperatures. (B-E) Wild-type, <italic toggle=\"yes\">tif51A-1</italic>, wild-type Tim50Pro and <italic toggle=\"yes\">tif51A-1</italic> Tim50Pro were cultured in SGal medium until reaching post-diauxic phase at 25°C, transferred to 37°C for 4 h and subjected to fluorescence microscopy (B,D). Cells were incubated for 30 mins with Mitotracker prior microscopy to stain the mitochondria (B). Quantification of Mitotracker fluorescent signal from at least 150 cells (C). Quantification of cells presenting 0, 1 or 2 Tim50 aggregates at 37°C is shown (E). (F) Wild-type, <italic toggle=\"yes\">tif51A-1</italic> and <italic toggle=\"yes\">tif51A-1</italic> carrying Tim50Pro were cultured as in (B). mRNA relative levels from mitoCPR genes were determined by RT-qPCR. (G) Wild-type, <italic toggle=\"yes\">tif51A-1</italic>, wild-type Tim50Pro and <italic toggle=\"yes\">tif51A-1</italic> Tim50Pro strains expressing Cyc1-nLuc (left) or Cox5a-nLuc (right) were cultured in YPD until early exponential phase and then transferred to 25°C or 37°C for 4 h. After addition of doxycycline to induce luciferase expression, the luminescence levels generated by the nanoluciferase after the addition of the furimazine substrate were measured along time and protein was quantified after 60 min. Data information: In (C,F,G) Results are presented as mean ± SD from three independent experiments. The statistical significance was measured by using a two-tailed Student t-test. p < 0.05, p < 0.001, *p < 0.001.</p></caption></fig>", "<fig position=\"float\" id=\"F6\"><label>Fig. 6.</label><caption><title>Model for the eIF5A-mediated regulation of the mitochondrial function.</title><p id=\"P58\">Upon eIF5A depletion, ribosomes translating TIM50 mRNA to synthesize the Tim50 proline-rich region become stalled and, thus, the mitochondrial import of Tim50-dependent proteins targeting the IMS, MIM and MM, is compromised. The non-imported mitochondrial precursors start aggregating in the cytosol bound to chaperone Hsp104 and the proteins translocating in the outer membrane become stalled. Then, the mitoCPR response is induced to clear the proteins accumulating in the mitochondrial surface through the action of Cis1 and Msp1. In addition, the lack of eIF5A reduces the translation of many RNAs encoding mitoproteins so the levels of most mitochondrial proteins become reduced. MOM: mitochondrial outer membrane; IMS: intermembrane space; MIM: mitochondrial inner membrane; MM: mitochondrial matrix. Figure was processed using BioRender software.</p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"SD1\" position=\"float\" content-type=\"local-data\"><label>Supplement 1</label></supplementary-material>" ]	[]	[ "<graphic xlink:href=\"nihpp-2023.12.19.572290v1-f0001\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572290v1-f0002\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572290v1-f0003\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572290v1-f0004\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572290v1-f0005\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572290v1-f0006\" position=\"float\"/>" ]	[ "<media xlink:href=\"media-1.pdf\" id=\"d64e1214\" position=\"anchor\"/>" ]	[{"label": ["1."], "surname": ["Roger", "Munoz-Gomez", "Kamikawa"], "given-names": ["AJ", "SA", "R"], "article-title": ["The origin and diversification of mitochondria."], "source": ["Curr Biol"], "volume": ["27"], "fpage": ["1177"], "lpage": ["1192"], "year": ["2017"]}, {"label": ["5."], "surname": ["Borst", "Grivell"], "given-names": ["Peter", "Leo A"], "article-title": ["Mitochondrial nucleic acids."], "source": ["Biochimie"], "volume": ["15"], "fpage": ["705"], "lpage": ["723"], "year": ["1973"]}, {"label": ["9."], "surname": ["Williams", "Jan", "Weissman"], "given-names": ["CC", "CH", "JS"], "article-title": ["Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling."], "source": ["Science (80- )"], "volume": ["346"], "fpage": ["748"], "lpage": ["751"], "year": ["2014"]}, {"label": ["15."], "surname": ["Wang", "Chen"], "given-names": ["X", "XJ"], "article-title": ["A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death."], "source": ["Nature"], "year": ["2015"]}, {"label": ["18."], "surname": ["Weidberg", "Amon"], "given-names": ["H", "A"], "article-title": ["Mitocpr\u2014a surveillance pathway that protects mitochondria in response to protein import stress."], "source": ["Science (80- )"], "volume": ["360"], "fpage": ["eaan4146"], "year": ["2018"]}, {"label": ["25."], "surname": ["Park", "Kar", "Banka", "Ziegler", "Chung"], "given-names": ["Ming-Hsu", "Ronak K", "Siddharth", "Andreas", "Wendy K"], "article-title": ["Post-translational formation of hypusine in eif5a: implications in human neurodevelopment."], "source": ["Amino Acids"], "fpage": ["1"], "lpage": ["15"], "year": ["2021"]}, {"label": ["26."], "surname": ["Barba-Aliaga", "Villarroel-Vicente", "Stanciu", "Corman", "Mart\u00ednez-Pastor", "Alepuz"], "given-names": ["M", "C", "A", "A", "MT", "P"], "article-title": ["Yeast translation elongation factor eif5a expression is regulated by nutrient availability through different signalling pathways."], "source": ["International Journal of Molecular Sciences"], "volume": ["22"], "fpage": ["219"], "year": ["2021"]}, {"label": ["37."], "surname": ["Li", "Vizeacoumar", "Bahr", "Li", "Warringer", "Vizeacoumar", "Min", "Vandersluis", "Bellay", "Devit"], "given-names": ["Zhaohui", "Franco J", "Sara", "Jie", "Jonas", "Frederick S", "Renqiang", "Benjamin", "Jeremy", "Michael"], "article-title": ["Systematic exploration of essential yeast gene function with temperature-sensitive mutants."], "source": ["Nature Biotechnology"], "volume": ["29"], "issue": ["4"], "fpage": ["361"], "lpage": ["367"], "year": ["2011"]}, {"label": ["39."], "surname": ["Hou", "Harjono", "Harvey", "Subramaniam", "Zid"], "given-names": ["Wanchen", "Veronica", "Adam T", "Arvind R", "Brian M"], "article-title": ["Quantification of elongation stalls and impact on gene expression in yeast."], "source": ["RNA"], "year": ["2023"]}, {"label": ["43."], "surname": ["Sanchez", "Lindquist"], "given-names": ["Y", "SL"], "article-title": ["Hsp104 required for induced thermotolerance."], "source": ["Science (80- )"], "volume": ["248"], "fpage": ["1112"], "lpage": ["1115"], "year": ["1990"]}, {"label": ["46."], "surname": ["Mokranjac", "Neupert"], "given-names": ["Dejana", "Walter"], "article-title": ["Thirty years of protein translocation into mitochondria: Unexpectedly complex and still puzzling."], "source": ["Biochimica et Biophysica Acta (BBA)-Molecular Cell Research"], "volume": ["1793"], "issue": ["1"], "fpage": ["1400"], "lpage": ["1407"], "year": ["2009"]}, {"label": ["47."], "surname": ["Chaudhuri", "Tripathi", "Gonzalez"], "given-names": ["Mousumi", "Abhay", "Frank S"], "article-title": ["Diverse functions of tim50, a component of the mitochondrial inner membrane protein translocase."], "source": ["International Journal of Molecular Sciences"], "volume": ["23"], "fpage": ["7779"], "year": ["2021"]}, {"label": ["59."], "surname": ["X Zhang", "Han", "Zhou", "Cai", "Li", "Liu", "Liu", "Wang", "Fan", "Li"], "given-names": ["S", "H", "L", "J", "N", "Y", "L", "C", "A"], "article-title": ["Timm50 promotes tumor progression via erk signaling and predicts poor prognosis of non-small cell lung cancer patients."], "source": ["Mol Carcinog"], "volume": ["39"], "fpage": ["110855"], "year": ["2019"]}, {"label": ["66."], "surname": ["Zuzuarregui", "Li", "Friedmann", "Ammerer", "Alepuz"], "given-names": ["A", "T", "C", "G", "P"], "article-title": ["Msb2 is a ste11 membrane concentrator required for full activation of the hog pathway."], "source": ["Biochim Biophys Acta - Gene Regul Mech"], "volume": ["1849"], "fpage": ["722"], "lpage": ["730"], "year": ["2015"]}]	{ "acronym": [], "definition": [] }	69	CC BY	no	2024-01-13 23:49:38	bioRxiv. 2023 Dec 19;:2023.12.19.572290	oa_package/a4/48/PMC10769225.tar.gz
PMC10769232	38187716	[ "<title>Background</title>", "<p id=\"P6\">Late-onset Alzheimer’s disease (LOAD2) is the most common form of dementia, caused by a combination of genetic and environmental factors<sup>##REF##26045020##1##–##REF##21539488##3##</sup>. Despite recent approval of anti-amyloid therapies such as Aduhelm<sup>®##UREF##0##4##</sup> and Leqembi<sup>®##UREF##1##5##</sup>, additional therapeutic options are essential to prevent or slow cognitive decline in most cases of LOAD. To achieve this, preclinical models that more faithfully reproduce the complex features of LOAD are required to maximize translatability of preclinical studies to the clinic.</p>", "<p id=\"P7\">The MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer’s disease) consortium is charged with creating and phenotyping new mouse models based on the genetics of LOAD<sup>##REF##33283040##6##</sup>. The IU/JAX/PITT MODEL-AD Center has focused on creating models on the C57BL/6J (B6J) genetic background that incorporate the e4 allele of the apolipoprotein E gene (<italic toggle=\"yes\">APOE4</italic>)<sup>##REF##35370604##7##</sup>, the greatest genetic risk factor for LOAD. In addition, we created the e3 (neutral) allele (<italic toggle=\"yes\">APOE3</italic>)<sup>##REF##35370604##7##</sup>. These humanized APOE alleles allow for the unrestricted use and breeding that was not readily available with previous versions<sup>##REF##35370604##7##</sup>. This allowed us to determine the effects of combining multiple genetic risk factors for LOAD. We generated and characterized B6J mice that were double homozygous for both <italic toggle=\"yes\">APOE4</italic> and the <italic toggle=\"yes\">R47H</italic> variant in <italic toggle=\"yes\">Trem2</italic> (Triggering receptor expressed on myeloid cells 2). These mice were termed LOAD1<sup>##UREF##2##8##</sup>. Although LOAD1 mice did not develop classic hallmarks of LOAD, such as amyloid pathology, neurodegeneration, and cognitive decline, they did show alterations in gene expression levels in the brain similar to those seen in LOAD patients, as well as changes in cerebrovascular blood flow and glucose uptake<sup>##UREF##2##8##</sup>.</p>", "<p id=\"P8\">We now present the comprehensive characterization of LOAD2 (B6J.<italic toggle=\"yes\">APOE4</italic>.<italic toggle=\"yes\">Trem2R47H</italic>.<italic toggle=\"yes\">hA</italic>β triple homozygous), where the Aβ sequence of the mouse <italic toggle=\"yes\">App</italic> gene of LOAD1 mice has been humanized<sup>##UREF##2##8##</sup>. Data support that the human Aβ sequence is more amyloidogenic than the mouse version and so we test the hypothesis that LOAD2 mice will develop features of LOAD that were absent in LOAD1 mice. In addition, we evaluate a high-fat diet/high-sugar diet (HFD), a common environmental stressor, that human and mouse studies show increases risk for LOAD<sup>##REF##12580703##9##, ##REF##35813947##10##</sup>. For instance, our previous study showed chronic consumption of a HFD exacerbated the genetic effects of LOAD1 mice carrying the <italic toggle=\"yes\">Plcg2M28L</italic><sup>##REF##35813947##10##</sup>. Here, using a combination of a cross-sectional and longitudinal design, cohorts of male and female LOAD1 and LOAD2 mice were fed either a control diet (CD) or HFD from 2 months of age and evaluated at 4, 12, 18 or 24 months of age. Data show that unlike LOAD1 mice, LOAD2 mice fed a HFD (LOAD2+HFD) resulted in age-related neurodegeneration, cognitive deficits, elevations in insoluble Aβ and LOAD-relevant imaging abnormalities, and increased neurofilament light chain (NfL) in the plasma. We propose LOAD2+HFD as a relevant mouse model for investigating therapeutic interventions independent of targeting tau and amyloid pathologies.</p>" ]	[ "<title>Methods</title>", "<title><italic toggle=\"yes\">Creation of the humanized A</italic>β allele</title>", "<p id=\"P9\">The humanized Aβ allele was created by direct delivery of CRISPR-Cas9 reagents to mouse zygotes of the APOE4/Trem2R47H model, (B6(SJL)-<italic toggle=\"yes\">Apoe</italic><sup><italic toggle=\"yes\">tm1.1(APOE4)Adiuj</italic></sup>\n<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">em1Adiuj</italic></sup>/J or “LOAD1”, JAX #28709, <ext-link xlink:href=\"https://www.jax.org/strain/028709\" ext-link-type=\"uri\">https://www.jax.org/strain/028709</ext-link>) which was previously described<sup>##UREF##2##8##</sup></p>", "<p id=\"P10\">Analysis of genomic DNA sequence surrounding the target region, using the Benchling (<ext-link xlink:href=\"http://www.benchling.com/\" ext-link-type=\"uri\">www.benchling.com</ext-link>) guide RNA design tool, identified a gRNA sequence (TTTGATGGCGGACTTCAAATC) with a suitable target endonuclease site in exon 14 of the mouse App locus. Streptococcus pyogenes Cas9 (SpCas9) V3 protein and gRNA were purchased as part of the Alt-R CRISPR-Cas9 system using the crRNA:tracrRNA duplex format as the gRNA species (IDT, USA). Alt-R CRISPR-Cas9 crRNAs (Product# 1072532, IDT, USA) were synthesized using the gRNA sequences specified in the DESIGN section and hybridized with the Alt-R tracrRNA (Product# 1072534, IDT, USA) as per manufacturer’s instructions. A single-stranded DNA repair construct (synthesized by Genscript) with the sequence 5’-CTGGGCTGACAAACATCAAGACGGAAGAGATCTCGGAAGTGAAGATGGATGCAGA ATTC<bold>C</bold>GACATGATTCAGGAT<bold>A</bold>TGAAGTCC<bold>AT</bold>CATCAAAAACTGGTAGGCAAAAATA AACTGCCTCTCCCCGAGATTGCGTCTGGCCAGATGAAAT-3’ was used to introduce the G601R, F606Y, and R609H amino acid changes in the mouse <italic toggle=\"yes\">App</italic> sequence (corresponding to G676R, F681Y and R864H in human <italic toggle=\"yes\">APP</italic>) such that the Ab-42 region matches the human sequence (##FIG##0##Figure 1A##).</p>", "<p id=\"P11\">Founders were bred to the LOAD1 model and genotyped for the humanized Aβ locus by PCR using forward primer 5’-CAGTTTTTGCCTCCTTGTGG-3’ and reverse primer 5’-GGCTTCTGCTCAGCAAGAACTA-3’. A positive reaction was determined by the presence of a band of 362bp. The resulting strain (“LOAD2”) is available as JAX #30670, B6J.Cg-<italic toggle=\"yes\">Apoe</italic><sup><italic toggle=\"yes\">tm1.1(APOE*4)Adiuj</italic></sup>\n<italic toggle=\"yes\">App</italic><sup><italic toggle=\"yes\">em1Adiuj</italic></sup>\n<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">em1Adiuj</italic></sup>/J (<ext-link xlink:href=\"https://www.jax.org/strain/030670\" ext-link-type=\"uri\">https://www.jax.org/strain/030670</ext-link>; B6J.<italic toggle=\"yes\">APOE</italic><sup><italic toggle=\"yes\">E4/E4</italic></sup>.<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">R47H/ R47H</italic></sup>.<italic toggle=\"yes\">App</italic><sup>hAβ/ hAβ</sup>). The <italic toggle=\"yes\">App</italic> allele alone is available as JAX #33013, B6J.Cg-<italic toggle=\"yes\">App</italic><sup><italic toggle=\"yes\">em1Adiu</italic>j</sup>/J (<ext-link xlink:href=\"https://www.jax.org/strain/033013\" ext-link-type=\"uri\">https://www.jax.org/strain/033013</ext-link>).</p>", "<title>Cohort generation and evaluation</title>", "<p id=\"P12\">To evaluate LOAD-relevant phenotypes, five cohorts of LOAD2 mice and controls were created at The Jackson Laboratory (JAX, cohort 1), Indiana University (IU, cohorts 2 and 3) and University of Pittsburgh (PITT, cohorts 4 and 5). Breeding, mouse husbandry, and assays common across sites were standardized as much as possible. Below, we provide brief details of each cohort and assays performed with full details included provided in ##SUPPL##0##Supplemental Methods##.</p>", "<title>Cohort 1 – The Jackson Laboratory</title>", "<p id=\"P13\">All procedures were approved by The Jackson Laboratory Institutional Animal Care and Use Committee (IACUC).</p>", "<title>Experimental groups:</title>", "<p id=\"P14\">To create experimental groups, B6J.<italic toggle=\"yes\">APOE</italic><sup><italic toggle=\"yes\">E4/E4</italic></sup>.<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">R47H/R47H</italic></sup>.<italic toggle=\"yes\">App</italic><sup>hAβ/+</sup> mice were intercrossed to create B6J.<italic toggle=\"yes\">APOE</italic><sup><italic toggle=\"yes\">E4/E4</italic></sup>.<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">R47H/R47H</italic></sup>.<italic toggle=\"yes\">App</italic><sup>hAβ/hAβ</sup> (LOAD2) and B6J.<italic toggle=\"yes\">APOE</italic><sup><italic toggle=\"yes\">E4/E4</italic></sup>.<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">R47H/R47H</italic></sup>.<italic toggle=\"yes\">App</italic><sup>+/+</sup> (LOAD1) control mice. In appreciation of sexual dimorphism observed in human aging and disease, four groups of male and female mice were established for a combination of longitudinal and cross-sectional phenotyping at 4-, 12-, 18-, and 24-months. The 18-months group was assessed for biometrics and plasma biomarkers at 4-, 8-, 12- and 18-months.</p>", "<p id=\"P15\">All mice were initially provided LabDiet<sup>®</sup> 5K52/5K67 (6% fat; control diet, CD). At 2 months of age, each experimental group was randomized into two groups, the control group, and the high-fat diet (HFD) group. The control groups continued on CD <italic toggle=\"yes\">ad libitum</italic>, while the HFD groups were provided ResearchDiet<sup>®</sup> feed D12451i (45% high fat, 35% carbohydrates) <italic toggle=\"yes\">ad libitum</italic>. Due to attrition between 18–24 months of age, the 24-month HFD cohort was not sufficiently powered and so not analyzed. For <italic toggle=\"yes\">in vivo</italic> studies – at least 10 mice/sex/genotype/age/diet were evaluated. For post-mortem analyses, 6 mice/sex/genotype/age/diet were evaluated unless otherwise stated.</p>", "<title>Phenotyping:</title>", "<p id=\"P16\">The cross-sectional phenotyping battery included <italic toggle=\"yes\">in vivo</italic> frailty, behavioral phenotyping, and metabolic profiling and biomarker (e.g., Neurofilament light chain, NfL) analyses in the plasma. Postmortem brain tissue was examined for transcriptomic and proteomic analyses as well as neuropathological indications of disease (amyloid, neuronal cell loss, and glial activation). For full details see ##SUPPL##0##Supplemental Methods## (##SUPPL##0##Supplemental Figure 1##).</p>", "<title>Cohorts 2: Indiana University</title>", "<p id=\"P17\">All procedures were approved by the Indiana University Institutional Animal Care and Use Committee (IACUC). The same bedding, light cycle, and water conditions as The Jackson Laboratory were used at Indiana University.</p>", "<title>Experimental groups:</title>", "<p id=\"P18\">LOAD2 mice were imported from JAX and bred at IU. LOAD2 mice were initially crossed to LOAD1 mice to create B6J.<italic toggle=\"yes\">APOE</italic><sup><italic toggle=\"yes\">E4/E4</italic></sup>.<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">R47H/R47H</italic></sup>.<italic toggle=\"yes\">App</italic><sup>hAβ/+</sup> mice that were then intercrossed to create B6J.<italic toggle=\"yes\">APOE</italic><sup><italic toggle=\"yes\">E4/E4</italic></sup>.<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">R47H/R47H</italic></sup>.<italic toggle=\"yes\">App</italic><sup>hAβ/hAβ</sup> (LOAD2) mice. One group of at least 10 male and 10 female mice were established for longitudinal phenotyping at 4, 12, and 18 months. Similar to the JAX cohort, mice were initially provided CD before half the mice in each group were switched to HFD.</p>", "<title>Phenotyping:</title>", "<p id=\"P19\">At 4, 12, and 18 months, mice underwent <italic toggle=\"yes\">in vivo</italic> MR imaging (T2 weighted images) and blood draws for biomarker (e.g., Aβ species, cytokines) analyses. For full details see ##SUPPL##0##Supplemental Methods##. At 18 months, tissues were collected as described for Cohort 1.</p>", "<title>Cohort 3: <italic toggle=\"yes\">Indiana University</italic></title>", "<p id=\"P20\">All procedures were approved by the Indiana University Institutional Animal Care and Use Committee (IACUC). The same bedding, light cycle, and water conditions as The Jackson Laboratory were used at Indiana University.</p>", "<title>Experimental groups:</title>", "<p id=\"P21\">Experimental groups of male and female LOAD2 mice on HFD or CD were established as described for Cohort 3 (n=12 mice/sex/genotype/age/diet). Three groups were established for cross-sectional analyses at 4, 12, and 18 months.</p>", "<title>Phenotyping:</title>", "<p id=\"P22\">To evaluate neurovascular uncoupling, <italic toggle=\"yes\">in vivo</italic> PET/CT imaging was performed on all mice measuring regional blood flow (via <sup>64</sup>Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone, <sup>64</sup>Cu-PTSM) and regional glycolytic metabolism (via 2-<sup>18</sup>F-2-deoxyglucose, <sup>18</sup>F-FDG). Findings from <italic toggle=\"yes\">in vivo</italic> PET/CT were confirmed using autoradiography. For full details see ##SUPPL##0##Supplemental Methods##.</p>", "<title>Cohort 4 and 5: University of Pittsburgh</title>", "<p id=\"P23\">All procedures were approved by the University of Pittsburgh Institutional Animal Care and Use Committee (IACUC). Detailed mouse husbandry, diet restriction, and phenotyping methods are included in the ##SUPPL##0##Supplemental Methods##.</p>", "<title>Experimental groups:</title>", "<p id=\"P24\">Two experimental cohorts were evaluated for plasma biomarkers and cognitive testing. Breeding pairs of LOAD2 mice were imported from JAX and bred at the University of Pittsburgh to create Cohort 4. One group of n=18 male and n=18 female mice were established for longitudinal blood plasma collection followed by cognitive assessments using the touchscreen. Subjects were reared on normal control diet (CD) (LabDiet<sup>®</sup> 5P76) provided <italic toggle=\"yes\">ad libitum</italic> until 2 months of age at which time n=13 male and n=14 female mice were randomly assigned to receive ad libitum HFD (LOAD2+HFD). For cohort 5, LOAD2 mice (B6J.<italic toggle=\"yes\">APOE</italic><sup><italic toggle=\"yes\">E4/E4</italic></sup>.<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">R47H/ R47H</italic></sup>.<italic toggle=\"yes\">App</italic><sup>hAβ/ hAβ</sup> ) were bred with C57BL/6J to provide littermate controls. The F1 offspring which were triple heterozygotes (B6J.<italic toggle=\"yes\">APOE</italic><sup><italic toggle=\"yes\">E4/+</italic></sup>.<italic toggle=\"yes\">Trem2</italic><sup><italic toggle=\"yes\">R47H/+</italic></sup>.<italic toggle=\"yes\">App</italic><sup>hAβ/+</sup>) were then crossbred to produce F2 offspring including the LOAD2 triple homozygote mice (n=9/sex) and triple wildtype littermate controls (n=6/sex). All mice were initially reared on CD, with n=3/sex wildtype controls and n=6/sex LOAD2 switched to ad libitum HFD at 6–12 months of age. Prior to touchscreen testing, mice were individually housed and restricted to 80–85% of free-feeding body weight. Mice were weighed daily and provided a ration of the respective CD or HFD diets that maintained them at 80–85% restriction.</p>", "<title>Phenotyping:</title>", "<p id=\"P25\">Blood plasma was evaluated longitudinally prior to the start of HFD, followed monthly for analysis of cytokines and every 3 months for analysis of Aβ species. To evaluate the effect of food restriction on plasma biomarker levels, brief 2-week periods of food restriction as described above were administered to Cohort 4 at 8–8.5 months of age and at 10–10.5 months of age. At 14 months of age, Cohort 4 was enrolled in Touchscreen cognitive testing and maintained continuously on dietary restriction until the conclusion of touchscreen testing (##FIG##7##Figure 8A##); while Cohort 5 began food restriction and touchscreen testing at 11–17 months of age (##SUPPL##0##Supplemental Figure 7A##). It is important to note that the present studies used a 10% sucrose solution for the reward which is a departure from the standard touchscreen protocols that use strawberry flavored milkshake-based rewards<sup>##REF##29924918##11##</sup>. We intentionally chose to avoid milk-based rewards given that the constituents of milk and dairy products may contribute to attenuation of AD related pathologies including amyloid deposition and inflammation<sup>##REF##32680941##12##–##UREF##3##14##</sup>. Notably 10% sucrose is a common and well-established reinforcer for mice in operant based tasks and therefore was a salient alternative as evidenced by the ability of all subjects to demonstrate consumption of the reward and acquire the touch-reward association during the initial phase of the task.</p>" ]	[ "<title>Results</title>", "<p id=\"P26\">LOAD2 mice were created at JAX and distributed to IU and PITT for evaluation of LOAD relevant phenotypes using the IU/JAX/PITT MODEL-AD center pipeline that includes a combination of human-relevant <italic toggle=\"yes\">in vivo</italic> and post-mortem assays. The primary goal of the phenotyping pipeline is to determine the utility of new LOAD models for preclinical testing. Five cohorts of LOAD2 and control mice fed either a HFD (high-fat diet) or CD (control diet) were evaluated at JAX (Cohort 1: biometrics, behavior, plasma biomarkers, neuropathology, transcriptomics, proteomics), IU (Cohort 2: MRI, plasma biomarkers and cytokines, biochemistry, neuropathology; Cohort 3: PET/CT, autoradiography), and PITT (Cohorts 4 and 5: longitudinal plasma biomarkers, Touchscreen cognitive testing) (##SUPPL##0##Supplemental Figure 1##). Unless otherwise stated, to evaluate LOAD2 phenotypes (on CD or HFD), LOAD1 mice were used as the control genotype to evaluate the effects of humanizing the Aβ sequence in the context of the <italic toggle=\"yes\">APOE4</italic> and Trem2R47H risk alleles (LOAD1). LOAD1 and LOAD2 mice both express humanized <italic toggle=\"yes\">APOE4</italic> and <italic toggle=\"yes\">Trem2R47H risk</italic> alleles on a B6J background, however LOAD2 animals also express a humanized allele for <italic toggle=\"yes\">App</italic> (##FIG##0##Figure 1A##).</p>", "<title>LOAD2 mice show diet- and age-dependent neuronal cell loss and plasma NfL increases (cohort 1)</title>", "<p id=\"P27\">Cohort 1 comprised four age groups (4, 12, 18 and 24 months). The 4-, 12-, and 18-month groups included LOAD1 and LOAD2 mice on both HFD and CD. The 24-month group included only mice on CD. We first evaluated the 18-month group using <italic toggle=\"yes\">in vivo</italic> assays following a longitudinal design. Longitudinal testing and sampling were performed at 4-, 12-, and 18-months of age. We observed significant, diet-driven increases in body weight with age (##FIG##0##Figure 1B##). All mice showed an increase in weight with age, but mice fed HFD showed pronounced weight gain until 18 months of age. Females on the HFD displayed significant weight gain from 4- to 12-months, but only made modest gains from 12- to 18- months. Males fed a HFD were more accelerated than females, and LOAD2 males were consistently heavier than LOAD1 males at all timepoints. However, fasted blood glucose measurements did not appear to be age-, diet-, or genotype-dependent, though slightly elevated levels were observed in LOAD2 mice fed HFD (LOAD2+HFD) (##FIG##0##Figure 1C##). As expected, age was a strong factor of increased frailty<sup>##REF##35115731##15##</sup> (##FIG##0##Figure 1D##). However, we did not see significant diet-related changes in frailty scores in females until 18 months of age and only in LOAD2 genotype animals. Males consistently displayed increased frailty driven by diet, but not genotype, as early as 8 months of age.</p>", "<p id=\"P28\">HFD reduced performance in open field assays compared to CD. Specifically total distance traveled decreased significantly only in LOAD2 animals (##SUPPL##0##Supplemental Figure 2A##), but performance was not affected by sex or genotype alone. Differences in total vertical activity were only observed in males, of both genotypes, to be decreased by HFD (##SUPPL##0##Supplemental Figure 2B##). Rotarod performance was decreased in a HFD-dependent manner only (##SUPPL##0##Supplemental Figure 2C##). LOAD2+HFD animals, however, particularly males, demonstrated a reduction in running wheel activity during the active period (dark cycle) compared to LOAD1 mice or those fed CD (##FIG##0##Figure 1E##). Hippocampal working memory in the spontaneous alternation assay as a measure of cognitive function was intact across all groups with all subjects performing >chance levels which is calculated as 22% in this assay (##FIG##0##Figure 1F##).</p>", "<p id=\"P29\">Brains from mice from the 18-month group were harvested (along with the 4-, 12-, and 24-month groups). One hemisphere (right) from each brain was prepared for transcriptomics and proteomics, while the other hemisphere (left) was evaluated for neuronal cell loss, microglia number, astrocyte reactivity and amyloid plaques in the cortex and hippocampus by immunofluorescence (##SUPPL##0##Supplemental Figure 3##). At 18 months of age, neuron counts in the cortex revealed a subtle but statistically significant decrease in NeuN+DAPI+ cells in female LOAD2+HFD compared to female LOAD2+CD and female LOAD1+HFD (##FIG##1##Figure 2 A##,##FIG##1##B##). No differences were observed in cortical IBA1+DAPI+ microglia number (##FIG##1##Figure 2 C##,##FIG##1##D##) across all groups, and a small but significant decrease in hippocampal astrocyte reactivity (assessed using GFAP+DAPI+) in male LOAD2+HFD mice compared to those fed a CD diet (##FIG##1##Figure 2 E##,##FIG##1##F##). ThioS staining revealed no evidence of amyloid plaques in any groups (##FIG##1##Figure 2G##). To determine whether neuronal cell changes in LOAD2+HFD was reflected by changes in the plasma, NFL, a clinically relevant biomarker<sup>##REF##19584430##16##</sup> was assessed. Plasma NfL levels were significantly increased in LOAD2 animals on both diets (##FIG##1##Figure 2H##). Similarly, we saw significant increase in LOAD1+HFD relative to LOAD1+CD.</p>", "<title>Differential analysis identifies strong transcriptional changes in female mice expressing humanized Aβ on high-fat high sugar diet (cohort 1)</title>", "<p id=\"P30\">To identify molecular effects of humanizing the Aβ peptide, we first performed pairwise differential analysis between LOAD2 and LOAD1 mice at all ages for both sexes. Differential expression analyses identified very few significantly differentially expressed genes (DEGs) (p < 0.05) at 4 and 18 months old LOAD2 mice compared to age and sex-matched LOAD1 mice (Supplementary Table A). At 12 months, there were 57 DEGs (38 upregulated, 19 downregulated; p < 0.05) in male LOAD2 mice, and 17 DEGs (3 upregulated, 14 downregulated; p < 0.05) in female LOAD2 mice (Supplementary Table A). KEGG functional enrichment analysis identified enrichment of “protein processing in ER” in upregulated DEGs in 12 months old LOAD2 male mice and “MAPK signaling pathway” in downregulated DEGs in 12 months old LOAD2 female mice (Supplementary Table B). At 24 months, there were only 5 significantly differentially upregulated genes (p < 0.05) in male LOAD2 mice, and 30 DEGs (12 upregulated, 18 downregulated; p < 0.05) in female LOAD2 mice (Supplementary Table A). Upregulated DEGs in male and female LOAD2 mice were enriched for the “motor proteins” KEGG pathways (Supplementary Table B).</p>", "<p id=\"P31\">Next, we performed differential analyses in 18-month-old LOAD2 and LOAD1 mice compared to age and sex-matched B6J control mice. In females, we observed only 9 significantly DEGs (3 upregulated, 6 downregulated) (p < 0.05) in LOAD2 mice on control diet (CD), while 2988 genes were significantly differentially expressed (1565 upregulated, 1423 downregulated) (p < 0.05) in LOAD2+HFD (Supplementary Table A). We observed 44 significantly DEGs (19 upregulated, 25 downregulated) (p < 0.05) in female LOAD1+CD, while 164 genes were significantly differentially expressed (117 upregulated, 47 downregulated) (p < 0.05) in female LOAD1+HFD (Supplementary Table A). In males, we observed a total of 7 and 23 significantly DEGs (p < 0.05) in LOAD1 and LOAD2 mice on CD, respectively, while 39 and 98 genes were significantly expressed (p < 0.05) in LOAD1 and LOAD2 mice on HFD, respectively (Supplementary Table A). Overall, we observed more differentially expressed genes in mice conditioned on HFD and this effect was more prominent in female mice expressing humanized Aβ.</p>", "<p id=\"P32\">Functional enrichment analyses of DEGs in female LOAD2+HFD identified enrichment of multiple KEGG pathways such as “glutamatergic synapse”, “dopaminergic synapse”, and “MAPK signaling pathway” in upregulated genes, while downregulated genes were enriched for KEGG pathways such as “lysosome”, “fatty acid metabolism”, “TCS cycle”, and “valine, leucine and isoleucine degradation”. Differentially upregulated genes in female LOAD1+HFD were enriched for “circadian entrainment”, while downregulated genes were enriched for “phagosome” KEGG pathway (Supplementary Table B). We did not observe enrichment for any KEGG pathways in DEGs in LOAD1 and LOAD2 mice on control diet.</p>", "<p id=\"P33\">Next, we assess the effect of HFD by performing differential analysis between mice fed the HFD with age, sex, and genotype-matched mice on CD. We observed 260 significantly DEGs (154 upregulated, 106 downregulated) (p < 0.05) in female LOAD2+HFD compared to female LOAD2+CD, while 45 significantly DEGs (9 upregulated, 36 downregulated) (p < 0.05) in male LOAD2+HFD compared to male LOAD2+CD (Supplementary Table A). In LOAD1 male mice, we observed a total of 12 DEGs (p < 0.05) on HFD compared to CD, while only 2 DEGs (p < 0.05) on HFD compared to CD in female LOAD1 mice (Supplementary Table A). Upregulated genes in female LOAD2 female mice on HFD compared to CD were enriched for KEGG pathways such as “glutamatergic synapse”, “dopaminergic synapse”, and “MAPK signaling pathway”, while downregulated genes in female LOAD2+HFD compared to CD were enriched for “motor proteins” pathway (Supplementary Table B).</p>", "<title>Gene modules associated with AD pathology driven by age and high-fat high-sugar diet</title>", "<p id=\"P34\">Differential expression analyses identified subtle changes at the gene level and suggested pronounced effect of LOAD2 genotype by high-fat/high-sugar diet (HFD) in aged mice. To further ensure these signals, we performed a weighted gene co-expression network analysis (WGCNA) <sup>##REF##24051961##17##</sup> on the brain transcriptome to identify gene expression changes in a system-level framework. WGCNA identified 30 distinct modules of co-expressed genes (Supplementary Table B2).</p>", "<p id=\"P35\">To understand the functional significance of these modules, we correlated each module eigengene with age, sex, diet, genotype, and measured behavioral assays such as cumulative frailty score, body weights, NfL, plasma cytokines, GFAP, Iba1 and NeuN counts (##SUPPL##0##Supplemental Figure 4##). Eighteen of these 30 modules were significantly correlated with age (p < 0.05) (turquoise, lightyellow, darkgreen, green, darkgrey, floralwhite, purple, brown4, red, skyblue3, lightcyan, orangred4, darkorange2, plum1, orange, lightcyan1, greenyellow, and blue). Six modules were significantly correlated with HFD (p < 0.05) (lightyellow, turquoise, brown4, darkgrey, darkred, orangered4). Seven modules were significantly correlated with sex (p < 0.05) (sienna3, greenyellow, orangered4, darkmagenta, skyblue3, red, bisque4). Two modules (greenyellow and sienna3) were significantly correlated with the Apoe4.Trem2*R47H allele combination in both LOAD1 and LOAD2 (p < 0.05), while five modules were significantly correlated with humanized Aβ specific to LOAD2 (p < 0.05) (brown, thistle3, greenyellow, blue, and orange) (##SUPPL##0##Supplemental Figure 4##).</p>", "<p id=\"P36\">We observed that HFD was strongly significantly correlated with the lightyellow module (r=0.45; p = 9 × 10<sup>−9</sup>), while age was strongly significantly correlated with both the turquoise (r=0.81; p = 2 × 10<sup>−35</sup>) and lightyellow modules (r=0.52; p = 1 × 10<sup>−11</sup>) (##SUPPL##0##Supplemental Figure 4##). To further elucidate the association of the lightyellow and turquoise modules with age, sex, and genotype-diet combinations, we performed linear regression analysis using module eigengene as the dependent variable. We determined that the lightyellow module was significantly positively correlated with LOAD1 and LOAD2 genotype with HFD (p < 0.05) and age (p < 0.001), while turquoise module was significantly positively correlated with age (p < 0.001) (##FIG##2##Figure 3A##). In summary, we observed age and genotype-by-diet effects on the lightyellow module, while the turquoise module is driven only by age. We also observed that the diet and age driven lightyellow module was significantly correlated (p < 0.05) with multiple assays such as NfL, frailty score, plasma cytokines (IL1β, IL10, IL5, IL6, KC-GRO) (##FIG##2##Figure 3B##, ##SUPPL##0##Supplemental Figure 4##). In contrast, the age driven turquoise module was significantly correlated (p < 0.05) with effect of age on behavior and weakly correlated with a few plasma cytokines (IL2, IFN-γ) and inflammatory cell counts (Iba1 and GFAP counts) (##FIG##2##Figure 3B##, ##SUPPL##0##Supplemental Figure 4##). The lightyellow module was uniquely driven by both age and diet and demonstrated strong positive associations with AD biomarkers such as NfL and multiple cytokines.</p>", "<p id=\"P37\">We further assessed the enrichment of AD biological domains<sup>##UREF##4##18##</sup> in gene modules. We found that genes in lightyellow modules were significant enriched for the Apoptosis (odds ratio=1.90, p = 2.11 × 10<sup>−4</sup>), Immune Response (odds ratio=1.63, p = 3.67 × 10<sup>−3</sup>), Lipid Metabolism (odds ratio=2.01, p = 3.64 × 10<sup>−6</sup>), Oxidative Stress (odds ratio=1.76, p = 3.32 × 10<sup>−2</sup>), and Vasculature (odds ratio=2.14, p = 1.14 × 10<sup>−4</sup>) AD biological domains (##FIG##2##Figure 3C##–##FIG##2##D##; Supplementary Table B3). We also identified GO-terms associated with these biological domains that are significantly enriched in lightyellow gene modules (##FIG##2##Figure 3C##–##FIG##2##D##, Supplementary Table B3). On the other hand, genes in the turquoise module were prominently enriched for the Immune Response biological domain (odds ratio=2.39, p = 1.8 × 10<sup>−49</sup>) (Supplementary Table B3). These data suggest that age is strongest risk factor for driving inflammatory changes, while diet effects in aged LOAD mice are associated with multiple AD endophenotypes such as lipid metabolism, immune response, and oxidative stress.</p>", "<title>LOAD mice display proteomics changes characteristic of AD</title>", "<p id=\"P38\">Tandem mass tag proteomics was performed on hemibrains from LOAD1 and LOAD2 mice at 4, 12, and 18 months of age on control diet. LOAD1 and LOAD2 mice fed HFD were also assayed at 18 months, paired with B6J controls on CD. A total of 10,406 proteins were quantified across 106 samples. To focus on effects in aged mice, we assessed protein expression changes in at 18-month-old LOAD1 and LOAD2 mice on CD and HFD compared to age-matched B6J mice on CD by one-way ANOVA with post-hoc Tukey significance testing (Supplementary Table C). In LOAD1 mice on CD, we observed 1666 significantly differentially expressed proteins (838 upregulated, 828 downregulated) (padj < 0.05), while a total of 2590 proteins were significantly differentially expressed (1237 upregulated, 1353 downregulated) (padj < 0.05) in LOAD1+HFD compared to B6J mice on CD (Supplementary Table C). In LOAD2+CD, we observed a total of 1102 significantly differentially expressed proteins (535 upregulated, 567 downregulated) (padj < 0.05) while in LOAD2+HFD we observed 1839 significantly differentially expressed proteins (897 upregulated, 942 downregulated) (padj < 0.05). We therefore observed hundreds of differentially expressed proteins in both LOAD1 and LOAD2, with greater numbers for both strains on HFD.</p>", "<p id=\"P39\">To assess disease relevant aspects of mouse models, we performed a correlation analysis between mouse models and 44 human proteomics modules from a LOAD study of the dorsolateral prefrontal cortex<sup>##REF##37414601##19##</sup>. These modules were functionally annotated and named based on protein enrichments and each was assessed for eigenprotein correlations to AD traits including neuropathological markers and cognitive outcomes<sup>##REF##37414601##19##</sup>. Twelve modules were significantly correlated to one or more traits, referred to here as AD modules<sup>##REF##37414601##19##</sup>. We compared protein expression changes in LOAD1 and LOAD2 mice relative to B6J mice at 18 months with changes observed in human AD subjects versus controls for each human protein module. This procedure allowed module-wide assessment of coordinated protein changes and therefore determined murine reproduction of each module that characterizes human LOAD.</p>", "<p id=\"P40\">LOAD1 and LOAD2 mice were significantly and positively correlated (p < 0.05) with multiple common human AD modules. These included M1_Synapse_Neuron, M3_Oligo_Myelination, and M12_Cytoskeleton (##FIG##3##Figure 4A##; Supplementary Table D). The M2_Mitochondria module exhibited significant positive correlation (p < 0.05) with all mouse models except LOAD2 mice on HFD, for which a positive correlation did not reach significance (p = 0.06) (##FIG##3##Figure 4A##; Supplementary Table D). Additional correlations reaching significance included LOAD1 mice on HFD and LOAD2 mice on both diets with M22_Post-Synaptic_Density and M38_Heat_Shock_Folding modules (##FIG##3##Figure 4A##; Supplementary Table D). LOAD2+HFD additionally showed significant positive correlations with M4_Synapse_Neuron, M7_MAPK_Metabolism, and M43_Ribonucleoprotein_Binding modules (##FIG##3##Figure 4A##; Supplementary Table D), whereas other mice (LOAD1+CD, LOAD1+HFD and LOAD2+CD) were positively correlated but below the significance threshold.</p>", "<p id=\"P41\">Overall, we detected genetic effects from aged LOAD1 and LOAD2 mice that correlated with multiple human AD proteomics modules that were generally enhanced by exposure to HFD, especially in LOAD2 mice. LOAD2+HFD were positively correlated with ten of the 44 total protein modules, of which five modules (M1_Synapse_Neuron, M3_Oligo_Myelination, M4_Synapse_Neuron, M7_MAPK_Metabolism, and M22_Post-Synaptic_Density) were correlated with AD traits<sup>##REF##37414601##19##</sup>. These modules frequently represented neuronal proteins, distinct from the immune and metabolic signatures observed in transcriptomic analyses.</p>", "<p id=\"P42\">To better understand the functions of proteins driving the significant positive correlations between LOAD2 mice on HFD and human AD, we isolated the proteins within each module with common directional changes (increased or decreased abundance) for LOAD2+HFD and human AD cases. We performed gene ontology enrichment analysis on these proteins. Proteins that showed mouse-human directional coherence in the M1_Synapse_Neuron module were enriched for biological functions including “synaptic vesicle cycle”, “vesicle-mediated transport in synapse”, and “synapse organization” (##FIG##3##Figure 4B##; Supplementary Table E). Proteins that showed directional coherence in the M4_Synapse_Neuron module were enriched for “synaptic vesicle cycle” and “exocytosis” biological functions (##FIG##3##Figure 4B##; Supplementary Table E). In the M22_Post-Synaptic_Density module, coherent mouse-human proteins were enriched for biological functions including “synapse organization”, “postsynapse organization”, and “dendrite development” (##FIG##3##Figure 4B##; Supplementary Table E). These functions represent the core neuronal processes recapitulated in LOAD2+HFD at the protein level.</p>", "<p id=\"P43\">Proteins in these synaptic AD protein modules mostly had reduced abundance in LOAD2.HFD mice (logFC < 0) compared to chow-fed B6J controls. This reduced expression of proteins associated with synapse/neuronal functions was similar to human AD cases (##FIG##3##Figure 4C##), although we note these mice did not exhibit frank neurodegeneration.</p>", "<p id=\"P44\">For non-synaptic modules, we found coherent proteins in the M3_Oligo_Myelination module were enriched for biological functions including “oligodendrocyte differentiation”, “myelination”, and “microtubule organization” (##FIG##3##Figure 4B##; Supplementary Table E). Proteins with directional coherence in the M7_MAPK_Metabolism module were enriched for biological functions such as “regulation of transforming growth factor beta production” and “carbohydrate metabolic process” (##FIG##3##Figure 4B##; Supplementary Table E). In the M28_Ribosome_Translation module, protein abundances mostly increased (logFC > 0) and were enriched for “ribosome biogenesis” and “cytoplasmic translation” (##FIG##3##Figure 4B##–##FIG##3##C##; Supplementary Table E). Finally, coherent proteins in the M38_Heat_Shock_Folding module were enriched for “protein folding” and “chaperone-mediated protein folding” biological functions (##FIG##3##Figure 4B##; Supplementary Table E). Proteins exhibiting directional coherence in the M3_Oligo_Myelination and M7_MAPK_Metabolism modules generally had greater abundances in LOAD2+HFD mice compared to B6J controls and human AD cases, corresponding to increased protein expression associated with ‘MAPK_metabolism’ and ‘Oligo myelination’ (##FIG##3##Figure 4C##).</p>", "<title>Longitudinal Volumetric Measurements reveals age-dependent changes in brain volume (cohort 2)</title>", "<p id=\"P45\">Longitudinal volumetric measurements were employed to elucidate age-dependent alterations in brain volume within Cohort 2. Building upon the findings derived from Cohort 1 at JAX, which encompassed indicators such as neuronal cell loss, increased levels of neurofilament light chain (NfL), and molecular manifestations of neuronal cell dysfunction (refer to ##FIG##0##Figures 1##–##FIG##3##4##), Cohort 2 was established at Indiana University. This cohort consisted of male and female mice designated as LOAD1 and LOAD2, subjected to either a standard control diet (CD) or a high-fat diet (HFD). The primary objective at Indiana University was to assess brain volumes through in vivo magnetic resonance (MR) imaging and to conduct a comprehensive evaluation of LOAD2+HFD mice for plasma and brain biomarkers, with potential implications for preclinical testing.</p>", "<p id=\"P46\">In vivo MR imaging was conducted on LOAD2 CD and HFD-fed mice at 4, 12, and 18 months of age. The mean whole brain volumes for male LOAD2 CD and HFD mice were 478.56±18.63 and 459.56±6.41 mm^3 at 4 months, 464.53±15.16 and 468.40±9.83 mm^3 at 12 months, and 502.68±13.59 and 470.25±6.37 mm^3 at 18 months, respectively. Correspondingly, the mean whole brain volumes for female LOAD2 CD and HFD mice were 468.19±7.28 and 467.42±6.52 mm<sup>3</sup> at 4 months, 479.84±12.60 and 483.48±8.20 mm<sup>3</sup> at 12 months, and 507.29±11.46 mm<sup>3</sup> and 487.37±11.86 mm<sup>3</sup> at 18 months.</p>", "<p id=\"P47\">Statistical analysis revealed a significant reduction in brain volume was observed at 4 and 18 months in LOAD2+HFD male mice (4 months, p=0.0225 and 18 months, p=7.88e-6), while no significant difference was observed at 12 months (p=0.5134). For LOAD2 female mice on a HFD, a significant difference was observed at 18 months (p=0.0186), but no significant disparities at 4 months (p=0.812) or 12 months (p=0.4911).</p>", "<p id=\"P48\">Among the 165 brain labels analyzed, 45, 57, and 95 brain areas exhibited significant volumetric reductions at 4, 12, and 18 months, respectively, for male mice. Similarly, for female mice, 47, 67, and 51 brain areas displayed significant reductions at 4, 12, and 18 months. Volumetric statistical maps were generated for both male and female LOAD2 CD and HFD mice at the time points, and the significant areas were superimposed onto the T2-weighted template image. Notably, the analyses unveiled a progressive increase in the number of significant areas with advancing age of the mice (##FIG##4##Figure 5A##).</p>", "<title>Plasma and Brain Cytokines Are Altered by HFD</title>", "<p id=\"P49\">We next used cohort 2 mice to identify cytokines in the plasma and brain that may be utilized as biomarkers for preclinical testing. Analysis of NfL and cytokines in the plasma revealed an increase in NfL at 12 months in HFD males (##FIG##4##Figure 5B##). By 18 months, however, the HFD effect was absent, but an increase in NfL was driven by age (##FIG##4##Figure 5A##). Aβ40 was lower in males fed a HFD at 12 and 18 months, but the same difference was not observed in females; Aβ42 levels were not significant at any time point, likely due to variability among groups, however, there was an overall trend for a reduction in Aβ42 in males fed a HFD at 12 and 18 months (##FIG##4##Figure 5 C##,##FIG##4##D##). In HFD animals, we found significant increases in TNFα (##FIG##4##Figure 5E##) in LOAD2+HFD males at 12 and 18 months, females were approaching a significant increase by 18 months, but did not reach significance (##FIG##4##Figure 5F##). Additional proinflammatory cytokines were examined (##FIG##4##Figure 5 G##–##FIG##4##I##), with reductions in IFNγ observed in HFD males at 12 and 18 months and age-related alteration in IL-6, IL-2 and IL1β. Interestingly, as a confirmation and extension of these data and to demonstrate cross-laboratory replicability, we also observed sustained TNFα levels in HFD mice from Cohorts 4 and 5 (University of Pittsburgh). LOAD2+HFD males from 2 months of age in Cohort 4 maintained significantly higher concentrations of TNFα in their plasma from 7 months of age onward compared to LOAD2 males fed CD, while females on HFD appeared to follow a similar trend as males but only reached significance at 8–8.5 and 15–18 months of age (##FIG##7##Figure 8B##).</p>", "<p id=\"P50\">At 18 months of age, the brains from longitudinal cohort 2 were processed for biochemistry. In the brain, female LOAD2+HFD had increased insoluble Aβ42 (##FIG##5##Figure 6A##), but both males and females on a HFD had reduced insoluble Aβ40 and soluble Aβ40 and 42 (##FIG##5##Figure 6 B##–##FIG##5##D##). With regards to proinflammatory cytokines, HFD reduced IL-5 and IL-4 in females (##FIG##5##Figure 6 F##–##FIG##5##G##), but increased IL-2, KC-GRO, and IL-12 in both males and females (##FIG##5##Figure 6 H##–##FIG##5##J##). Interesting, in the brain (as compared to plasma), TNFα (##FIG##5##Figure 6K##) remained unchanged. Proinflammatory IL-10 was increased in males and females on a HFD (##FIG##5##Figure 6L##).</p>", "<title>In vivo PET/CT Analysis of Regional Neurovascular Uncoupling (cohort 3)</title>", "<p id=\"P51\">Cohort 3 mice (female and male LOAD1 and LOAD2 mice on CD and HFD) were established at Indiana University (see <xref rid=\"S6\" ref-type=\"sec\">Methods</xref>) to assess neurovascular uncoupling of <sup>18</sup>F-FDG and <sup>64</sup>Cu-PTSM, as measurements of cerebral glucose uptake and brain perfusion. Consistent with transcriptomics (##FIG##2##Figure 3##–##FIG##3##4##), along with blood and brain cytokines (##FIG##4##Figures 5##–##FIG##5##6##), the addition of HFD to 12 mo LOAD1 mice (relative to 12 mo LOAD on CD) resulted in a Type 1 neurovascular uncoupling of perfusion and glycolytic metabolism, which was sexually dimorphic in nature. Across multiple brain regions, denoted by region annotation (##FIG##6##Figure 7A##), female LOAD1 mice showed a significant reduction in glucose uptake, coupled with a hyperemia of the same brain regions, consistent with a cytokine driven diabetic phenotype. Statistical comparison revealed that dorsal-medial-ventral areas of the Auditory Cortex (AuDMV), Dysgranular Insular Cortex (DI), Lateral Orbital Cortex (LO), Primary Motor (M1) and Secondary Motor (M2) Cortex, Parietal Association Cortex (PtA), Retrosplenial Dysgranular Cortex (RSC), Primary Somatosenory Cortex (S1), and Thalmus (TH) were significantly different (p<0.05, unpaired t-test) relative to the control diet groups in female mice (##FIG##6##Figure 7A##, top panel). By comparison, regional uncoupling analysis of male LOAD1+HFD only showed significant changes (p<0.05, unpaired t-test) in the Dorsolateral Orbital Cortex (DLO), Primary Motor (M1) and Secondary Motor (M2) Cortices.</p>", "<p id=\"P52\">Importantly, the addition of hAβ onto the LOAD1 background (yielding LOAD2), showed a Type 2 neurovascular uncoupling phenotype when placed on a HFD (relative to LOAD2 on a CD), which was only observed in the female cohort. Unlike LOAD1 mice, female LOAD2 mice on a HFD showed a significant increase in glucose uptake concomitant with regional reductions in tissue perfusion (##FIG##6##Figure 7B##) and aligned with the transcriptomic network changes (##FIG##2##Figure 3B##), and blood cytokine levels for TNFα, IL1β and IL6 (##FIG##4##Figure 5##). Statistical analysis of brain regions revealed that Corpus Callosum (CC), Entorhinal Cortex (ECT), LO, Medial Orbital Cortex (MO), Perirhinal Cortex (PRH), Prelimbic Cortex (PRL), and Ventral Orbital Cortex (VO) all were significantly different (p<0.05, unpaired t-test) from control diet groups (##FIG##6##Figure 7A##, top panel) in female LOAD2 mice. By contrast, male LOAD2+HFD showed different brain regions, which were uncoupled with treatment, with the AuDMV, Dorsintermed Entorhinal Cortex (DLIVEnt), ECT, PRH, RSC, Temporal Association Cortex (TeA), and Primary and Secondary Visual Cortex (V1V2).</p>", "<p id=\"P53\">To elucidate the role of aging on gene x environmental effect, we performed neurovascular uncoupling analysis on LOAD2 mice at 18 mo. Unlike LOAD1 and LOAD2 at 12 mos which showed a Type 1 and Type 2 uncoupling phenotype respectively, LOAD2 at 18 mos revealed a hypermetabolic and hyperemic phenotype in both sexes, which resulted in nearly all brain regions increasing in glucose uptake paired with increases in tissue perfusion (##FIG##6##Figure 7C##). This increase in both perfusion and metabolism at this age, and is consistent with the plasma cytokine data (##FIG##7##Figure 8##) that show a significant elevation in TNFα, IL-6 and IL-5, which are markers of cell activation and proliferation and are consist with clinical reports of prodromal conversion from healthy controls to MCI.</p>", "<title>Evaluation of age-dependent plasma biomarkers and Touchscreen cognitive testing (Cohorts 4 and 5)</title>", "<p id=\"P54\">To further consider the relevance of the LOAD2 mice as a model for preclinical testing, a group of male and female LOAD2 mice fed a CD or HFD from 2 months of age (cohort 4) and a group of male and female LOAD2 and wildtype littermate controls (WT) fed CD or HFD from 6+ months of age (cohort 5) were established at the University of Pittsburgh. The goal of these cohorts was to track longitudinal biomarker measures for cytokines and Aβ throughout aging, in order to investigate the inflection point at which biomarkers revealed pathological consequences of environment x aging x gene effects, in order to identify a window for therapeutic intervention for future preclinical testing. In addition to biomarker analysis through aging, the cohort were also evaluated for cognitive function assessed by a touchscreen testing battery as well as evaluating the effects of food restriction necessary for touchscreen testing on cytokine levels (##FIG##7##Figure 8## and ##SUPPL##0##Supplemental Figure 7##).</p>", "<p id=\"P55\">Similar to cohort 2 at IU (##FIG##4##Figure 5E##), LOAD2 males fed HFD in cohort 4 had increased levels of plasma TNFα at 12 and 18 months of age relative to LOAD2 males fed CD (12 months, p=0.0001 and 18 months, p=0.0002). In fact, analysis of monthly plasma cytokines revealed increased TNFα as early as 4 months of age (p=0.0377) with consistent increases from 7 months of age onward in LOAD2+HFD males compared to LOAD2+CD males (p<0.05, ##FIG##7##Figure 8B##). The effects of HFD on plasma TNFα was less robust in females, consistent with data from cohort 2 at IU. We observed an overall trend of higher concentrations of plasma TNFα in females fed HFD compared to females fed CD, but those levels were significantly different only at 8–8.5 months (p<0.05) and 15–18 months of age (p=0.0198 at 15 months and p=0.0068 at 18 months; ##FIG##7##Figure 8A##). In addition to TNFα, we also measured 9 other cytokines, 7 of which were above the lower limits of detection (see ##SUPPL##0##Supplemental methods##). Plasma levels of IL-6 (p=0.0022) and IL-10 (p=0.0375) were significantly higher in LOAD2+HFD males compared to LOAD2+CD males at 7 months of age, and levels of IL-10 (p=0.0025) but not IL-6 (p=0.0832) were also higher at 8 months of age in HFD males (##FIG##7##Figure 8C##, ##FIG##7##D##) prior to the first trial of food restriction that preceded touchscreen testing. Interestingly, plasma levels of IL-5 were significantly higher in LOAD2 females, regardless of diet, compared to males at several time points (p<0.05, ##FIG##7##Figure 8G##) while other plasma cytokines measured – IL-1β, IFNγ, KC-GRO and IL-2 (##FIG##7##Figure 8E##, ##FIG##7##F##, ##FIG##7##H##, and ##FIG##7##I##) – did not show diet- or sex-related effects in this cohort. In cohort 5, the middle-aged (6–12 months old) start for HFD (##SUPPL##0##Supplemental Figure 7A##) produced a more modest effect on plasma TNFα with LOAD2+HFD males showing higher concentrations of plasma TNFα at 4 months on diet relative to WT males on CD (p=0.0241) and at 5 months on diet relative to LOAD2 and WT males on CD (p=0.0451 and p=0.0034), LOAD2+HFD females showing higher concentrations of TNFα relative to LOAD2+CD females only at 5 months on diet (p=0.0291), and WT males but not females on HFD showing higher concentrations of TNFα relative to WT+CD mice also only at 5 months on diet (p=0.0091 males and p=0.998 females, ##SUPPL##0##Supplemental Figure 7B##). In all other cytokines measured – IL-6, IL-10, IL-1β, IFNγ, IL-5, KC-GRO and IL-2 (##SUPPL##0##Supplemental Figure 7C##–##SUPPL##0##I##) – there was no significant effect of diet on LOAD2 or WT males or females, though we did again observe a sex-effect in plasma IL-5 with concentrations being higher in LOAD2 females compared to LOAD2 males regardless of diet (p<0.01 at 2 months on diet and p<0.05 at 3 months on diet, ##SUPPL##0##Supplemental Figure 7G##).</p>", "<p id=\"P56\">Concentrations of plasma Aβ40 and 42 were also altered by HFD in cohort 4 (##FIG##7##Figure 8J##–##FIG##7##K##) and by genotype but not diet or sex in cohort 5 (##SUPPL##0##Supplemental Figure 7 J##,##SUPPL##0##K##) consistent with the observation that HFD started earlier in life (cohort 4) produces a more robust phenotype than when initiated mid-life (cohort 5). Male LOAD2 mice +HFD beginning from 2 months of age had increased levels of plasma Aβ40 at 15 (p=0.01) and 18 months of age (p=0.0365) relative to LOAD2 +CD males while female LOAD2+HFD beginning from 2 months of age had increased plasma Aβ40 at 18 months (p<0.0001) relative to LOAD2+CD females (##FIG##7##Figure 8J##). As demonstrated in ##SUPPL##0##Fig S6A## LOAD2 mice beginning HFD at 6+ months of age (cohort 5) failed to demonstrate increases in plasma Aβ40 relative to LOAD2+CD (##SUPPL##0##Supplemental Figure 7J##). Plasma Aβ42 was significantly increased in LOAD2+HFD females from cohort 4 compared to LOAD2+CD females at 18 months of age (p<0.0001, ##FIG##7##Figure 8K##) and compared to age-matched WT+CD females (p=0.0319, ##SUPPL##0##Figure S6##K).</p>", "<p id=\"P57\">While there was robust cross-cohort and cross-laboratory replicability for plasma cytokines irrespective of the different laboratory environments, we observed divergent results for plasma Aβ for cohort 2 (##FIG##4##Figure 5C##, ##FIG##4##D##) versus cohorts 4 and 5 (##FIG##7##Figure 8J##, ##FIG##7##K## and ##SUPPL##0##Supplemental Figure 7J##, ##SUPPL##0##K##). Two major factors may contribute to these differences beyond different laboratory environments: 1) plasma Aβ was analyzed from anesthetized subjects during terminal procedures for cohort 2 whereas cohorts 4 and 5 were longitudinally sampled in non-anesthetized mice; and 2) Cohorts 4 and 5 were subjected to periods of food restriction which was not a factor for cohort 2. It is well documented that variations in plasma Aβ are influenced by environmental factors including stress<sup>##REF##28158298##20##</sup>. Despite the cross-lab variability for Aβ, irrespective of transient stressors, TNFα levels were sustained consistently across cohorts and align with transcriptomic and proteomic data which demonstrates the robustness of the LOAD2 x age x HFD model for preclinical studies of therapeutic interventions independent of amyloid.</p>", "<p id=\"P58\">We assessed the cognitive function of both cohort 4 and 5 using a touchscreen assay battery. All subjects demonstrated the ability to associate the response (nosespoke touch) with the presentation of a reward as measured by the ability to meet a priori criterion of 2 consecutive sessions of 30 rewards earned within 45 minutes. Interestingly, despite similar food restriction across cohorts, there was a significant effect of diet with either WT or LOAD2 mice regardless of HFD initiation (at 2 months or at 6+ months) failing to acquire the task as measured by % accuracy not exceeding chance levels (50%). LOAD2+HFD mice required a greater number of days to meet criteria relative to LOAD2 mice on control diet [One way ANOVA [F (3, 24) = 5.290; P=0.0061; ##FIG##7##Figure 8M##]. Within sex analysis revealed a statistically significant increase in females reared on HFD (T-test; p<0.05) and a modest non-significant increase in males reared on HFD (T-test; p=0.38). Within control diet groups, there was no effect of genotype or sex (p>0.05). During the punish incorrect phase, 100% of CD mice, irrespective of genotype met criteria however only 27% of LOAD2+HFD male mice met a priori completion criteria for this task while 0% of female LOAD2+HFD mice met criteria. Analysis of accuracy levels during initial acquisition of the task prior to subjects advancing to the location discrimination phase (Training Days 1–18) revealed a statistically significant impairment in HFD treated subjects relative to genotype and age- and sex-matched non-HFD controls as measured by two-way repeated measures ANOVA: [F (5, 33) = 9.047; p<0.001; ##FIG##7##Figure 8M##]. Analysis of WT and LOAD2 mice exposed to HFD at middle-age (6+ months age) revealed a less aggressive phenotype as indicated by lower plasma cytokine levels and lower plasma Aβ40 and Aβ42 when compared with plasma levels from mice exposed to HFD at 2 months of age (##FIG##7##Figure 8##). ##SUPPL##0##Supplemental Figure 7M## illustrates performance of aged (18+ month) LOAD2 mice on CD (purple diamonds) and age- and sex-matched C57BL/6J (WT) mice on control diet (n=3–5 per genotype) on the LD task for both large (easy) and small (hard) separation conditions (mean ± s.e.m.). As expected, the increase in task difficulty was significant across genotypes as measured by increased number of trials required to reach criterion for easy relative to hard [F (1, 12) = 5.156; P=0.04]. While there was a modest increase in the number of trials to reach criterion in LOAD2 mice relative to WT the effect of genotype was not significant [F (1, 12) = 0.4134; P=0.53].</p>" ]	[ "<title>Discussion</title>", "<p id=\"P59\">Despite the recent approval of anti-amyloid therapies, there remains a need for improved therapies for Alzheimer’s disease. A key component of therapeutic testing is the development of mouse models that recapitulate the complexity of LOAD. Here we introduce LOAD2 mice – triple homozygous for <italic toggle=\"yes\">APOE4</italic>, <italic toggle=\"yes\">Trem2R47H</italic> and hAβ. Although they lack amyloid and TAU pathologies, in combination with a HFD, LOAD2 mice show age-dependent development of key aspects of LOAD. Specifically, at 18 months of age, LOAD2+HFD, show loss of neurons in the cortex, increased insoluble Aβ42, brain region-specific volumetric changes, neurovascular uncoupling, and cognitive deficits, consistent with the prodromal stages of AD. Interestingly, these changes correlated with elevated plasma NfL and cytokine levels – clinically relevant biomarkers associated with LOAD and emphasize the robustness of modeling genetics x age x environment.</p>", "<p id=\"P60\">Neuronal cell number was evaluated by counting NeuN+DAPI+ cells in cortex and hippocampus and revealed a modest reduction in female LOAD2+HFD mice (##FIG##1##Figure 2##). Coupled with transcriptomic and proteomic signatures (##FIG##2##Figures 3## and ##FIG##3##4##), neurovascular uncoupling (##FIG##6##Figure 7##), and cognitive deficits (##FIG##7##Figure 8##), these data suggest circuit dysfunction in LOAD2+HFD mice. Specific circuits are differentially susceptible to aging and/or AD and so neuronal cell loss may be a result of sporadic loss of neurons or loss of neurons within a specific circuity<sup>##REF##32492070##21##–##REF##29573818##24##</sup>. The mechanism by which neurons die in LOAD2+HFD mice is still to be determined. One recent study used a chimeric model system to show that human neurons in the mouse brains exposed to amyloid died by necroptosis<sup>##REF##37708272##25##</sup>, although mouse neurons did not. Evaluating positive markers of programmed cell death (TUNEL, CASPASE3, MEG3) would provide insight into mechanisms driving reduced cortical neurons in female LOAD2+HFD mice. It is also expected that synaptic changes/loss would precede neuronal cell loss and further work is needed to determine this. Also, myelin integrity was not evaluated and may be disrupted in LOAD2 mice.</p>", "<p id=\"P61\">As observed in human AD<sup>##REF##37414601##19##</sup>, we detected distinct proteomic and transcriptomic signatures in our LOAD mouse models. Transcriptomic signals tended to represent immune, vascular, and lipid metabolism (##FIG##2##Figure 3##), whereas proteomic signatures were focused in synaptic and myelination modules (##FIG##3##Figure 4##). The advent of proteomic technologies that commonly quantify around 10,000 proteins, such as the TMT approach used here, now enable deep characterization to reveal such differences. We also note that AD-relevant transcriptomic changes tended to be driven by age and diet (##FIG##2##Figure 3A##) while proteomic changes were primarily due to APOE4 and <italic toggle=\"yes\">Trem2R47H</italic> genetics and somewhat exacerbated by diet. These results demonstrate the importance of multi-omic analyses in fully characterizing causal factors (<italic toggle=\"yes\">e.g.,</italic> genetics, diet, age) and affected processes (<italic toggle=\"yes\">e.g.,</italic> synaptic, immunological) in translational research.</p>", "<p id=\"P62\">Data-driven analysis of transcriptomes through gene co-expression networks revealed two modules, denoted turquoise and lightyellow, that highlighted a molecular separation between normal age-related changes and changes related to AD-relevant biomarkers (##FIG##2##Figure 3##). While both modules were enriched for immune response, this enrichment was more significant in the turquoise (p = 1.8 × 10<sup>−49</sup>) than the lightyellow (p = 3.7 × 10<sup>−3</sup>) module (Supplementary Table B3). This suggests a more focused immune component in the lightyellow module, led by cytokine signaling (##FIG##2##Figure 3C##) and often co-annotated to lipid metabolism (##FIG##2##Figure 3D##). Furthermore, the lightyellow module was much more correlated with circulating cytokines and NfL, while the turquoise module was linked to IBA1 and GFAP markers (##FIG##2##Figure 3B##). These results suggest a signature for AD-related transcriptomic changes (the lightyellow module) that is distinct from usual brain aging (the turquoise module) and driven by diet in LOAD mice.</p>", "<p id=\"P63\">Though no deficits in hippocampal spatial working memory as measured by the spontaneous alternation task were observed in LOAD2+HFD mice (##FIG##0##Figure 1##), across two separate cohorts, aged mice reared on HFD either from 2 months of age or from 6+ months of age failed to meet acquisition criteria as measured by % correct responses less than 50% (chance levels) indicative of a learning impairment (##FIG##7##Figure 8## and ##SUPPL##0##Supplemental Figure 7##). The lack of ability to learn the task is unlikely to be explained by food motivation, as both HFD and CD groups were sufficiently restricted, and all groups independent of diet or genotype acquired initial touch-reward association. This indicates that failure of HFD mice to accurately perform the task is more likely a feature of impaired learning due to the combination of advanced age x environmental risk (e.g. HFD), than reward salience. Further studies may be required to investigate methods for enhancing motivation for rewards in mice reared on HFD which may include more aggressive water restriction protocols as HFD treated mice even in the presence of strawberry-milk shake reinforcer also have issues with touchscreen tasks (personal communication with Dr. Lisa Saksida, also see<sup>##UREF##5##26##</sup>). Regardless, for aged WT and LOAD2 mice on control diet, results from daily assessments on task acquisition reveal modest cognitive impairments in LOAD2 relative to WT. While modest, these cognitive deficits are further strengthened by proteomic analysis of LOAD2 mice revealing alterations in synaptic signaling. While we were not able to conduct additional cognitive tests in this advanced aged cohort due to attrition and eventual mortality, as subjects aged to 24 months by the conclusion of testing, these data indicate that translational touchscreen tests may be more sensitive for detecting more specific cognitive domains than traditional single day behavioral tests in mice that have been historically used for assessing cognition.</p>", "<p id=\"P64\">Commensurate with the cytokines and multi-omic (##FIG##2##Figure 3B##) associations, cerebral perfusion and metabolism via uncoupling analysis revealed a sexually dimorphic dysregulation with age and genotype (##FIG##6##Figure 7##,##FIG##6##B##). Importantly, the addition of a HFD in LOAD1 mice, resulted in Type 1 uncoupling (i.e. reductions in glycolysis and compensatory hyperemia), consistent with a cytokine<sup>##REF##28291788##27##–##REF##23296339##30##</sup> driven down regulation of insulin receptors<sup>##REF##16357086##28##</sup>, which have been shown to result in a reduction in neuronal glucose uptake via GLUT transporters<sup>##REF##20396480##29##–##REF##22622580##31##</sup>. Importantly, these data closely parallel the Type 2 diabetic phenotype<sup>##REF##22476196##32##, ##REF##24529528##33##</sup> with reactive hyperemia via activation of eNOS<sup>##REF##16043715##34##</sup>.</p>", "<p id=\"P65\">To further explore the impact of environment on gene and sex, analysis of neurovascular uncoupling was performed to assess the degree of regional metabolic dysregulation in LOAD2 mice. Unlike the base model, LOAD2+HFD at 12 mos resulted in a Type 2 neurovascular uncoupled phenotype (i.e. increased glycolysis and reduced perfusion) which was only observed in female mice. These data align with cytokines (i.e. TNFα, IL-2) and immunopathology changes (##FIG##1##Figure 2##, ##FIG##4##5##) at this age, and are consistent with previous reports of cytokine driven astrocytic proliferation and GLUT1 expression<sup>##REF##35849149##35##</sup>. By contrast, LOAD2+HFD mice at 18 mos, resulted in whole brain increases in perfusion and metabolism. Importantly, these changes were observed in both sexes, and was consistent with reports of prodromal hyper-metabolism<sup>##REF##25267349##36##–##REF##36776238##39##</sup>and hyperemia<sup>##REF##32615887##40##</sup>observed in clinical patients, suggesting that this model recapitulates the earliest manifestations of LOAD.</p>", "<p id=\"P66\">Collectively, data presented here suggest that LOAD2+HFD mice, particularly are presenting with early stages of LOAD by 18 months of age. Further work is needed to develop models that present a wider range of LOAD pathologies. We were unable to determine whether aging LOAD2+HFD longer would have enhanced their LOAD-relevant phenotypes. This is because LOAD2+HFD mice showed an increased incidence of tumors when aged beyond 18 months of age. Control mice, including WT mice, showed similar phenotypes, suggesting this resulted from chronic consumption of HFD (from 2 months). Interestingly, LOAD2+CD mice aged to 24 months or LOAD2+HFD after 12 months of age did not show as severe phenotypes as 18 months old LOAD2H+HFD from 2 months of age, highlighting the significance of environmental influence of chronic exposure to HFD. Several additional strategies are being tested to develop improved LOAD models. Alternative diets, e.g., a milder western diet, are being tested that may recapitulate LOAD2-relevant phenotypes of a HFD without the presence of age-related tumors and attrition. We are also evaluating additional genetic risk factors on the LOAD2 background that impact lipid metabolism (<italic toggle=\"yes\">Abca7A1527G</italic>), neuroinflammation (<italic toggle=\"yes\">Plcg2M28L</italic>) and vascular health/metabolism (<italic toggle=\"yes\">Mthfr677C>T</italic>). Perturbing these specific pathways may exacerbate the effects of <italic toggle=\"yes\">APOE4</italic>, Trem2R47H and hAβ in LOAD2. Tau pathology was not evaluated in LOAD2 mice and was not expected due to the lack of a humanized <italic toggle=\"yes\">MAPT</italic> gene. Strains where the mouse <italic toggle=\"yes\">Mapt</italic> gene has been replaced by human <italic toggle=\"yes\">MAPT</italic> are now available and therefore, mouse models carrying combinations of <italic toggle=\"yes\">hA</italic>β, <italic toggle=\"yes\">hMAPT</italic>, genetic risk factors (e.g., <italic toggle=\"yes\">APOE4</italic>) are now being created and will be exposed to environmental risk factors such as HFD and toxic metals to evaluate their potential as preclinical models of AD.</p>", "<p id=\"P67\">In conclusion, the interaction of genetic risk and aging leads to a phenotype worsened by environmental factors, mirroring the risk for LOAD. This includes a pronounced neuroinflammation phenotype with cognitive impairment, unrelated to amyloid accumulation. Multi-omic analysis identified molecular signatures, such as synaptic signaling deficits, aligning with the observed cognitive impairment. The LOAD2 model, characterized by translational blood and imaging biomarkers, emerges as a crucial tool for preclinical drug testing in ADRD patients without prominent amyloid, potentially offering a more representative model of sporadic LOAD.</p>" ]	[]	[ "<p id=\"P1\">First authors</p>", "<title>Structured Abstract</title>", "<title>INTRODUCTION:</title>", "<p id=\"P2\">MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models.</p>", "<title>METHODS:</title>", "<p id=\"P3\">We created the LOAD2 model by combining APOE4, Trem2*R47H, and humanized amyloid-beta. Mice aged up to 24 months were subjected to either a control diet or a high-fat/high-sugar diet (LOAD2+HFD) from two months of age. We assessed disease-relevant outcomes, including in vivo imaging, biomarkers, multi-omics, neuropathology, and behavior.</p>", "<title>RESULTS:</title>", "<p id=\"P4\">By 18 months, LOAD2+HFD mice exhibited cortical neuron loss, elevated insoluble brain Aβ42, increased plasma NfL, and altered gene/protein expression related to lipid metabolism and synaptic function. In vivo imaging showed age-dependent reductions in brain region volume and neurovascular uncoupling. LOAD2+HFD mice also displayed deficits in acquiring touchscreen-based cognitive tasks.</p>", "<title>DISCUSSION:</title>", "<p id=\"P5\">Collectively the comprehensive characterization of LOAD2+HFD mice reveal this model as important for preclinical studies that target features of LOAD independent of amyloid and tau.</p>" ]	[ "<title>Supplementary Material</title>" ]	[ "<title>Acknowledgments</title>", "<p id=\"P78\">The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (<ext-link xlink:href=\"https://adknowledgeportal.org/\" ext-link-type=\"uri\">https://adknowledgeportal.org</ext-link>). Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG36836 (RNAseq), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at <ext-link xlink:href=\"http://www.radc.rush.edu/\" ext-link-type=\"uri\">www.radc.rush.edu</ext-link>. Mount Sinai Brain Bank data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The Mayo RNAseq study data was led by Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Samples were provided from the following sources: The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program was supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research.</p>", "<p id=\"P79\">The authors are grateful for the technical support of the IUSM Biomarker Core.</p>", "<p id=\"P80\">The authors would like the thank the Neurobehavioral Phenotyping core at Jackson Laboratory for their assistance and support during the <italic toggle=\"yes\">in vivo</italic> testing of these animals.</p>", "<p id=\"P81\">The authors are grateful for the technical support of the University of Pittsburgh Preclinical Phenotyping Core facility as well as the following research staff: Gabi Little, Jason Hart, Aman Reddy, Umesh Nepali, Jenny Willis, and Amber Sanders</p>", "<title>Data Availability Statement</title>", "<p id=\"P77\">The MODEL-AD data sets are available via the AD Knowledge Portal (<ext-link xlink:href=\"https://adknowledgeportal.org/\" ext-link-type=\"uri\">https://adknowledgeportal.org</ext-link>). The AD Knowledge Portal is a platform for accessing data, analyses, and tools generated by the Accelerating Medicines Partnership (AMP-AD) Target Discovery Program and other National Institute on Aging (NIA)-supported programs to enable open-science practices and accelerate translational learning. The data, analyses and tools are shared early in the research cycle without a publication embargo on secondary use. Data is available for general research use according to the following requirements for data access and data attribution (<ext-link xlink:href=\"https://adknowledgeportal.org/DataAccess/Instructions\" ext-link-type=\"uri\">https://adknowledgeportal.org/DataAccess/Instructions</ext-link>). For access to content described in this manuscript see: <ext-link xlink:href=\"10.7303/syn53128146\" ext-link-type=\"doi\">https://doi.org/10.7303/syn53128146</ext-link></p>" ]	[ "<fig position=\"float\" id=\"F1\"><label>FIGURE 1:</label><caption><p id=\"P100\">Longitudinal metabolic and behavioral phenotyping of mice on high-fat diet.</p><p id=\"P101\">LOAD1 (<italic toggle=\"yes\">APOE4/Trem2R47H</italic>) and LOAD2 (<italic toggle=\"yes\">hAbeta/APOE4/Trem2R47H</italic>) animal strains differ in the <italic toggle=\"yes\">App</italic> allele with a humanized Abeta1–42 region (G601R, F606Y, R609H in the mouse gene, corresponding to amino acid positions 676, 681, 684 in the human <italic toggle=\"yes\">APP</italic> locus) (A). Alignment of mouse (top; Uniprot ID P12023) and humanized (bottom; Uniprot ID P05067) amyloid precursor protein (APP) amino acid sequences. White letters denote non-homology. Red arrows indicate cleavage sites of processing enzymes. Yellow arrows denote sites of humanizing mutations in <italic toggle=\"yes\">App</italic> allele (LOAD1, top, and LOAD2, bottom). (Cohort 1) Animals of an 18-month longitudinal cohort were assayed at 4-, 12-, and 18-months of age. Males and females, of LOAD1 and LOAD2 genotypes, fed either control diet (CD) or high-fat diet (HFD) beginning at 2-months of age were measured for body weight (B), fasted blood glucose (C), and frailty assay index score (D), as a measure of general animal health changes. Running wheel assay measured average animal activity time for three days and nights at the 18-month age timepoint (E). Spontaneous alternation behavioral assay was utilized to measure cognition longitudinally across ages at the 18-month age timepoint (F). (Three-way ANOVA [sex, genotype, diet effects]; =p<0.05)</p></caption></fig>", "<fig position=\"float\" id=\"F2\"><label>FIGURE 2:</label><caption><p id=\"P102\">Neuropathological assessment of brain tissue.</p><p id=\"P103\">Immunohistochemistry of brain tissue in the cortex and hippocampus from 18-month-old animals stained for cell markers to reveal genotype- and diet-driven differences in glial cell densities. Slices of brain hemispheres were stained with (A,B) NeuN (neurons) or (C,D) IBA1 (microglia) (representative cortical images shown from LOAD2 females with DAPI co-stain) and counted relative to area. Astrocytes (GFAP) quantitated in the hippocampus of LOAD2 females fed either CD or HFD (E-F). ThioS staining of brain tissue to visualize amyloid plaques (representative images shown from LOAD2 females) (G). Inlay: scaled image of 12mo B6J.<italic toggle=\"yes\">APP-SAA</italic> hyper-amyloid positive controls. LISA testing for neurofilament light-chain (NfL) in plasma derived from terminal, peripheral blood samples at 18-months of age. Linear regression analyses were performed to identify effect of each factor on NfL levels (H). (NeuN=neuronal marker; ThioS=amyloid plaques; GFAP=astrocyte marker; IBA1=microglial marker. Scale bar equals 100μm.)</p></caption></fig>", "<fig position=\"float\" id=\"F3\"><label>FIGURE 3:</label><caption><p id=\"P104\">A gene module associated with AD biomarkers is driven by age and high-fat high-sugar diet.</p><p id=\"P105\">The lightyellow gene module was associated with advanced ages (p < 0.001) and both genotype on HFD (p < 0.05), while the turquoise module was associated with age only (p < 0.001) (A). Correlations between the turquoise and lightyellow module eigengenes. Lightyellow was significantly correlated with frailty score, body weight, NfL, and many plasma cytokines (IL-1β, IL-2, IL-12p70, IL-10, IL-5, IL-6, KC-GRO), while the age-driven turquoise module was correlated with behavioral assay (frailty score and body weights) and weakly correlated with a few plasma cytokines (IL-2, IFNγ) and inflammatory cell counts (IBA1 and GFAP counts) (B). Positive correlation coefficients are shown in blue and negative correlations in red, proportional to color intensity and circle size, with frames for significant correlations (FDR < 0.05). AD-related biological domain enrichment analysis in the age and HFD driven lightyellow module gene set using Fisher exact test, with the top six enriched GO terms within each enriched bidomain (C). Network of genes in each enriched biological domain and the lightyellow module (D).</p></caption></fig>", "<fig position=\"float\" id=\"F4\"><label>FIGURE 4:</label><caption><p id=\"P106\">LOAD mice exhibit proteomics changes similar to human LOAD.</p><p id=\"P107\">Correlation coefficients between 18-month-old LOAD mouse models and 44 human proteomics co-expression modules [Johnson et al Ravi’s Ref ##REF##12580703##9##] (A). Modules in bold face were significantly correlated to one or more AD traits. Circles corresponds to positive (blue) and negative (red) Pearson correlation coefficients for protein expression changes in LOAD mice (log fold change of LOAD strains versus B6J) and human disease (log fold change for cases versus controls). Color intensity and size of the circles are proportional to the Pearson correlation coefficient, with significant correlations (p < 0.05) framed. LOAD1 and LOAD2 mice were significantly and positively correlated (p < 0.05) with multiple human AD modules, primarily related to synaptic function. Five top enriched GO terms for proteins with common directional changes for 18-month-old LOAD2 mice on HFD and human AD cases (B). Protein module network with common directional changes for 18-month-old LOAD2 mice on HFD and human proteomics modules (C). Blue (red) nodes correspond to increased (reduced) protein abundance in both 18-month-old LOAD2 HFD mice compared to B6J mice and human AD cases versus controls.</p></caption></fig>", "<fig position=\"float\" id=\"F5\"><label>FIGURE 5.</label><caption><p id=\"P108\">High fat diet reduces brain volume in multiple brain regions and alters plasma biomarkers.</p><p id=\"P109\">Volume statistics maps for LOAD2 male at 4 months, 12 months and 18 months. The significant brain areas were overlaid over gray scale subject template image. (The p-values were converted into logarithmic scale between range −5 to −1. S1, Primary Somatosensory Cortex; Cpu, striatum; LO, Lateral Orbital Cortex; V1M, Primary Visual Cortex, Monocular area; S2, Secondary Somatosensory Cortex; S1HL Primary Somatosensory Cortex, Hindlimb; S1BF Primary Somatosensory Cortex, Barrel Field; M1, Primary Motor Cortex; M2 Secondary Motor Cortex; IC Inferior Colliculus; cc Corpus Callosum; Pir, Piriform cortex. Volume statistics maps for Load2 female at 4 months, 12 months and 18 months. The significant brain areas were overlaid over gray scale subject template image. The p-values were converted into logarithmic scale between range −5 to −1. A29c, Cingulate Cortex; cg, Cingulum; SPT, Septum; FrA, Frontal Association Area; IC, Inferior Colliculus; S1HL, Primary Somatosensory Cortex, Hindlimb; LO, Lateral Orbital Cortex; M1 Primary Motor Cortex; M2 Secondary Motor Cortex; cc, Corpus Callosum; Cpu, Striatum) (A). At 12 months of age, NfL is increased in high fat diet males, but not in females (B). However, by 18 months of age, aging has a greater effect on NfL, with increases in NfL between 12 and 18 months in both males and female mice. Plasma Aβ40 is reduced in high fat diet males at 12 and 18 months of age but is unchanged in female mice at any timepoint (C). Aβ42 is not altered by a high fat diet (D). TNF-α is increased in male mice on a high fat diet at both 12 and 18 months of age (E). Females have increased TNF-α at 18 months of age, but it does not reach the level of significance. IFNγ is reduced at 12- and 18-month male mice on a high fat diet (F). IL-6 is increased in male mice between 12–18 months of age, but there is no effect of high fat diet (G). In females, IL-6 is not altered. IL-2 increases between 4–12 months in males and females regardless of diet (H). By 18 months, IL-2 is reduced in both males and females. IL-1β increases with age between 12–18 months regardless of diet (I). p<0.05, p<0.01, p<0.001, **P<0.0001.</p></caption></fig>", "<fig position=\"float\" id=\"F6\"><label>FIGURE 6:</label><caption><p id=\"P110\">Brain biomarkers in a longitudinal cohort of LOAD2 mice fed a high fat diet.</p><p id=\"P111\">At 18 months, insoluble Aβ42 is increased in female mice on a high-fat diet (A), however, insoluble Aβ40 is decreased in both sexes (B). Soluble Aβ40 (C) and Aβ42 (D) are both reduced at 18 months in high fat diet animals of both sexes. IL-1β is reduced in males on a high fat diet (E) but remains unchanged in females. IL-5 (F) is unchanged in male mice, but is reduced in females on a HFD. IL-4 (G) is also reduced in females fed a HFD. IL-2 (H) is increased in males, but not females. KC-GRO (I) and IL-12 (J) are increased in both males and female mice on a high fat diet. TNF-α (K) remains unchanged on a high fat diet. IL-10 (L) was significantly increased in males and females on HFD. p<0.05, p<0.01, p<0.001, ***P<0.0001.</p></caption></fig>", "<fig position=\"float\" id=\"F7\"><label>FIGURE 7:</label><caption><p id=\"P112\">Neurovascular Uncoupling of LOAD1 and LOAD2 mouse models.</p><p id=\"P113\">The degree of neurovascular coordination in LOAD1 (A) and LOAD2 mouse models (B) conditioned on high-fat diet (HFD), we performed uncoupling analysis. (Left) Uncoupling analysis chart in male (blue) and female (red) mice at 12 months, with many brain regions showing significant decreases in metabolism with increases in perfusion. LOAD2 animals aged to 18 months (C) were similarly analyzed. (Upper Right) Female and (Lower Right) Male p-value males showing which regions were significantly different for perfusion, metabolism, and uncoupling.</p></caption></fig>", "<fig position=\"float\" id=\"F8\"><label>FIGURE 8:</label><caption><p id=\"P114\">Comprehensive validation of LOAD2 mouse model for preclinical drug testing.</p><p id=\"P115\">As a confirmation and extension of initial characterization data of the LOAD2 mouse model conditioned on high-fat diet (HFD) to serve as a potential model for preclinical testing, independent cohorts were evaluated for disease trajectory of serial plasma biomarkers and cognitive testing. A) Illustration of timeline and procedures; B) plasma TNF-α (pg/mL); C) Plasma IL-6 (pg/mL); D) plasma IL-10 (pg/mL); E. Plasma IL-1β (pg/mL); F) plasma IFNy (pg/mL), G) plasma IL-5 (pg/mL); H) plasma KC-GRO (pg/mL); I) plasma IL-2 (pg/mL); J) plasma Aβ40 (pg/mL); K) plasma Aβ42 (pg/mL); L) calculated Aβ 42:40 ratio in plasma; M) Learning curves of aged (14+ month) LOAD2 mice ± HFD in comparison to age- and sex-matched WT controls during the acquisition phase of the touchscreen cognitive testing battery. Plasma cytokines and plasma Aβ were measured using MesoScale Discovery multiplex ELISA kits (in accordance with the manufacturer’s protocol.</p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"SD1\" position=\"float\" content-type=\"local-data\"><label>Supplement 1</label><caption><p id=\"P68\">SUPPLEMENTAL FIGURE 1: Study design.</p><p id=\"P69\">This was a multi-site, multi-cohort study. At each site, mice were provided a high fat diet or control diet starting at 2 months of age. At the Jackson Laboratory, the 18-month cohort only received a control diet. In cohort 1, four cohorts of mice were aged to 4, 12, 18, 24 months of age. Multiple ‘omics studies, behavior and cognition and neuropathology studies were completed. In cohort 2, at Indiana University, one cohort of mice were age to 18 months and plasma was collected at 4, 12 and 18 months for biomarker analysis. At each timepoint, mice had MRIs completed for volumetric analysis. Brains were collected at the termination of the study for neurodegeneration and neuroinflammation studies. In cohort 3 at Indiana University, two cohorts of mice were aged to 12 and 18 months and underwent PET/CT studies for two tracers, FDG and PTSM. In cohort 4 at University of Pittsburgh, mice were aged to 18 months, undergoing serial blood draws monthly and completing touch screen testing.</p><p id=\"P70\">Supplemental Figure 2: Longitudinal behavioral phenotyping of mice on high-fat diet.</p><p id=\"P71\">Males and females, of LOAD1 and LOAD2 genotypes, fed either control diet (CD) or high-fat diet (HFD) beginning at 2-months of age until 18-months of age were subjected to open field assay, measuring animal movements by way of total distance traveled (A) and total vertical activity (B) during 60 minute observation testing period. Rotarod assay measured the latency to fall times, over three consecutive trials, as a measure of motor coordination (C). (Three-way ANOVA [sex, genotype, diet effects]; =p<0.05)</p><p id=\"P72\">Supplemental Figure 3: Immunohistochemistry analysis. Representative, collated images of whole hemisphere, coronal sections displaying both cortical and hippocampal regions of interest, used for glia cell density measurements and neuropathological assessment of brain tissue from cohort 1 (JAX). Brains are from 12mo females from either LOAD2 (control diet) and B6J.<italic toggle=\"yes\">APP</italic><sup><italic toggle=\"yes\">SAA</italic></sup> strains. NeuN=neuronal marker; ThioS=amyloid plaques; GFAP=astrocyte marker; IBA1=microglial marker. Scale bar equals 1,000μm (1mm).</p><p id=\"P73\">Supplemental Figure 4: Mouse modules and trait relationships. Transcriptome module correlations and FDR values for module eigengenes and age, sex, diet, genotype, and measured behavioral assays, body weights, NfL, cytokine levels, and GFAP, IBA1, and NeuN cell counts.</p><p id=\"P74\">Supplemental Figure 5: Neurodegeneration and gliosis in the cortex and subiculum. At 18 months old (Indiana University cohort 2), GFAP was used to label reactive astrocytes, which were increased in female mice on a high fat diet in the cortex. IBA1 was utilized to study microglia, which were increased in females on a high fat diet. Neurons (labeled with NeuN) were not changed in the cortex or subiculum.</p><p id=\"P75\">Supplemental Figure 6: Touchscreen task acquisition is impaired in mice with genetic + environmental risk for AD. Initial touch-reward associations in LOAD2 mice + high-fat diet (HFD) in comparison to LOAD2 and WT mice maintained on a control diet (CD). Data are analyzed as number of days required for individuals to meet a priori task completion criteria.</p><p id=\"P76\">Supplemental Figure 7: Evaluation of disease trajectory of LOAD2 mice conditioned on a High Fat Diet beginning mid-life at 6 months of age. In comparison to LOAD2 mice conditioned on HFD from 2 months of age, starting HFD after 6 months of age results in a milder phenotype (see ##FIG##7##Figure 8## for comparison). Chronic HFD exposure produces sustained TNF-α levels in male and female LOAD2 mice relative to WT or LOAD2 mice maintained on control diet (CD); consistent with HFD exposure from adolescence (see ##FIG##7##Figure 8##). Other plasma biomarkers were not significantly elevated and sustained relative to mice on CD. A) Illustration of timeline and procedures; B) plasma TNF-α (pg/mL); C) Plasma IL-6 (pg/mL); D) plasma IL-10 (pg/mL); E. Plasma IL-1β (pg/mL); F) plasma IFNy (pg/mL), G) plasma IL-5 (pg/mL); H) plasma KC-GRO (pg/mL); I) plasma IL-2 (pg/mL); J) plasma Aβ40 (pg/mL) at 12–18 months of age; K) plasma Aβ42 (pg/mL) at 12–18 months of age. Plasma cytokines and plasma Aβ were measured using MesoScale Discovery multiplex ELISA kits in accordance with the manufacturer’s protocol. (<italic toggle=\"yes\">P</italic><0.05 and **<italic toggle=\"yes\">P</italic><0.01 between diet groups; ^<italic toggle=\"yes\">P</italic><0.05 between sexes). One way ANOVA within sex was used to analyze Aβ40 and Aβ42 in 12–18-month aged mice across treatment groups. L) Touchscreen acquisition task data demonstrating impairment of HFD treatment independent of genotype in aged (18+month LOAD2 and WT mice). Both WT+HFD and LOAD2+HFD to fail to learn the task as measured by % accuracy less than chance levels (<50%) (n=3–5 per genotype/diet; combined sexes). Only CD treated WT and LOAD2 mice met acquisition criteria and advanced to assessments of pattern separation as measured by the spatial-location discrimination task. M.) Modest impairments in pattern separation of aged LOAD2 mice (18+ month) relative to age-matched WT (n=3–5 per genotype; sexes combined). Data for touchscreen are presented as mean ± sem.</p></caption></supplementary-material>" ]	[ "<fn-group><fn id=\"FN2\"><p id=\"P82\">SUPPLEMENTARY TABLE A: Differentially expressed genes in mouse models.</p><p id=\"P83\">Differentially expressed genes (DEGs) in mouse strains. Sheet1: DEGs observed in LOAD2 compared to age and sex-matched LOAD1 mice at all ages for both sexes. Sheet 2: DEGs observed in 18-month-old LOAD2 and LOAD1 mice on chow diet and HFD compared to age and sex-matched C57BL/6J mice on chow diet. Sheet 3: DEGs observed in HFD mice compared to sex and strain-matched mice on chow diet at 18 months.</p><p id=\"P84\">SUPPLEMENTARY TABLE B: Enriched KEGG pathways in mouse models.</p><p id=\"P85\">Sheet 1: enriched KEGG pathways for the significantly up and down-regulated genes in LOAD2 mouse strains compared to age and sex-matched LOAD1 mice at all ages for both sexes. Sheet 2: enriched KEGG pathways in the significantly up and down-regulated genes in 18-month-old LOAD2 and LOAD1 mice on chow diet and HFD compared to age and sex-matched C57BL/6J mice on chow diet. Sheet 3: enriched KEGG pathways in the significantly up and down-regulated genes in HFD mice compared to sex and strain-matched mice on chow diet at 18 months.</p><p id=\"P86\">SUPPLEMENTARY TABLE B2: Mouse modules of co-expressed genes.</p><p id=\"P87\">Genes in each of 30 mouse modules of co-expressed genes identified through WGCNA of mouse transcriptomics data.</p><p id=\"P88\">SUPPLEMENTARY TABLE B3: Enrichment of AD biological domains in mouse modules.</p><p id=\"P89\">Enrichment of AD biological domains and member Gene Ontology terms in each mouse module of co-expressed genes.</p><p id=\"P90\">SUPPLEMENTARY TABLE C: Differentially expressed proteins in mouse models.</p><p id=\"P91\">Differentially expressed proteins in 18-month-old LOAD1 and LOAD2 mice on chow and HFD compared to age-matched C57BL/6J mice on chow diet.</p><p id=\"P92\">SUPPLEMENTARY TABLE D: Correlations between changes in mouse models and case-control changes in 44 human protein co-expression modules.</p><p id=\"P93\">Pearson correlation coefficients and corresponding p-values for the correlation between protein expression changes in LOAD1 and LOAD2 mice relative to B6J mice at 18 months with changes observed in human AD subjects versus controls for each human protein module, as shown in ##FIG##3##Figure 4A##.</p><p id=\"P94\">SUPPLEMENTARY TABLE E: Enriched Gene Ontology terms in proteins driving the significant positive correlations between LOAD2 mice on HFD and human AD proteomics modules.</p><p id=\"P95\">Enriched GO terms in proteins with common directional changes for 18-month-old LOAD2 mice on HFD and human AD cases, as shown in ##FIG##3##Figure 4##.</p></fn><fn id=\"FN3\"><p id=\"P96\">Consent Statement</p><p id=\"P97\">Due to the nature of this study, consent for human subjects was not needed.</p></fn><fn fn-type=\"COI-statement\" id=\"FN4\"><p id=\"P98\">Conflicts of Interest</p><p id=\"P99\">The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"nihpp-2023.12.19.571985v1-f0001\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.571985v1-f0002\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.571985v1-f0003\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.571985v1-f0004\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.571985v1-f0005\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.571985v1-f0006\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.571985v1-f0007\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.571985v1-f0008\" position=\"float\"/>" ]	[ "<media xlink:href=\"NIHPP2023.12.19.571985v1-supplement-1.pdf\" id=\"d64e1551\" position=\"anchor\"/>" ]	[{"label": ["4."], "collab": ["Biogen"], "source": ["FDA Approves Updated ADUHELM"], "sup": ["\u2122"], "year": ["2021"], "comment": ["cited", "Available from"], "date-in-citation": ["2023 11/21"], "ext-link": ["https://investors.biogen.com/news-releases/news-release-details/fda-approves-updated-aduhelmtm-prescribing-information-emphasize"]}, {"label": ["5."], "collab": ["FDA"], "source": ["FDA Converts Novel Alzheimer\u2019s Disease Treatment to Traditional Approval"], "year": ["2023"], "comment": ["cited", "Available from"], "date-in-citation": ["2023 11/21"], "ext-link": ["https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval"]}, {"label": ["8."], "surname": ["Kotredes", "Oblak", "Pandey", "Lin", "Garceau", "Williams", "Uyar", "O\u2019Rourke", "O\u2019Rourke", "Ingraham", "Bednarczyk", "Belanger", "Cope", "Foley", "Logsdon", "Mangravite", "Sukoff Rizzo", "Territo", "Carter", "Sasner", "Lamb", "Howell"], "given-names": ["KP", "AL", "RS", "PB", "D", "HM", "A", "R", "S", "C", "D", "M", "ZA", "KE", "BA", "LM", "SJ", "PR", "GW", "M", "BT", "GR"], "article-title": ["Uncovering disease mechanisms in a novel mouse model expressing humanized APOE\u03b54 and Trem2*R47H."], "source": ["Frontiers in Aging Neuroscience."], "year": ["2021"]}, {"label": ["14."], "surname": ["Cary", "Wiley", "Gockley", "Keegan", "Heath", "Mangravite", "Logsdon", "Longo", "Levey", "Greenwood", "Carter"], "given-names": ["GA", "JC", "J", "S", "L", "LM", "BA", "FM", "A", "AK", "GW"], "collab": ["R. R. Butler I", "The Emory-Sage SGCT-ADC"], "article-title": ["Genetic and Multi-omic Risk Assessment of Alzheimer\u2019s Disease Implicates Core Associated Biological Domains."], "source": ["medRxiv."], "comment": ["2022:2022.12.15.22283478."], "pub-id": ["10.1101/2022.12.15.22283478"]}, {"label": ["18."], "surname": ["Ano", "Nakayama"], "given-names": ["Y", "H"], "article-title": ["Preventive Effects of Dairy Products on Dementia and the Underlying Mechanisms."], "source": ["Int J Mol Sci."], "year": ["2018"], "volume": ["19"], "issue": ["7"], "comment": ["Epub 20180630."], "pub-id": ["10.3390/ijms19071927"]}, {"label": ["26."], "surname": ["Urai", "Aguillon-Rodriguez", "Laranjeira", "Cazettes", "Mainen", "Churchland"], "given-names": ["AE", "V", "IC", "F", "ZF", "AK"], "collab": ["International Brain L"], "article-title": ["Citric Acid Water as an Alternative to Water Restriction for High-Yield Mouse Behavior."], "source": ["eNeuro."], "year": ["2021"], "volume": ["8"], "issue": ["1"], "comment": ["Epub 20210211."], "pub-id": ["10.1523/ENEURO.0230-20.2020"]}]	{ "acronym": [], "definition": [] }	40	CC BY	no	2024-01-13 23:49:38	bioRxiv. 2023 Dec 20;:2023.12.19.571985	oa_package/3f/2c/PMC10769232.tar.gz
PMC10769236	38187590	[ "<title>INTRODUCTION</title>", "<p id=\"P4\">Animals rely on multiple chemosensory systems to adjust their behavior and physiology in response to changing external conditions and internal states. These include olfactory systems to recognize volatile chemicals and gustatory systems to detect ingested (often water-soluble) chemicals as well as low volatility, surface-associated chemicals. Detection relies on the cell-specific expression of distinct members of large families of membrane-spanning chemoreceptors<sup>##REF##24607224##1##</sup>. Given their central role in transduction, determining the three-dimensional structures of chemoreceptors is important to understand the molecular mechanisms, including ligand recognition and selectivity, that govern chemosensory system function.</p>", "<p id=\"P5\">Insects are major sources of terrestrial biomass and biodiversity with major impacts on ecology and human health<sup>##REF##26034274##2##,##REF##36735788##3##</sup>. For example, some insects provide vital ecosystem services like pollination<sup>##REF##27894123##4##</sup>, while others are disease vectors<sup>##UREF##0##5##</sup> or agricultural pests that threaten food security<sup>##REF##35461930##6##</sup>. Insect chemoreceptors influence feeding, reproduction, and other vital behaviors<sup>##REF##24607224##1##,##REF##26477743##7##</sup>, and are often accessible to external interventions (e.g., environmental chemical exposure). Therefore, knowledge of insect chemoreceptor structures and mechanisms can influence the development and use of agents for conservation and control efforts.</p>", "<p id=\"P6\">Among arthropods, including insects, Gustatory Receptors (GRs) have emerged as major mediators of chemosensation<sup>##REF##30312552##8##</sup>, with 60 GR genes in <italic toggle=\"yes\">Drosophila melanogaster</italic><sup>##REF##30312552##8##</sup>, 72 GR genes in the dengue vector mosquito <italic toggle=\"yes\">Aedes aegypti</italic><sup>##REF##30429615##9##</sup>, and 65 GR genes in the silkworm <italic toggle=\"yes\">Bombyx mori</italic><sup>##REF##19133074##10##</sup>. Many GRs are expressed in gustatory neurons, where they regulate feeding<sup>##REF##24607224##1##</sup>. For example, in <italic toggle=\"yes\">D. melanogaster</italic>, eight GRs contribute to sweet compound detection<sup>##REF##25702577##11##</sup>, while six commonly-expressed GRs act alongside more than 20 additional GRs to detect bitter compounds<sup>##REF##31839451##12##</sup>. GRs can also act in olfactory neurons; for example, disease-spreading mosquitoes use GR-mediated detection of carbon dioxide (CO<sub>2</sub>) to help locate human hosts<sup>##REF##24581501##13##</sup>. GRs are also used to sense internal stimuli. In <italic toggle=\"yes\">D. melanogaster</italic>, Gr43a acts as an internal nutrient sensor in the brain, monitoring hemolymph fructose levels to control satiety<sup>##REF##23178127##14##</sup> and egg production<sup>##REF##36827377##15##</sup>. Thus, GRs detect a diverse array of chemical stimuli to control insect behavior and physiology.</p>", "<p id=\"P7\">GRs mediate chemosensation by forming ligand-gated cation channels<sup>##REF##27132146##16##–##REF##31760135##18##</sup>. GRs belong to the seven-transmembrane ion channel (7TMIC) superfamily, a large group of eukaryotic proteins that share transmembrane topologies, but little sequence identity<sup>##UREF##1##19##</sup>. In addition to GRs, insects contain other 7TMICs, including the Olfactory Receptors (ORs)<sup>##REF##30312552##8##,##UREF##1##19##</sup>. The ORs diverged from within the GR family >400 million years ago and now form another large family of chemoreceptors in many insects (e.g., <italic toggle=\"yes\">D. melanogaster</italic> encodes 68 GRs and 60 ORs)<sup>##REF##30312552##8##</sup>. Although they share limited amino acid identity with GRs (<15%), ORs retain the 7TMIC organization and function as ligand-gated cation channels<sup>##REF##18408712##20##,##REF##18408711##21##</sup>. However, ORs are primarily involved in olfaction rather than gustation<sup>##REF##30312552##8##</sup>. In most insects, individual ORs assemble with a common OR coreceptor (ORCO) to form functional ion channels<sup>##UREF##2##22##</sup>. While GRs lack an analogous coreceptor, many GRs also function in a combinatorial fashion<sup>##REF##31598735##23##</sup>. However, some GRs form functional homomeric ion channels—these include <italic toggle=\"yes\">D. melanogaster</italic> Gr43a and its <italic toggle=\"yes\">Bombyx mori</italic> ortholog (Bm)Gr9, which are selectively activated by fructose<sup>##REF##21709218##17##</sup>. While GR function has been extensively studied in animals, BmGr9 is one of the few GRs so far shown to form functional channels with native-like properties in heterologous expression systems<sup>##REF##21709218##17##</sup>. For this reason, we chose BmGr9 as an initial GR family member for structural determination.</p>", "<p id=\"P8\">Although no experimental structure of a GR is available, there are structures of the fig wasp (<italic toggle=\"yes\">Apocrypta bakeri</italic>) (Ab)Orco<sup>##REF##30111839##24##</sup> and the jumping bristletail <italic toggle=\"yes\">Machilis hrabei</italic> (Mh)Or5, a homomeric OR that does not require an ORCO and is activated by a broad panel of odorants<sup>##REF##34349260##25##</sup>. While GRs are evolutionarily related to ORs, their sequences are highly divergent and the agonists they recognize are chemically distinct (from water-soluble for many GRs to hydrophobic for many ORs). The similarity of GR and OR protein folds, and the extent to which GR and OR family members exhibit unique structural features that support their distinct functions, are unknown. Also unknown is whether the conformational changes induced by ligand agonists to open the ion pore differ between GRs and ORs, and how those changes are transmitted from the ligand-binding pocket to the pore.</p>", "<p id=\"P9\">Here we present a structure of BmGr9 in both the closed agonist-free state and in an open state in the presence of D-fructose. BmGr9 forms a homotetramer with a quadrivial pore architecture, and ligand binding results in ligand-binding pocket contraction and replacement of hydrophobic by hydrophilic residues at the extracellular gate of the ion pore. A set of four ordered phospholipids are found to lie horizontally in the plane of the membrane, with their headgroups interacting with conserved polar groups on the pore-lining transmembrane helix S7b and penetrating into the ion pore through fenestrations between subunits. Finally, we generate a structure-based sequence alignment and uncover distinct patterns of ligand-binding pocket residue conservation in GR subfamilies associated with distinct ligand classes. Together, these findings provide a high-resolution view of a GR family member, identify specific functions for conserved residues in long-established GR sequence motifs, and provide a starting point for more comprehensive analyses of this large and divergent family of sensory receptors.</p>" ]	[ "<title>STAR Methods</title>", "<title>RESOURCE AVAILABILITY</title>", "<title>Lead contact</title>", "<p id=\"P43\">Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Rachelle Gaudet (<email>[email protected]</email>).</p>", "<title>Materials availability</title>", "<p id=\"P44\">Plasmids generated are available from the lead contact with a completed materials transfer agreement.</p>", "<title>Data and code availability</title>", "<p id=\"P45\">The cryo-EM maps have been deposited to the Electron Microscopy Data Bank (EMDB) (accession numbers: EMD-43129 and EMD-43130, respectively, for the agonist-free and fructose-bound maps), and the refined coordinates to the Protein Data Bank (PDB IDs: 8VC1 and 8VC2, respectively, for the agonist-free and fructose-bound BmGr9 structures). The GR family sequence alignment and phylogenetic tree have been deposited XXXX. All other data is available from the corresponding authors upon reasonable request.</p>", "<p id=\"P46\">This paper does not report any original code.</p>", "<p id=\"P47\">Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.</p>", "<title>EXPERIMENTAL MODEL AND SUBJECT DETAILS</title>", "<p id=\"P48\">The <italic toggle=\"yes\">E. coli</italic> DH5α strain, cultured in LB medium (Thermo Fisher Scientific) at 37°C, was used to amplify plasmids. Human embryonic kidney (HEK) 293F inducible GnTI-suspension cells (Thermo Fisher Scientific, A39242) were cultured in Expi293 expression medium (Thermo Fisher Scientific) at 37°C, supplied with 8% CO<sub>2</sub>. HEK293T cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Corning) supplemented with 10% (v/v) fetal bovine serum (Corning), 1X GlutaMAX (Gibco), and 100 U/mL penicillin-streptomycin (Lonza) at 37°C and 5% CO<sub>2</sub>. <italic toggle=\"yes\">Xenopus laevis</italic> oocytes (EcoCyte Bioscience) were cultured at 18°C in ND96 media containing (mM): 2 KCl, 96 NaCl, 2.0 MgCl<sub>2</sub>, 1.8 CaCl<sub>2</sub>, 5 HEPES-NaOH pH 7.4 supplemented with penicillin/streptomycin.</p>", "<title>METHOD DETAILS</title>", "<title>Constructs</title>", "<p id=\"P49\">For protein expression and cryo-EM, the BmGr9 sequence (gift from Kazushige Touhara)<sup>##REF##21709218##17##</sup> was inserted into the pHR-CMV-TetO2_3C-Twin-Strep lentiviral expression plasmid with a IRES EmGFP reporter (Addgene ID: 113883) that was modified to introduce an N-terminal Twin-Strep tag (WSHPQFEKGGGSGGGSGGSAWSHPQFEK). For electrophysiology experiments, the same N-terminally tagged BmGr9 open reading frame was inserted into pOX (Addgene ID: 3780) using Gibson assembly.</p>", "<title>Stable polyclonal cell line for BmGr9 expression</title>", "<p id=\"P50\">BmGr9 was expressed using a lentivirus expression system to create a stable polyclonal cell line in the Expi293F inducible GnTI-cell line (ThermoFisher Scientific) using published protocols<sup>##REF##30455477##42##</sup>. Briefly, lentiviral particles were produced by co-transfecting 1.8×10<sup>7</sup> HEK293T cells seeded 24 hours prior with 16 µg of the lentiviral expression plasmid described above, 16 µg psPAX2 packaging plasmid (Addgene ID: 12260), and 16 µg pMD2.G envelope plasmid (Addgene ID: 12259) using polyethylenimine (Polysciences). The lentivirus-containing supernatant was harvested after 3 days, then applied to 10×10<sup>6</sup> Expi293F inducible GnTI-cells and incubated for 3 days to allow for genomic integration and establishment of a polyclonal stable cell line. Transduced cells were expanded and frozen in aliquots for long-term storage and use.</p>", "<title>Protein expression and purification</title>", "<p id=\"P51\">The stably transduced polyclonal cell line was grown at 37°C with 8% carbon dioxide in Expi293 expression medium (ThermoFisher Scientific) to 3×10<sup>6</sup> cells/mL, then induced with 5 μg/mL doxycycline and 5 mM sodium butyrate for 72 hours. Cells were collected by centrifugation at 600 g for 10 min, washed with phosphate buffered saline (PBS; Corning), resuspended in lysis buffer (20 mM Tris pH 8.25, 150 mM NaCl, 1 μM pepstatin A, 1 mM phenylmethylsulfonylfluride (PMSF), 1 mM benzamidine), and lysed using an Avestin Emulsiflex C5 with 4 passes at 5–15 kpsi. The lysate was cleared using a 15 min low-speed spin (9,700 g) and membranes were pelleted at 185,000 g for 2 hours, flash frozen, and stored at −80°C. All purification steps were performed at 4°C. Thawed membranes from 2 L of culture were homogenized in 120 mL solubilization buffer (PBS, 1 μM pepstatin A, 1 mM PMSF, 1 mM benzamidine, and 2% (w/v) n-dodecyl β-<sc>d</sc>-maltoside (DDM; Anatrace)) using a glass Potter-Elvehjem grinder, then rocked for 1.5 hr at 4°C. Detergent-insoluble material was pelleted at 185,000 g for 40 min and the supernatant was loaded onto a 1-mL Strep-Tactin XT 4Flow cartridge at 1 mL/min at 4°C. The resin was washed 5 × 2 column volumes (CV) of wash buffer (100 mM Tris pH 8.0, 150 mM NaCl, 1 mM EDTA, 0.05% (w/v) DDM, 1 mM DTT) then 6 × 0.5 CV of elution buffer (wash buffer with 50 mM biotin). To elute BmGr9, the column was rocked for 30 min with 3 CV of elution buffer and collected by displacing the column with 1 additional CV. The rocking elution was repeated 4–5 times until all protein was eluted. Elutions containing BmGr9 were combined and further purified using size exclusion chromatography (SEC) on a Superose 6 10/300 GL (Cytiva) equilibrated with SEC buffer (20 mM Tris-HCl pH 8.25, 150 mM NaCl, 1 mM DTT, 1 mM EDTA, 0.01% glyco-diosgenin (GDN; Anatrace)). For the fructose-bound structure the SEC buffer also contained 270 mM D-fructose. BmGr9-rich fractions were combined, concentrated to 3.2–3.3 mg/mL with a 100 kDa molecular weight cut-off centrifugal filter (Millipore), and used immediately for preparing cryo-EM grids.</p>", "<title>Cryo-EM sample preparation</title>", "<p id=\"P52\">Concentrated BmGr9 protein (3 μL) was deposited onto 400 mesh Quantifoil Cu 1.2/1.3 grids that had been glow discharged in a PELCO easiGLOW (Ted Pella) at 0.39 mBar, 15 mA for 30 s. Agonist-free samples were vitrified in 100% liquid ethane using a Vitrobot Mark IV (Thermo Fisher Scientific), with a wait time of 0 s, blot time of 3 s, drain time of 0 s, and a blot force of 0 at 100% humidity. Fructose-bound samples were prepared with a blot time of 9 s.</p>", "<title>Cryo-EM data collection and processing</title>", "<p id=\"P53\">Cryo-EM data were collected on a 300 kV Titan Krios G3i Microscope (Thermo Fisher Scientific) equipped with a K3 direct electron detector (Gatan) and a GIF quantum energy filter (20 eV) (Gatan) using counted mode at the Harvard Cryo-Electron Microscopy Center for Structural Biology at Harvard Medical School. Data were acquired utilizing image shift and real-time coma correction by beamtilt using the automated data collection software SerialEM<sup>##REF##16182563##43##</sup>; nine holes were visited per stage position acquiring two movies per hole. Details of the data collection and dataset parameters are summarized in ##TAB##0##Table 1##. Dose-fractionated images were gain normalized, aligned, dose-weighted and summed using MotionCor2<sup>##REF##28250466##44##</sup>. Contrast transfer function (CTF) and defocus value estimation were performed using CTFFIND4<sup>##REF##26278980##45##</sup>. Details of the data processing strategy are shown in ##SUPPL##0##Figure S2##. In short, particle picking was carried out using crYOLO<sup>##REF##31240256##46##</sup>) followed by 3D classification within Relion<sup>##REF##23000701##47##</sup>. For the fructose-bound sample, a second round of 3D classification was performed to further improve the particle set (##SUPPL##0##Figure S4##). The selected particles were then subjected to Bayesian polishing following 3D refinement with C4 symmetry imposed. The data then underwent CTF refinement and nonuniform refinement with C4 symmetry imposed, in cryosSPARC<sup>##REF##28165473##48##</sup>. Outputs from nonuniform refinement underwent CryoSPARC Local Refinement to produce the final 2.85 Å (3.23 Å C1) and 3.98 Å (6.4 Å C1) reconstructions for the Apo and Fructose samples respectively. Structural biology applications used in this project were compiled and configured by SBGrid<sup>##REF##24040512##49##</sup>.</p>", "<title>Model building and refinement</title>", "<p id=\"P54\">A monomeric model of BmG9 was generated using ColabFold<sup>##REF##35637307##50##</sup>. The rank 1 model was placed in the map with 4-fold symmetry using DockInMap in PHENIX<sup>##REF##31588918##51##</sup>, and refined through cycles of manual rebuilding in Coot<sup>##REF##20383002##52##</sup>, real-space refinement in PHENIX with macrocycles including morphing, global minimization, nhq_flips, and ADP, under secondary structure and NCS constraints, and remodeling by simulations run in the ISOLDE plugin of ChimeraX<sup>##REF##29872003##53##</sup>. The refinement statistics are summarized in ##TAB##0##Table 1##.</p>", "<title>Electrophysiology</title>", "<p id=\"P55\"><italic toggle=\"yes\">Xenopus laevis</italic> oocytes (EcoCyte Bioscience) were injected with 20 ng cRNA and cultured at 18°C in ND96 media containing (mM): 2 KCl, 96 NaCl, 2.0 MgCl<sub>2</sub>, 1.8 CaCl<sub>2</sub>, 5 HEPES-NaOH pH 7.4 supplemented with penicillin/streptomycin. Electrophysiological recordings were performed two days after injection by two-electrode voltage clamp using a OC-725 amplifier. Whole-cell currents were elicited by 2.5-s voltage ramp from −150 to +90 mV from a holding potential of −80 mV in ND96 (pH 7.4), filtered at 1 kHz, and recorded in pCLAMP 8 software (Molecular Devices).</p>", "<title>Generation of multiple sequence alignments</title>", "<p id=\"P56\">The members of the GR family of proteins display a high degree of functional and sequence diversity which makes their sequence alignment and functional classification a difficult task. To explore the sequence-function relationship of GRs, we first created a seed alignment of 57 different GR sequences from <italic toggle=\"yes\">D. melanogaster</italic> by structurally aligning monomer models downloaded from the AlphaFold Protein Structure Database<sup>##REF##34293799##26##</sup> using MUSTANG<sup>##REF##16736488##54##</sup>. Using this seed alignment, we created a profile hidden Markov model (HMM) using the hmmbuild tool from the HMMER software package (<ext-link xlink:href=\"http://www.hmmer.org\" ext-link-type=\"uri\">hmmer.org</ext-link>) and searched the Uniref50 database (release-2023_02) for sequences matching this profile HMM using the hmmsearch tool in HMMER. We filtered the set of sequences obtained in the previous step to select sequences with bit score larger than 50, sequence length between 300 and 600, and from species belonging to the class insecta. Next, we added the sequences of known fructose-activated GRs to this filtered set of sequences. We also added sequences of the two odorant receptor proteins with published structures, AbOrco and MhOr5, to generate the final set of 1895 sequences. We then aligned these sequences to the profile HMM created in the first step.</p>", "<p id=\"P57\">We created a multiple sequence alignment of insect ORs using a method similar to the one we used for creating the alignment of GRs. We created a profile HMM from structural alignment of 62 Alphafold2 models of <italic toggle=\"yes\">D. melanogaster</italic> ORs and identified insect sequences of 300–600 amino acids in length. Some of these sequences turned out to be ORCO proteins which we removed from this set and added the sequence for MhOr5. Finally, we aligned this set of sequences to the profile HMM that was created in the first step to create an alignment of 3885 OR sequences.</p>", "<p id=\"P58\">We used the previously published alignment of 176 ORCO sequences<sup>##REF##30111839##24##</sup> without any modifications.</p>", "<title>Phylogenetic tree construction and classification</title>", "<p id=\"P59\">Using IQ-TREE 2<sup>##REF##32011700##55##</sup>, we inferred 20 separate maximum likelihood phylogenetic trees from the alignment of 1895 GR sequences with the Le-Gascuel (LG) substitution model<sup>##REF##18367465##56##</sup>, optimized equilibrium frequencies, and across-site rate variation using the discrete gamma model with 8 categories. We selected the tree with the best log likelihood as the final tree for further analysis. The resulting tree with aBayes posterior probability branch support values is in ##SUPPL##0##Figure S10##, and the annotated tree in ##SUPPL##0##Figure S11##. Based on the position of the AbOrco and MhOr5 sequences and annotations of nearby sequences, we determined that one small clade in the tree contained ORs (41 sequences), marking the branch point of divergence of ORs from the GR family. These 41 sequences were removed from the ‘all GR’ set of 1854 sequences for further analyses.</p>", "<p id=\"P60\">For the next part of our analysis, we assumed that GRs that appear in the same subfamily of the tree to be functionally related to each other. This assumption was supported by the fact that all known D-fructose receptors—DmGr43a, BmGr9, AgGr25, <italic toggle=\"yes\">Helicoverpa armigera</italic> Gr4, and <italic toggle=\"yes\">Apis mellifera</italic> Gr3—clustered in the same subfamily. We extracted the corresponding set of 74 sequences, which we refer to as the Gr43a subfamily. To functionally identify other subfamilies in the tree, we looked for <italic toggle=\"yes\">D. melanogaster</italic> GRs in each subfamily and assigned the function of the <italic toggle=\"yes\">D. melanogaster</italic> GRs found in that subfamily to the entire subfamily. Using this strategy, we extracted two more subfamilies in addition to Gr43a subfamily for further analysis (##SUPPL##0##Figure S11##): The Gr63a subfamily containing known CO<sub>2</sub> receptors (107 sequences) and the Gr5a subfamily containing many known sugar receptors (251 sequences).</p>", "<title>Sequence conservation analysis</title>", "<p id=\"P61\">For the OR family and each of the three GR subfamilies chosen for further analysis, we selected a structural model of a representative GR: the agonist-free MhOr5 structure (PDB ID: 7LIC) for the OR family; the agonist-free BmGr9 structure for the Gr43a subfamily; and the AlphaFold2 models of Gr5a (UniProt ID: Q9W497) and Gr63a (UniProt ID: Q9VZL7) for the Gr5a and Gr63a subfamilies, respectively. For each of the five corresponding sequences alignments, we performed sequence conservation analysis using ConSurf<sup>##REF##27166375##29##,##REF##20478830##57##,##REF##12499312##58##</sup>, using the WAG evolutionary model.</p>", "<title>Ligand-binding pocket analysis</title>", "<p id=\"P62\">The predicted ligand-binding pockets for the Gr5a and Gr63a subfamilies were identified in the central region of the transmembrane S1-S6 bundle of each representative Alphafold2 model. We confirmed that the approximate size and location of each predicted pocket was a reasonable representative by comparing them to 4–5 additional AlphaFold2 models chosen from different branches of the same subfamily. The experimentally determined ligand-binding pocket of BmGr9 was used for the Gr43a subfamily and of MhOr5 for the OR family. All residue positions with solvent-exposed atoms facing the respective pockets were selected (##SUPPL##0##Figure S12##). The observed amino acid frequencies at each position were computed from the respective sequence alignment. The heatmaps in ##FIG##5##Figure 6## were obtained by summing the amino acid frequencies according to the following amino acid groupings based on chemical properties: aliphatic (Ala, Cys, Leu, Met, Val; black), polar (Asn, Gln, Ser, Thr; orange), negatively charged (Asp, Glu; red), positively charged (Arg, Lys; blue), aromatic (His, Phe, Trp, Tyr; green), and shape-determining (Gly, Pro; pink) residues.</p>", "<title>Determination of loop lengths</title>", "<p id=\"P63\">Despite high diversity and low sequence similarity of GR proteins, our structure-based and profile HMM-assisted approach produced an alignment with high overlap (>80%) coverage for the transmembrane helix regions (##SUPPL##0##Figure S6B##). Assuming that sequence regions corresponding to transmembrane helices are well aligned with each other, the poorly aligned regions between two transmembrane helices must correspond to the loops that connect those helices. Because we have the experimentally determined structure of BmGr9, we used its sequence as a reference to define boundaries of helices S1 to S7 for all sequences in the GR alignment and the selected subfamily alignments (helix boundaries for S1 are residues 52–79; S2, 90–135; S3, 141–176; S4, 178–229; S5, 287–339; S6, 345–389; S7a, 395–409; S7b, 424–444). For the OR alignment, we similarly used the MhOr5 structure as a reference (S1, 49–76; S2, 78–123; S3, 130–159; S4, 198–251; S5, 317–368; S6, 371–415; S7a, 420–434; S7b, 448–472). To determine the loop lengths, we counted the number of residues connecting the two adjacent transmembrane helices in each sequence, after shortening each helix by 1 residue on each end to allow for noise in the alignment. To avoid including incomplete sequences, we only counted sequences that had non-zero loop length.</p>", "<title>Pore dimension analysis</title>", "<p id=\"P64\">We used the HOLE program<sup>##REF##9195488##59##</sup> to analyze the dimensions of ion conduction pores of agonist-free and fructose-bound structures of BmGr9.</p>", "<title>Fructose docking</title>", "<p id=\"P65\">We used AutoDock Vina<sup>##REF##19499576##60##,##REF##34278794##61##</sup> to dock β-<sc>d</sc>-fructopyranose in the fructose-bound structure. The AutoDock search space was set to a cuboid of 25 × 30 × 40 Å<sup>3</sup> spanning the length and width of a monomer. We then used real-space refinement in PHENIX<sup>##REF##31588918##51##</sup> (macrocycles including morphing, global minimization, nhq_flips, and ADP, under secondary structure and NCS constraints) with the AutoDock rank 1 position of fructose which modeled the fructose into the density.</p>", "<title>QUANTIFICATION AND STATISTICAL ANALYSIS</title>", "<p id=\"P66\">For the electrophysiology experiments described in ##FIG##0##Figure 1A## and ##SUPPL##0##S1A##–##SUPPL##0##D##, n refers to independent biological replicates. Shapiro-Wilk tests were used to assess the normality of all datasets (p≤0.05 rejected normal distribution). Nonparametric tests consisted of Kruskal-Wallis followed by a Steel-Dwass post hoc test for multiple comparisons (JMP11, SAS).</p>" ]	[ "<title>RESULTS</title>", "<title>Overall structure of an insect gustatory receptor</title>", "<p id=\"P10\">To determine the structure of BmGr9, we produced and purified N-terminally TwinStrep-tagged BmGr9 using HEK293 cells. When expressed in <italic toggle=\"yes\">Xenopus</italic> oocytes, this construct is activated by D-fructose with an EC<sub>50</sub> of 22 mM, but not by D-glucose (##FIG##0##Figures 1A## and ##SUPPL##0##S1A##–##SUPPL##0##D##), consistent with the published EC<sub>50</sub> value and specificity of wildtype BmGr9<sup>##REF##21709218##17##</sup>. We produced detergent-solubilized BmGr9 (##SUPPL##0##Figure S1E##) and used single-particle cryo-EM to obtain a 2.85-Å density map (##FIG##0##Figures 1B##–##FIG##0##C##, ##SUPPL##0##S2## and ##SUPPL##0##S3##) which we used to build and refine a structural model of BmGr9 (##FIG##0##Figure 1D##–##FIG##0##E##). We also purified BmGr9 in the presence of D-fructose (##SUPPL##0##Figure S1F##) and obtained a 3.98-Å density map which we used to model the D-fructose-bound conformation (##SUPPL##0##Figures S4## and ##SUPPL##0##S5##). We first describe the structural features of BmGr9 using the higher-resolution agonist-free structure, then compare the D-fructose-bound and agonist-free structures to define the fructose-mediated structural changes.</p>", "<p id=\"P11\">As anticipated from its homology to ORs, each BmGr9 subunit contains an N-terminal intracellular S0 helix and seven transmembrane helices (S1 to S7) with S7 broken into S7a and S7b (##FIG##0##Figure 1D##). BmGr9 is a tetramer with C4 symmetry, with the ion pore on the central four-fold axis (##FIG##0##Figure 1E##). The BmGr9 structure encompasses most of the protein, except for a disordered intracellular loop between S4 and S5 (residues 232–269), and the N and C termini (15 and 5 residues, respectively). Helices S1 and S3 only span the thickness of the lipid bilayer, while S2, S4, S5, S6, and S7a extend into the intracellular space to form an anchor domain similar to that observed in AbOrco and MhOr5 (##FIG##0##Figure 1D##; <sup>##REF##30111839##24##,##REF##34349260##25##</sup>). Helix S7b contributes to the pore and helices S0-S6 expand outward from the central pore axis to form the ligand-binding pocket (##FIG##0##Figure 1E##). The main intersubunit contacts are around the transmembrane pore and the intracellular anchor domain (##FIG##0##Figure 1D##–##FIG##0##E##), burying a total of ~2200 Å<sup>2</sup> of surface area per subunit with ~965 Å<sup>2</sup> from the pore region and ~1235 Å<sup>2</sup> from the anchor. The four anchor domains thus form a tight intracellular bundle whereas deep lipid inlets largely isolate each subunit in the membrane plane (##FIG##0##Figure 1E##).</p>", "<title>BmGr9 and MhOr5 have distinct structural features</title>", "<p id=\"P12\">Both AbOrco and MhOr5 assemble as tetramers with a central ion pore formed by the C-terminal transmembrane segment, S7b. The core of each individual subunit of MhOr5 has a ligand-binding site in the middle of the membrane bilayer plane that appears inaccessible to aqueous solvent, consistent with its selectivity for hydrophobic ligands. Based on the pairwise superpositions of individual subunits, the structure of BmGr9 is more distant from AbOrco and MhOr5 than they are from each other (root mean squared distance (RMSD) values of 4.7 Å, 5.1 Å, and 3.8 Å for the BmGr9-AbOrco, BmGr9-MhOr5, and AbOrco-MhOr5 pairs, respectively). The secondary structure elements of BmGr9 are well defined in our cryo-EM density maps (##SUPPL##0##Figure S6A##), and several of these elements differ in length and orientation relative to the membrane plane when compared to MhOr5 (##FIG##1##Figure 2A##–##FIG##1##B##).</p>", "<p id=\"P13\">The most prominent structural differences between BmGr9 and MhOr5 are starred in ##FIG##1##Figure 2A##–##FIG##1##B##. They include: (i) BmGr9 has a β-hairpin between the S0 and S1 helices, which neatly tucks under S0 (##FIG##1##Figure 2C##); (ii) The S1-S2 loop is longer in BmGr9 than in MhOr5 (10 versus 4 residues), and the S3-S4 loop—which closes access to the eugenol-binding pocket in MhOr5—is much shorter in BmGr9 than in MhOr5 (1 versus 28 residues); (iii) The BmGr9 S2 helix extends further into the intracellular space (7 residues longer than in MhOr5) and is more curved, with two kinks that lead the S2 helix to pack against the rest of the anchor domain; (iv) The S6 helix is longer in BmGr9 (45 versus 34 residues), with a sharp kink at the intracellular membrane boundary; and (v) the extracellular tip of the BmGr9 S4 helix has another sharp kink.</p>", "<p id=\"P14\">The combination of these five structural differences generates two global differences between BmGr9 and MhOr5. First, the differences in orientation and position of the S1-S6 helices within the plane of membrane (##FIG##1##Figure 2C##–##FIG##1##D##) and the lengths of the extracellular loops (##FIG##1##Figure 2A##–##FIG##1##B##) generate very different ligand-binding pockets (##FIG##1##Figure 2E##–##FIG##1##F##). BmGr9 has a ~12-Å deep solvent-accessible ligand-binding pocket that totals ~600 Å<sup>3</sup> in volume, whereas MhOr5 has a much smaller pocket (~100 Å<sup>3</sup>) that is located deeper in the membrane plane and is occluded from the extracellular solvent by its longer S3-S4 loop. Furthermore, S5 forms part of the fructose-binding pocket walls in BmGr9, unlike the S5 in MhOr5 which is not in direct contact with the eugenol-binding pocket (top and middle cross-sections in ##FIG##1##Figure 2C##–##FIG##1##D##). Second, the presence of the S0-S1 β-hairpin and the longer S2 helix in BmG9 provide more extensive structural connections between the ligand-binding pocket formed by helices S1-S6 in the transmembrane domain and the intracellular anchor domain.</p>", "<p id=\"P15\">To assess whether structural features discussed in this study are linked to specific sequence signatures, we created separate family-wide sequence alignments of 1854 GRs and 3885 ORs (excluding ORCOs) from insects using a structure-based approach leveraging the AlphaFold Protein Structure Database<sup>##REF##34293799##26##</sup> (see <xref rid=\"S13\" ref-type=\"sec\">methods</xref> for details). The sequence coverage of the two alignments is excellent, particularly at alignment positions corresponding to secondary structure elements (##SUPPL##0##Figure S6B##). From the aligned GR sequences, we extracted a subalignment of 74 DmGr43a subfamily members containing BmGr9 and the other experimentally validated fructose receptor orthologs, and we also used a previously published alignment of 176 ORCO sequences<sup>##REF##30111839##24##</sup>.</p>", "<p id=\"P16\">Sequence covariation among the 1854 aligned GR sequences supports the idea that several of the structural features distinct to BmGr9 in comparison to MhOr5 are conserved in GRs, with 28 strongly evolutionarily coupled residue pairs (>90% confidence; ##SUPPL##0##Figure S6C##–##SUPPL##0##D##). There is one evolutionarily coupled residue pair crosslinking the two strands of the N-terminal S0-S1 β-hairpin, suggesting that this β-hairpin is also conserved in GRs. A single pair is in the transmembrane region, corresponding to the buried salt bridge between E200 and R361 just below the base of the ligand-binding pocket. Intriguingly, this salt bridge is conserved in MhOr5 (D220 and R387), but not in AbOrco, suggesting that it is best conserved in subunits that naturally bind ligands. The twenty-six remaining pairs are all intrasubunit contacts within the anchor domain, and several of those link the extended intracellular portion of the S2 helix to S4 and S5. This suggests that the extended S2 helix (when compared to MhOr5; ##FIG##1##Figure 2A##–##FIG##1##B##), and its packing against S4 and S5 to expand the anchor domain, is a conserved feature in GRs. This connection of the S2 helix to the anchor domain could provide additional leverage for allosteric communications between the ligand-binding pocket and other regions of the tetrameric ion channels, including the ion pore and its gate.</p>", "<title>Lipid headgroups penetrate the ion pore through intersubunit fenestrations</title>", "<p id=\"P17\">The cryo-EM map of agonist-free BmGr9 also contains strong density features that do not correspond to protein, especially in the lipid inlets between subunits (##FIG##2##Figure 3A##). We assigned several of these features to ordered phospholipids rather than detergent based on their well resolved bidentate shapes. Because no lipids were added during protein purification, we infer that these lipids originated from the HEK293 cell membrane and remained bound to the protein through sample preparation. We assigned these densities as phosphatidylcholine (PC; the most common lipid in HEK293 cells<sup>##REF##26663081##27##</sup>), although the headgroups are unmodeled due to missing density.</p>", "<p id=\"P18\">Four ordered lipids (one per subunit) project their head group from within the hydrophobic region of the bilayer into the aqueous ion pore, filling fenestrations in the pore walls at subunit interfaces (##FIG##2##Figure 3B##–##FIG##2##C##). The lipid enters the pore between S7b helices of adjacent subunits at the level of the inner leaflet. Interestingly, while associated lipids were not reported for AbOrco and MhOr5, analogous fenestrations capable of accommodating a lipid are observed in both structures (##SUPPL##0##Figure S7A##–##SUPPL##0##B##). Furthermore, bidentate densities consistent with such a pore-penetrating lipid are also observed in the map of our fructose-bound BmGr9 structure, as well as in the maps reported for eugenol-bound and DEET-bound MhOr5 (##SUPPL##0##Figure S7C##–##SUPPL##0##E##). The position of these pore-penetrating lipids suggests that they could contribute to the structural stability of the ion pore upon tetramerization, influence ion conduction and selectivity, or both.</p>", "<p id=\"P19\">In BmGr9, T435 and Y437 form polar contacts with the headgroup of the pore-penetrating lipid (##FIG##2##Figure 3D##–##FIG##2##E##). For Y437, tyrosine is highly conserved at this position across GRs (80.7%; ##FIG##2##Figure 3F##) and ORCOs (99.4%; position 466 in AbOrco), and corresponds to the second residue of the GR family signature motif T<bold>Y</bold>hhhhhQF<sup>##REF##26354932##28##</sup> (where h is any hydrophobic amino acid). Tyrosine is also common at the corresponding position in ORs (52.9%; position 461 in MhOr5). For T435, small polar residues are common at this position in GRs (34.6% S, T, or N), while a tyrosine is common in ORs (51.1%), preserving the potential to hydrogen-bond with the lipid headgroup. The hydrophobic tails of the pore-penetrating lipids interact with non-polar sidechains from S7b and S5. As expected from their membrane-embedded positions, hydrophobic residues are enriched at each of these positions in GRs, ORCOs, and ORs (##FIG##2##Figure 3D##–##FIG##2##F##).</p>", "<p id=\"P20\">In summary, three observations suggest that the presence of pore-penetrating lipids is a conserved feature across both the GR and OR families: all available structures have fenestrations between S7b helices of adjacent subunits; lipid-shaped densities are present in similar positions in maps of both BmGr9 and MhOr5 structures, and the general properties of the lipid-interacting residues are conserved at the corresponding positions in sequence alignments of GRs and ORs.</p>", "<title>Pore gate opening involves an interaction network conserved between GRs and ORs</title>", "<p id=\"P21\">The BmGr9 pore has the same quadrivial architecture as AbOrco<sup>##REF##30111839##24##</sup> and MhOr5<sup>##REF##34349260##25##</sup> with a singular extracellular path down the center of the tetramer that opens into a large vestibule in the center of the membrane plane, then diverges into four lateral conduits formed between subunits (##FIG##3##Figures 4A## and ##SUPPL##0##S8A##–##SUPPL##0##D##). The density for the central pore helix S7b and its sidechains is excellent in both the agonist-free and fructose-bound BmGr9 maps (##SUPPL##0##Figure S6##). In the agonist-free structure, starting from the extracellular face of the channel, the pore begins with a closed double-layer hydrophobic gate formed by F444 and I440 at the C terminus of S7b (##FIG##3##Figure 4A##–##FIG##3##C##). Like L473 in AbOrco and V468 in MhOr5 (##SUPPL##0##Figure S8E##), the F444 sidechains from each BmGr9 subunit protrude into the channel lumen to close the ion pore down to a diameter of 2.5 Å, creating a hydrophobic plug (##FIG##3##Figure 4A##–##FIG##3##C##). Below the hydrophobic gate, two threonines (T429 and T436) form two rings of hydroxyls that can stabilize cations (##FIG##3##Figure 4C##). AbOrco and MhOr5 also have hydroxyls in the same positions (##SUPPL##0##Figure S8E##). T436 is highly conserved across insect GRs—it is the first residue of the <bold>T</bold>YhhhhhQF signature motif. T429 is less conserved although predominantly polar or charged (71%, 100%, 74% across GRs, ORCOs and ORs respectively; ##SUPPL##0##Figure S8F##).</p>", "<p id=\"P22\">Located immediately below F444 near the extracellular opening of the ion pore, Q443 points away from the pore in the agonist-free structure but rotates into the ion pathway in the fructose-bound structure (##FIG##3##Figure 4C##–##FIG##3##F##). The Q443 sidechains thus create a hydrophilic ring more suitable for cation conduction in the fructose-bound structure, although the pore diameter is largely unchanged (##FIG##3##Figure 4B##). In addition to its twisting along the helix axis, the C terminus of S7b also moves out from the center of the tetramer by ~4 Å. T436, near the pore-penetrating lipid headgroup, acts as a fulcrum for these movements, such that only the portion of S7b above T436 moves (##FIG##3##Figure 4G##). As a result, the pore widens the most at the other hydrophobic constriction, with the Cα-to-Cα distance between opposing I440 residues increasing from 9.6 Å to 11.8 Å, and the pore diameter from 2.5 Å to 3.2 Å (##FIG##3##Figure 4B##–##FIG##3##C##).</p>", "<p id=\"P23\">Q443 and F444 are highly conserved in GRs and ORCOs; they are the last two residues of the GR family signature TYhhhhh<bold>QF</bold> motif<sup>##REF##26354932##28##</sup> (##SUPPL##0##Figure S8F##). In BmGr9, the signature motif adheres to the GR consensus: 436-TYLVILIQF-444. This motif is notably less conserved in ORs, most of which form heteromers with ORCO<sup>##REF##30312552##8##,##REF##18408712##20##</sup>; however, this glutamine is conserved in homotetrameric MhOr5, which is from a basal insect species that lacks an ORCO ortholog<sup>##REF##27166375##29##</sup>. This Q467 in MhOr5 also swings into the pore upon agonist-induced channel opening and mutating it to alanine or arginine eliminated agonist-activated calcium influx, suggesting that this rearrangement is critical for receptor function<sup>##REF##34349260##25##</sup>.</p>", "<p id=\"P24\">Mutations of the hydrophobic gate residues in BmGr9 (I440 and F444) also support a role for both residues in gating<sup>##REF##36209821##30##</sup>. I440 mutations (I440A and I440Q) increased the inward resting current and decreased the responsiveness to fructose compared to wildtype, suggesting that the hydrophobic gate has been disrupted, allowing cations to pass through the pore without agonist binding<sup>##REF##36209821##30##</sup>. The F444A mutation increased the EC<sub>50</sub> for fructose and reduced the fructose-induced currents, suggesting a change in open-closed equilibrium or conductance<sup>##REF##36209821##30##</sup>.</p>", "<p id=\"P25\">Pore helix S7b is tightly packed with—and its movements coupled to—helix S5, which connects directly to the binding pocket in BmGr9 (##FIG##3##Figure 4H##–##FIG##3##J##). BmGr9 residues L441 on S7b and Y332 on S5 correspond to MhOr5 residues L465 and Y362, respectively, two highly conserved and evolutionarily coupled hydrophobic amino acids in ORs that also move in concert between the agonist-free and eugenol bound MhOr5 structures<sup>##REF##34349260##25##,##REF##25584517##31##</sup>. The Y362A mutation in MhOr5 impaired eugenol activation while Y362F showed no effect, supporting the importance of the aromatic group at this position<sup>##REF##25584517##31##</sup>. BmGr9 residue Y332 is highly conserved in GRs while L441 is conserved as an aliphatic residue (##FIG##2##Figure 3F##). Mutations to alanine of either Y332, L441, or two other conserved hydrophobic residues at the S7b-S5 interface—L438 and I335—increased the resting current of BmGr9<sup>##REF##36209821##30##</sup>, suggesting that the tight packing of S7b and S5 is required for proper ligand gating.</p>", "<p id=\"P26\">The S5-S7b interaction connects the pore to the binding pocket, suggesting that small fructose-induced movements in S5 could gate the pore. Y332 is part of a highly conserved TPY motif in the Gr43a subfamily (##FIG##3##Figure 4J##). T330 faces the ligand-binding pocket and likely interacts with the fructose (see also below). P331 breaks the backbone hydrogen-bonding pattern on S5, and thus could reduce the energy barrier to local rearrangements and thus facilitate allosteric communication between the ligand-binding pocket and the pore.</p>", "<title>Fructose-binding pocket is lined with polar and aromatic residues</title>", "<p id=\"P27\">In contrast to the solvent-inaccessible eugenol-binding cavity observed in MhOr5<sup>##REF##34349260##25##</sup>, BmGr9 has a deep solvent-accessible cavity at the analogous location, with its opening on the extracellular face near the center of each subunit (##FIG##1##Figure 2##, ##SUPPL##0##S9A##–##SUPPL##0##B##). In each subunit, the extracellular termini of helices S0-S6 splay out, with helices S2-S5 forming the walls of this deep pocket. At the bottom of this pocket, the fructose-bound map contains additional density when compared to the agonist-free map (##FIG##4##Figure 5A##–##FIG##4##B##). While the resolution of the map at this location is not high enough to resolve the fructose binding pose, the location is consistent with published mutational analysis<sup>##REF##36209821##30##</sup>. Furthermore, computational docking suggests that a fructose molecule is readily accommodated in this pocket. That is, when docking a β-<sc>d</sc>-fructopyranose (the most abundant form of D-fructose in solution<sup>##REF##34784518##32##</sup>), the most energetically favored positions are just adjacent to the observed density (##SUPPL##0##Figure S9C##). Upon real-space refinement of the protein model and docked fructose against the cryo-EM map, the fructose roughly fits inside the density (##SUPPL##0##Figure S9C##). We are therefore confident in assigning the bottom of the deep pocket as the fructose-binding site, and discuss it as such below, although we refrain from describing specific fructose-protein interactions.</p>", "<p id=\"P28\">Nine of the 21 residues on the fructose-binding pocket surface are highly conserved in the Gr43a subfamily (>66% identity; ##FIG##4##Figure 5C##–##FIG##4##D##). As described above, the TPY motif on S5 connects the binding pocket to the pore movements (##FIG##3##Figures 4H## and ##FIG##4##5D##). S5 residue T330, along with H326, faces the binding pocket. Both are highly conserved and are near the other highly conserved polar and aromatic residues in the bottom half of the ligand-binding pocket (S2 residue D99; S4 residues Y186, Y190, and W193 (68.6% Y and 80% aromatic); and S6 residues Q351, W354, and H358). Of the 21 residues we include as forming the pocket, 7 have been previously investigated by mutagenesis<sup>##REF##36209821##30##</sup>. Of those, conserved residues D99, W193, W354, and H358, as well as D165 and F189 (70% conserved as an aromatic residue), are all essential for BmGr9 function, as mutating each residue individually to alanine dramatically reduced or eliminated fructose-activated channel function<sup>##REF##36209821##30##</sup> (##FIG##4##Figure 5E##). Two additional residues (of 16 tested) adjacent to but not on the surface of the binding pocket, V103 and L161 (81.7% and 58.0% aliphatic, respectively), were also important for the fructose response (##FIG##4##Figure 5E##); they may structurally enable the allosteric communication between the ligand-binding site and the pore gate. The overall high level of sequence conservation in the pocket (9 of the 45 most conserved residues in the BmGr9 subfamily), particularly at the bottom of it, suggests that maintaining aromatic and hydrophilic sidechains is important for ligand binding and is an important first step to convert fructose binding to pore opening.</p>", "<p id=\"P29\">In both a superposition of the agonist-free and fructose-bound BmGr9 subunit structures (##FIG##4##Figure 5F##) and an alignment-free distance difference matrix (##SUPPL##0##Figure S9D##), we observe relative movements of helices S2-S6 that reshape the binding pocket upon agonist binding (##FIG##4##Figures 5F## and ##SUPPL##0##S9A##–##SUPPL##0##B##). S2—with its highly conserved D99 residue closest to the cryo-EM density assigned to fructose—moves the most, and most helices move inward towards the central axis of the protein (##FIG##4##Figure 5F##). This coordinated movement of the helices could convey changes caused by fructose binding to the gates of the ion pore.</p>", "<title>Ligand-binding pocket comparison across the GR family</title>", "<p id=\"P30\">Using the experimentally determined BmGr9 structure as a reference point, we explored the potential of bioinformatic approaches to inform structure-function relationships among GRs more broadly across the GR family. To assess evolutionary relationships among GRs, we created a phylogenetic tree from our structure-based multiple sequence alignment of 1854 GRs and 41 ORs (##FIG##5##Figures 6A## and ##SUPPL##0##S10##). As chemical detection is a primary function of these receptors, we focused our analysis on the putative ligand-binding pockets of members of four subfamilies that contain members with relatively well-established chemosensory functions: the Gr5a and Gr43a subfamilies, which mediate sugar sensing; the Gr63a subfamily, which mediates CO<sub>2</sub> sensing; and the ORs, which mediate responses to volatile organic compounds (##FIG##5##Figures 6A## and ##SUPPL##0##S11##).</p>", "<p id=\"P31\">Experimentally determined structures are available for an OR (MhOR5) and for BmGr9 (a Gr43a ortholog), but not for Gr5a or Gr63a subfamily members, although AlphaFold predictions are available. We assessed the ability of AlphaFold2 to provide accurate structural predictions of GR and OR family members by comparing the monomeric models of BmGr9 and AbOrco from the AlphaFold database<sup>##REF##34293799##26##</sup> to their experimentally determined agonist-free structures (the database has no MhOr5 model). While neither structure was in the AlphaFold2 training set, both models correspond well to the respective structures (RMSD values of 0.9 Å for BmGr9 and 0.3 Å for AbOrco). We thus used the AlphaFold models of <italic toggle=\"yes\">D. melanogaster</italic> Gr5a and Gr63a to identify the residues likely to form the surfaces of their putative ligand-binding pockets (##SUPPL##0##Figure S12##). Using ConSurf<sup>##REF##27166375##29##</sup>, we mapped sequence conservation across 251 Gr5a and 107 Gr63a subfamily members to the corresponding representative AlphaFold model, and of 74 Gr43a subfamily members and 3885 ORs to the structures of BmGr9 and MhOr5, respectively (##FIG##5##Figure 6B##–##FIG##5##E##, ##SUPPL##0##S12##).</p>", "<p id=\"P32\">While the Gr5a and Gr43a subfamilies are evolutionarily divergent (##FIG##5##Figure 6A##), both contain receptors involved in sugar detection, raising the possibility of similarities in their ligand-binding pockets. Indeed, despite their distinct evolutionary histories, their putative ligand-binding pockets are similarly enriched for aromatic and polar amino acids. Among Gr43a subfamily members, nine of the 21 pocket-lining positions are most commonly occupied by aromatic amino acids, along with four by polar, two by acidic, one by basic, and five by aliphatic amino acids (##FIG##5##Figure 6B##). Among Gr5a subfamily members, 11 of the 31 pocket-lining residues are most commonly occupied by aromatic amino acids, 12 by polar, one by acidic, one by basic, and six by aliphatic amino acids (##FIG##5##Figure 6C##). Of the most highly conserved positions (ConSurf score ≥8), six are aromatic, two polar and one negatively charged in the Gr43a subfamily (##FIG##5##Figure 6B##), while seven are aromatic, seven polar, two aliphatic, one positively and one negatively charged in the Gr5a subfamily (##FIG##5##Figure 6C##). This abundance of aromatic, polar, and charged amino acids is consistent with the role of aromatic and hydrophilic residues in sugar binding in other proteins<sup>##REF##21458998##33##,##REF##26561965##34##</sup>. As detailed below, it is not shared by Gr63a subfamily members or ORs.</p>", "<p id=\"P33\">Despite similarities in the chemical character of the binding pockets between the Gr43a and Gr5a subfamilies, their pocket sizes differ dramatically (##SUPPL##0##Figure S12A##–##SUPPL##0##B##, ##SUPPL##0##E##). The predicted Gr5a binding pocket is much larger than the pocket we observe in the BmGr9 structure (~2100 Å<sup>3</sup> versus ~600 Å<sup>3</sup>; ##SUPPL##0##Figure S12E##). The larger pocket in Gr5a arises from several key predicted structural differences: Gr5a’s longer S3-S4 loop forms a V-shape with two short helices that enable S3 and S4 to splay further from the subunit center to enlarge the pocket, while its shorter S1-S2 loop further widens the exposed opening (##SUPPL##0##Figure S13B##). These structural features of Gr5a are present across the subfamily, with shorter S1-S2 and longer S3-S4 loops a distinct feature of Gr5a subfamily members compared to other GRs or to ORs (##SUPPL##0##Figure S13A##; p<0.01 Steel-Dwass test). These larger pockets could accommodate a wider variety of sugars, consistent with the ability of gustatory neurons expressing Gr5a subfamily members to respond to polysaccharides as well as monosaccharides<sup>##REF##25702577##11##</sup> (##SUPPL##0##Figure S12##).</p>", "<p id=\"P34\">The Gr63a subfamily forms another divergent clade of GRs, whose members can form CO<sub>2</sub> sensors<sup>##REF##24607224##1##,##REF##24581501##13##</sup> (##FIG##5##Figure 6A##). In contrast to the sugar receptors above, aliphatic amino acids predominate in the putative ligand-binding pockets of Gr63a subfamily members, with 20 of 24 pocket-lining positions mostly occupied by aliphatic amino acids, and just three by aromatic, and one by polar amino acids (##FIG##5##Figure 6D##). Similarly, for ORs, which are primarily involved in the detection of volatile organic compounds, 8 of the 10 pocket-lining positions are most commonly occupied by aliphatic amino acids, with the remaining two positions mostly occupied by aromatic amino acids (##FIG##5##Figure 6E##). The pocket sizes of representatives of both of these subfamilies are substantially smaller than those of the sugar receptors (~150 Å<sup>3</sup> for the Gr63a AlphaFold model and ~100 Å<sup>3</sup> for the MhOr5 structure; ##SUPPL##0##Figure S12C##–##SUPPL##0##E##). Thus, receptors implicated in detecting different classes of chemicals differ in both pocket size and chemical composition, consistent with key roles in determining ligand specificity.</p>" ]	[ "<title>DISCUSSION</title>", "<p id=\"P35\">Our work provides an initial view of the structural features that underlie the chemoreceptor activity of a member of the insect gustatory receptor family. The structure of the BmGr9 homotetramer bears substantial resemblance to the distantly related olfactory receptor MhOr5, including its quadrivial channel architecture. However, BmGr9 contains an additional S0-S1 β-hairpin and a longer S2 helix that together provide more extensive structural connections between the anchor domain and the transmembrane regions than in MhOr5. BmGr9’s ligand-binding pocket also differs from that in MhOr5, as the BmGr9 pocket is much larger and involves additional receptor surfaces, is lined with aromatic and polar residues rather than hydrophobic residues, and is open to the extracellular milieu. These distinct characteristics provide a structural basis for the distinct functions of the two receptors, with MhOr5 acting as an olfactory receptor for volatile, hydrophobic compounds like eugenol, and BmGr9 acting as a gustatory receptor for fructose, a water-soluble carbohydrate. Sequence analyses indicate that these distinctive features are conserved across other ORs and Gr43a subfamily members. At a mechanistic level, fructose binding to BmGr9 elicits small movements of the S1-S6 helices that surround the ligand-binding pocket. These movements narrow the pocket, with the movement of S5, which interacts with both the bound fructose and the S7b pore helix, potentially promoting the pore-opening motion of S7b.</p>", "<p id=\"P36\">Although GRs exhibit substantial sequence diversity, they do share a characteristic sequence motif near their C-termini: TYhhhhhQF<sup>##REF##30312552##8##</sup>. In the BmGr9 structures, we observe a clear function associated with each of the 4 most highly conserved amino acids present in this motif on the pore-forming helix S7b. The TY pair shapes the structure and hydrophilic character of the ion pathway: the four T436 sidechains form a hydrophilic ring below the second hydrophobic gate—formed by the middle hydrophobic residue (I440) in the conserved motif—while the Y437 sidechains interact with pore-penetrating phospholipid headgroups. The QF pair plays a role in gating. The F444 sidechains from each of the four subunits form a hydrophobic plug at the extracellular pore opening in the closed agonist-free state. These phenylalanines swing out of the way upon fructose binding, as the adjacent Q443 sidechains swing into the pore, making the opening hydrophilic. The conservation of the sequences in this motif across the GR family suggests that helix S7b’s contributions to BmGr9 function will be conserved in other GRs.</p>", "<title>Pore-penetrating lipids as a common feature of GRs and ORs</title>", "<p id=\"P37\">Based on the available experimental structural data for BmGr9, AbOrco<sup>##REF##30111839##24##</sup>, and MhOr5<sup>##REF##34349260##25##</sup>, as well as the conservation of the TY sequence motif in GRs, ORs and ORCOs, the pore-penetrating lipids we observe bound to BmGr9 are likely a feature conserved across the superfamily. Fenestrations in the pore walls are observed in all available structures and density consistent with a lipid is present in both agonist-free and fructose-bound BmGr9 structures, suggesting that the lipids form part of a stable pore structure. Fenestrations opening the ion path to the membrane environment have been observed in several other ion channel families, including ionotropic glutamate receptors, cys-loop receptors, voltage-gated potassium channels and sodium channels, and mechanosensitive two-pore domain potassium (K2P) channels<sup>##REF##25766236##35##–##REF##33674151##39##</sup>. In some channels, such fenestrations are transient, while in others they are observed in both closed and open channel states. In many cases these fenestrations allow activators or blockers to enter the pore—including some endogenous ligands, and they have been implicated in the mechanisms of well-established drugs including common local and general anesthetics<sup>##REF##33674151##39##,##REF##35418860##40##</sup>. The fenestrations in insect GR and OR channels could therefore also represent opportunities for chemical modulation of their activity.</p>", "<title>Ligand-binding pockets of evolutionarily divergent sugar-sensing GRs share common features</title>", "<p id=\"P38\">The BmGr9 ligand-binding pocket in our structures differs significantly from a previously reported homology model, which was not based on AlphaFold<sup>##REF##36209821##30##</sup>. Only ~7 of the 21 residues that participate in the pocket in our experimentally determined structure are shared with the earlier prediction<sup>##REF##36209821##30##</sup>. Observed contributions of residues from the S5 helix and the S1-S2 extracellular loop to the pocket were not predicted in the earlier model, and the pocket-lining residues in the S2, S3, S4 and S6 helices largely differ. Strikingly, six of the eight mutations from that study that had strong effects on fructose-induced currents<sup>##REF##36209821##30##</sup> face the experimentally determined binding pocket. In contrast, of the 11 mutations with no effect<sup>##REF##36209821##30##</sup>, none face the experimentally determined binding pocket. These mutagenesis results suggest that residues distributed around the pocket are important for fructose binding and channel gating. This likely enables the exquisite selectivity of BmGr9 for fructose among other monosaccharides<sup>##REF##21709218##17##</sup>.</p>", "<p id=\"P39\">Our bioinformatics analyses leveraging AlphaFold, which more accurately models BmGr9, indicate that the ligand-binding pockets of Gr5a subfamily members—a second set of GRs involved in sugar sensing—share characteristics with those of the Gr43a subfamily. As the two subfamilies are otherwise evolutionary divergent, this likely reflects convergence between these families of sugar receptors. That the pocket is larger in the Gr5a subfamily also suggests a structural explanation for the responsiveness of gustatory neurons expressing Gr5a subfamily members to di- and poly- as well as monosaccharides<sup>##REF##25702577##11##</sup>, whereas BmGr9 and its orthologs like Gr43a are fructose-specific. Finally, our bioinformatics analyses suggest the members of the Gr63a subfamily of CO<sub>2</sub> receptors have highly hydrophobic binding pockets (##FIG##5##Figure 6##). This suggests that CO<sub>2</sub> detection could involve hydrophobic interactions with pocket residues or binding of a hydrophobic ligand or co-factor. Taken together, this work illustrates how the combination of experimental structures and structure-based sequence analyses can help delineate the evolution and function of large protein families like the insect GRs and ORs.</p>", "<p id=\"P40\">Expanding these comparisons to different GRs subfamilies with well-defined ligand classes, the predicted ligand-binding pocket dimensions and chemical properties are shaped by structural features that are conserved within subfamilies but differ between subfamilies with distinct ligand types. For example, G5a subfamily members have large and polar predicted pockets strongly suggesting that they are indeed di- or polysaccharide-gated ion channels, consistent with their role in sugar detection in sensory neurons. Our work thus illustrates that the combination of experimental structures and structure-based sequence analyses can help delineate the evolution and function of large protein families like the insect GRs and ORs.</p>", "<title>Limitations of this study</title>", "<p id=\"P41\">At the structural level, although agonist binding to BmGr9 promotes structural changes conducive to ion flow, the ion path appears too narrow for ion conduction in the structures captured here. In the agonist-free state, the extracellular entrance to BmGr9’s ion pore is sealed by a double-layered hydrophobic gate formed by helix S7b. Upon agonist binding, S7b movements replace the outer layer of the gate’s hydrophobic plug (formed by an F444 from each subunit) with hydrophilic residues (Q443), and they also increase the distance between the hydrophobic residues (I440) of the gate’s inner layer, dilating the pore by ~1.8 Å. However, agonist binding does not dramatically alter the narrowest constriction of the ion pore, with an oxygen-to-oxygen distance of ~5.4 Å at the level of Q443 in fructose-bound BmGr9. This contrasts with the ~9.2 Å oxygen-to-oxygen distance reported for the analogous Q467 position in agonist-bound MhOr5<sup>##REF##34349260##25##</sup>. This suggests that additional pore conformations exist for BmGr9. Structure determination in a lipid environment, such as in nanodiscs, rather than in detergent, could reveal these additional conformational shifts. Finally, it will also be of interest to examine the positioning of the pore-penetrating lipids in a lipid environment.</p>", "<p id=\"P42\">While our bioinformatic analyses explore GRs beyond BmGr9, the depth of analysis is constrained by the paucity of functional information about most GRs. Mechanistic studies of GRs have proven challenging, with most attempts to study GRs in heterologous expression systems failing to observe channel activity (BmGr9 is an exception). While genetic evidence suggests that many GRs participate in heteromeric complexes, which GRs hetero-oligomerize and which GRs participate in ligand binding or serve primarily structural roles remain to be established. A second limitation of our bioinformatic analyses is that while AlphaFold2 predictions agree well with the experimentally determined structures of AbOrco and BmGr9, this does not guarantee that all predictions will be as accurate. However, the presence of shared, and potentially convergent, features in the ligand-binding pockets of evolutionarily divergent sugar receptors, and their contrast with receptors for other classes of chemicals, supports the utility of this approach for capturing structural features on a scale not readily achieved by experimental determination alone.</p>" ]	[]	[ "<p id=\"P1\">Author contributions</p>", "<p id=\"P2\">H.M.F., R.M.W., W.J.L., P.A.G. and R.G. designed experiments. H.M.F. performed molecular biology, protein expression and purification, cryo-EM sample preparation, cryo-EM data collection, model building and refinement, and structural analyses under the supervision of R.M.W. and R.G. R.M.W. supervised the collection of and analyzed the cryo-EM data. W.J.L. performed molecular biology and oocyte electrophysiology. H.M.F., S.W., D.L.T., P.A.G. and R.G. designed and performed bioinformatic and statistical analyses. H.M.F., S.W., R.M.W., W.J.L., P.A.G. and R.G. created the figures. H.M.F., S.W., P.A.G. and R.G. wrote the paper, with input from all authors.</p>", "<title>SUMMARY</title>", "<p id=\"P3\">Gustatory Receptors (GRs) are critical for insect chemosensation and are potential targets for controlling pests and disease vectors. However, GR structures have not been experimentally determined. We present structures of <italic toggle=\"yes\">Bombyx mori</italic> Gr9 (BmGr9), a fructose-gated cation channel, in agonist-free and fructose-bound states. BmGr9 forms a tetramer similar to distantly related insect Olfactory Receptors (ORs). Upon fructose binding, BmGr9’s ion channel gate opens through helix S7b movements. In contrast to ORs, BmGR9’s ligand-binding pocket, shaped by a kinked helix S4 and a shorter extracellular S3-S4 loop, is larger and solvent accessible in both agonist-free and fructose-bound states. Also unlike ORs, fructose binding by BmGr9 involves helix S5 and a binding pocket lined with aromatic and polar residues. Structure-based sequence alignments reveal distinct patterns of ligand-binding pocket residue conservation in GR subfamilies associated with distinct ligand classes. These data provide insight into the molecular basis of GR ligand specificity and function.</p>" ]	[ "<title>Supplementary Material</title>" ]	[ "<title>Acknowledgements</title>", "<p id=\"P67\">We thank Elizabeth J. May for help with the development of the HEK293-based protein expression system, José A. Velilla, Shamayeeta Ray, Gerardo E. Zavala and Samuel P. Berry for sharing technical expertise, and Leslie Griffith and members of the Garrity and Gaudet labs for discussions and comments on the manuscript. Funding was provided by National Institute of Deafness and Other Communication Disorders grant R21DC018497 (P.A.G. and R.G.), National Institute of General Medical Sciences grants R01GM120996 (R.G.) and R01GM096053 (D.L.T), National Institute of Allergy and Infectious Diseases R01AI157194 (P.A.G.), NSF Simons center at Harvard Simons postdoctoral award (S.W.), Charles A. King Trust Postdoctoral Research Fellowship, Bank of America, N.A., Co-Trustees (W.J.L.), and a Warren Alpert Foundation Distinguished Scholar Award (W.J.L.). We acknowledge the use of resources from the Harvard Cryo-EM Center for Structural Biology.</p>" ]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1.</label><caption><title>Cryo-EM structure of a tetrameric insect gustatory receptor, BmGR9</title><p id=\"P70\">(A) D-Fructose dose-response profile of twin-strep-tagged BmGR9 expressed in <italic toggle=\"yes\">Xenopus</italic> oocytes. The currents were measured at −80 mV (n = 11; data are shown as mean ± SEM), and the resulting EC<sub>50</sub> value is 22 mM.</p><p id=\"P71\">(B-C) Surface representation of the Coulomb potential map of agonist-free BmGr9 (2.85 Å resolution; contour level of 0.24, around the protein structure), viewed from the membrane plane (B) and extracellular side (C). Each subunit of the tetramer is colored differently.</p><p id=\"P72\">(D) Cartoon representation of two opposing subunits from the BmGr9 tetramer viewed from the membrane plane. Black horizontal lines indicate the membrane boundaries. The intracellular anchor domain is indicated and the helices of one subunit are labeled.</p><p id=\"P73\">(E) Cartoon representation of the BmGr9 tetramer viewed from the extracellular side. The location of the pore and the fructose-binding pocket are indicated and the helices of one subunit are labeled. See also ##SUPPL##0##Figures S1##–##SUPPL##0##S5##.</p></caption></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2.</label><caption><title>BmGr9 and MhOr5 have distinct structural features</title><p id=\"P74\">(A-B) Diagrams comparing the topology of BmGr9 (A) and MhOr5 (B). Several of the features distinct between BmGr9 and MhOr5—such as loop and helix lengths, and kinks in helices—are highlighted with a star.</p><p id=\"P75\">(C-D) Transmembrane helix packing arrangements of BmGr9 (C) and MhOr5 (D) at different cross-sections (top, middle, bottom) across the membrane plane, as indicated on the cartoon representation of one subunit on the left-hand side. For each cross-section, the position of each transmembrane helix segment is illustrated, along with the protein surface boundary as a grey line. Internal cavities are marked in white when accessible to the extracellular aqueous solvent, and in darker grey for solvent-occluded cavities. Stars mark the fructose-binding pocket of BmGr9 (C) and the eugenol-binding pocket of MhOr5 (D). Of note, the S5 helix forms part of the fructose-binding pocket walls in BmGr9, but it is not in direct contact with the eugenol-binding pocket in MhOr5.</p><p id=\"P76\">(E-F) Vertical slices through the ligand-binding pocket in the transmembrane domain of one subunit of BmGr9 (E) and MhOr5 (F). The approximate position of the ligand is marked by a star, and the approximate distance from the extracellular membrane boundary to the bottom of the pocket is indicated on the left.</p><p id=\"P77\">See also ##SUPPL##0##Figure S6##.</p></caption></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3.</label><caption><title>Lipid headgroups penetrate the BmGr9 pore through intersubunit fenestrations</title><p id=\"P78\">(A) Cryo-EM map of agonist-free BmGr9 including non-protein densities (contour level 0.254). Each protein subunit of the tetramer is colored in a different pastel color, densities corresponding to ordered lipid or detergent molecules are orange, except for those of the pore-penetrating lipids which are colored black. The cross-section illustrated in (B) is indicated by the black outline.</p><p id=\"P79\">(B) Transmembrane cross-section of BmGr9 (viewed from extracellular side) highlighting densities (black transparent surface) for lipid with headgroups penetrating into the pore. Modeled lipids are shown as sticks (carbon in black, oxygen in red, phosphorus in orange). Only the phosphate of the lipid headgroup is modeled as the rest is disordered and lacks density.</p><p id=\"P80\">(C) View from the membrane plane of pore-penetrating lipid and corresponding cryo-EM density, highlighting its bidentate shape.</p><p id=\"P81\">(D) View of pore-penetrating lipid from membrane plane, with sidechains within 4.2 Å of the lipid shown as sticks. The lipid headgroup contacts the S7b helices from two BmGr9 subunits (blue and yellow, respectively), whereas the lipid interactions with the yellow S5 helix are hydrophobic contacts with a lipid tail. One turn of the blue S7b helix is transparent so that T429 is visible. Two highly conserved polar residues are starred.</p><p id=\"P82\">(E) Schematic of the interactions between a pore-penetrating lipid and two BmGr9 subunits (blue and yellow, respectively). Atoms are colored as in (D). The diagram was made with LigPlot+<sup>##REF##21919503##41##</sup>.</p><p id=\"P83\">(F) Sequence logos of the helix S7b positions (grey box) of alignments of 1854 insect GR sequences, 176 ORCO sequences, and 3885 insect OR sequences, colored as follows: green, polar amino acids (G,S,T,Y,C,Q,N); blue, basic (K,R,H); red, acidic (D,E); and black, hydrophobic (A,V,L,I,P,W,F,M)). Residues interacting with the pore-penetrating lipids are marked with stars (polar residues) or arrowheads (aliphatic residues) colored according to panels (D) and (E). The pore-gating residues are marked by black arrowheads.</p><p id=\"P84\">See also ##SUPPL##0##Figure S7##.</p></caption></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4.</label><caption><title>Fructose binding induces pore opening in BmGr9 through concerted motions of a conserved network of residues</title><p id=\"P85\">(A) Cartoon representation of agonist-free BmGr9 with its quadrivial pore illustrated as a surface colored according to its diameter. Black lines make the membrane boundaries. The vertical axis for panel (B) is indicated on the right-hand side.</p><p id=\"P86\">(B) Diameter of the central ion conduction pathway (solid lines) and the lateral conduits (dashed lines) of agonist-free (orange) or fructose-bound (blue) BmGr9. The y axis shows the distance from the outer membrane boundary toward the intracellular space for the central pore, and the distance along the conduit for the lateral conduits.</p><p id=\"P87\">(C) Cartoon representation of two opposing S7b helices with the sidechains of pore-lining residues in sticks for agonist-free (left) and fructose-bound (right) BmGr9. The pore surface at the central vertical cross-section is marked by curved lines. F444 creates a hydrophobic seal in agonist-free BmGr9, whereas Q443 creates a hydrophilic ring more suitable for cation conduction in fructose-bound BmGr9 although the pore diameter is largely unchanged. The Cα-to-Cα distances between the two opposing hydrophobic gate residues I440 are indicated and marked by dashed black lines.</p><p id=\"P88\">(D) Superposition of agonist-free (orange) and fructose-bound (blue) BmGr9. The inset panels E-I are indicated.</p><p id=\"P89\">(E-F) Zoomed-in view of from the extracellular side of the agonist-free (E) and fructose-bound (F) BmGr9 central pore with conserved gating residues Q443 and F444 shown as sticks. The twisting motion of the gating residues and displacement of the C termini of the S7b helices upon fructose binding are indicated by arrows.</p><p id=\"P90\">(G) One S7b helix viewed from the center of the ion pore, from the superimposed structures of the agonist-free (orange) and fructose-bound (blue) BmGr9 tetramer. The pore-lining sidechains are shown as sticks and labeled. Black arrows mark the central axes of the top half of the helices, highlighting the 20° kink and displacement upon fructose binding.</p><p id=\"P91\">(H-I) Zoomed-in view of the interaction between helices S5 and S7b in the agonist-free (H) and fructose-bound (I) BmGr9 structures. P331 is marked by a purple Cα sphere. Mutations to alanine of the residues labeled in bold and marked by the other Cα spheres increase basal currents<sup>##REF##36209821##30##</sup>. Pore-gating Q443 and F444, and the conserved T330 residue facing the fructose-binding pocket are also shown as sticks for reference.</p><p id=\"P92\">(J) Sequence logos of the C-terminal half of S5 and of S7b for the alignment of Gr43a subfamily members (74 sequences). The BmGr9 sequence is indicated below. Residues forming the hydrophobic S5-S7b interface are marked by black dots, and locations of the alanine mutations that increase basal currents are marked by arrowheads. The conserved TPY motif in S5 and pore-gating residues in S7b are highlighted in grey.</p><p id=\"P93\">See also ##SUPPL##0##Figure S8##.</p></caption></fig>", "<fig position=\"float\" id=\"F5\"><label>Figure 5.</label><caption><title>BmGr9 ligand-binding pocket and its fructose-induced conformational changes</title><p id=\"P94\">(A) Cryo-EM density around the ligand-binding site for the agonist-free BmGr9 map contoured at 3.5σ. Nearby sidechains are shown as sticks and labeled.</p><p id=\"P95\">(B) Cryo-EM density around the ligand-binding site for the agonist-free BmGr9 map contoured at 4.5σ (cyan). The black star marks strong density not observed in the agonist-free map shown in panel A, as indicated by the presence of a 10σ density feature (magenta).</p><p id=\"P96\">(C) Sequence logos from the Gr43a subfamily alignment covering motifs participating in the ligand-binding pocket, with the corresponding secondary structure elements indicated above, and the BmGr9 sequence included below each logo. The 21 residues with surface accessible to the pocket are shaded grey, and black arrowheads mark highly conserved pocket-facing residues highlighted in panel D. Blue arrowheads mark positions assessed by alanine substitutions in BmGr9<sup>##REF##36209821##30##</sup>; light blue showed no change in fructose response, bright blue showed reduced response to fructose.</p><p id=\"P97\">(D-F) Cartoon representations of one BmGr9 subunit viewed from the extracellular side, with the black star marking the approximate fructose position.</p><p id=\"P98\">(D) Residues participating in the binding pocket are shown as sidechain sticks for highly conserved residues or marked by Cα spheres for the others (corresponding to black arrowheads and grey highlights in panel C, respectively).</p><p id=\"P99\">(E) Positions previously assessed by alanine substitutions in BmGr9<sup>##REF##36209821##30##</sup>. Mutations to the eight sidechains shown in sticks eliminated fructose-induced currents, while mutations at the 15 other positions marked by spheres had no effect on fructose-induced currents. Positions facing the ligand-binding pocket are dark orange, others are in light orange. The cartoon representation transparency reveals otherwise hidden spheres.</p><p id=\"P100\">(F) Superimposed individual subunits of agonist-free (orange) and fructose-bound (blue) BmGr9 with black arrows highlighting the movement of helices from agonist-free to fructose-bound.</p><p id=\"P101\">See also ##SUPPL##0##Figure S9##.</p></caption></fig>", "<fig position=\"float\" id=\"F6\"><label>Figure 6.</label><caption><title>ligand pocket comparison across GR family</title><p id=\"P102\">(A) Phylogenetic tree of 1895 insect GR sequences with subfamilies of interest highlighted in grey. The tree includes a clade of 41 OR sequences. Drosophila GRs are represented by black dots. (See also ##SUPPL##0##Figures S10##–##SUPPL##0##11##.)</p><p id=\"P103\">(B-E) Cartoon representations of single subunits of a representative subfamily member viewed from the extracellular side. The secondary structure cartoons are colored by ConSurf<sup>##REF##27166375##29##</sup> score based on the sequence alignment of the corresponding GR subfamily. The Cα carbons of residues forming part of the predicted ligand-binding pocket and crevice are represented as a sphere. Each of these residues is labeled with its residue number in the reference protein and a heatmap capturing the frequency of different amino acid types at that position in the aligned sequences of the corresponding GR subfamily. In each heatmap, from left to right are aliphatic amino acids (Ala, Cys, Leu, Met, Val; black), polar (Asn, Gln, Ser, Thr; orange), negatively charged (Asp, Glu; red), positively charged (Arg, Lys; blue), aromatic (His, Phe, Trp, Tyr; green), or shape-determining (Gly, Pro; pink) residues. The following subunits and corresponding protein (sub)families are illustrated: (B) Gr43a subfamily (74 sequences) on the agonist-free BmGr9 structure; (C) Gr5a subfamily (251 sequences) on the AlphaFold2 model of Gr5a (UniProt ID: Q9W497); (D) Gr63a subfamily (107 sequences) on the AlphaFold2 model of Gr63a (UniProt ID: Q9VZL7); and (E) the OR family (3885 sequences) on the agonist-free MhOr5 structure (PDB ID: 7LIC). (See also ##SUPPL##0##Figures S10##–##SUPPL##0##S13##.)</p></caption></fig>" ]	[ "<table-wrap position=\"float\" id=\"T1\"><label>Table 1:</label><caption><p id=\"P104\">Cryo-EM data collection, refinement, and validation statistics</p></caption><table frame=\"hsides\" rules=\"groups\"><colgroup span=\"1\"><col align=\"left\" valign=\"middle\" span=\"1\"/><col align=\"left\" valign=\"middle\" span=\"1\"/><col align=\"left\" valign=\"middle\" span=\"1\"/><col align=\"left\" valign=\"middle\" span=\"1\"/><col align=\"left\" valign=\"middle\" span=\"1\"/></colgroup><thead><tr><th align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><th colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\">Agonist-free BmGR9<break/>EMD-43129<break/>PDB 8VC1</th><th colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\">Fructose-bound BmGR9<break/>EMD-43130<break/>PDB 8VC2</th></tr></thead><tbody><tr><td colspan=\"5\" align=\"left\" valign=\"middle\" rowspan=\"1\">\n<bold>Data collection and processing</bold>\n</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Magnification</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\">60,240</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Voltage (kV)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\">300</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Electron exposure (e<sup>−</sup>/Å<sup>−2</sup>)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">74.492</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">80.144</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Defocus range (μm)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\">0.8, 2.2</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Pixel size (Å)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\">0.83</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Symmetry imposed</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">C4</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">C4</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Initial particle images (no.)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">1,955,549</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">1,141,024</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Final particle images (no.)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">1,011,451</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">233,351</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Map Resolution (Å)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">2.85</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">3.98</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> FSC threshold</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\">0.143</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Map resolution range (Å)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">2.51–9.3</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">3.4–10.9</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">\n<bold>Refinement</bold>\n</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Initial model used</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">ColabFold-generated</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Agonist-free BmGr9</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Model resolution (Å)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">3.00</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">4.20</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> FSC threshold</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.500</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.500</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Map-sharpening B-factor (Å<sup>2</sup>)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">150.9</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">181.3</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Model composition</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> Non-hydrogen atoms</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">13,128</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">11,796</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> Protein residues</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">1,564</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">1,516</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">B factors (Å<sup>2</sup>)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> Protein</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">58.19</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">43.02</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">RMSD</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> Bond lengths (Å)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.01</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.003</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> Bond angles (°)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.977</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.709</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">\n<bold>Validation</bold>\n</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">MolProbity score</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">1.20</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">1.16</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Clashscore</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">4.03</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">2.91</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Poor rotamers (%)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.30</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.31</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">Ramachandran plot</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"/></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> Favored (%)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">97.83</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">97.60</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> Allowed (%)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">2.07</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">2.40</td></tr><tr><td align=\"left\" valign=\"middle\" rowspan=\"1\" colspan=\"1\"> Disallowed (%)</td><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.00</td><td colspan=\"2\" align=\"center\" valign=\"middle\" rowspan=\"1\"/><td align=\"center\" valign=\"middle\" rowspan=\"1\" colspan=\"1\">0.00</td></tr></tbody></table></table-wrap>" ]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"SD1\" position=\"float\" content-type=\"local-data\"><label>Supplement 1</label></supplementary-material>" ]	[ "<fn-group><fn fn-type=\"COI-statement\" id=\"FN2\"><p id=\"P68\">Declaration of interests</p><p id=\"P69\">The authors declare no competing interests.</p></fn></fn-group>", "<table-wrap-foot><fn id=\"TFN1\"><p id=\"P105\">EMD, Electron Microscopy Database; PDB, Protein Data Bank, FSC, Fourier shell correlation; RMSD, root mean squared deviation.</p></fn></table-wrap-foot>" ]	[ "<graphic xlink:href=\"nihpp-2023.12.19.572336v1-f0001\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572336v1-f0002\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572336v1-f0003\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572336v1-f0004\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572336v1-f0005\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.19.572336v1-f0006\" position=\"float\"/>" ]	[ "<media xlink:href=\"media-1.pdf\" id=\"d64e1333\" position=\"anchor\"/>" ]	[{"label": ["5."], "collab": ["World Health, O."], "year": ["2014"], "article-title": ["A global brief on vector-borne diseases."], "source": ["World Health Organization."], "volume": ["2014"], "ext-link": ["https://iris.who.int/handle/10665/111008"]}, {"label": ["19."], "surname": ["Benton", "Himmel"], "given-names": ["R.", "N.J."], "year": ["2023"], "article-title": ["Structural screens identify candidate human homologs of insect chemoreceptors and cryptic Drosophila gustatory receptor-like proteins."], "source": ["Elife"], "volume": ["12"], "pub-id": ["10.7554/eLife.85537"]}, {"label": ["22."], "surname": ["Yan", "Jafari", "Pask", "Zhou", "Reinberg", "Desplan"], "given-names": ["H.", "S.", "G.", "X.", "D.", "C."], "year": ["2020"], "article-title": ["Evolution, developmental expression and function of odorant receptors in insects."], "source": ["J Exp Biol"], "volume": ["223"], "pub-id": ["10.1242/jeb.208215"]}]	{ "acronym": [], "definition": [] }	61	CC BY	no	2024-01-13 00:14:50	bioRxiv. 2023 Dec 19;:2023.12.19.572336	oa_package/52/26/PMC10769236.tar.gz
PMC10769249	38187708	[ "<title>INTRODUCTION:</title>", "<p id=\"P2\">For cancer immunotherapies such as ICT, T cell recognition of tumor antigens is critical for efficacy<sup>##REF##24457417##1##</sup>. In contrast to aberrantly expressed non-mutant antigens, tumor-specific neoantigens (NeoAgs) formed from somatic alterations in cancer cells are not subject to immune tolerance and are exclusively expressed in cancer cells, making them favorable cancer vaccine targets<sup>##REF##23258224##2##, ####REF##25838375##3##, ##REF##26258412##4####26258412##4##</sup>. Significant progress has been made in the field of NeoAg cancer vaccine development, showing promise in early-phase clinical trials<sup>##UREF##0##5##, ####REF##28678784##6##, ##REF##28678778##7##, ##REF##30568305##8##, ##REF##33064988##9##, ##REF##33473220##10##, ##REF##37165196##11####37165196##11##</sup>. Despite this progress, many fundamental questions regarding NeoAg vaccines remain unclear<sup>##UREF##0##5##,##REF##28678784##6##,##REF##33473220##10##,##REF##32728218##12##</sup>, including how to best combine therapeutic vaccines with other T cell-directed therapeutic modalities including ICT to promote optimal outcomes in cancer patients. A more refined understanding of how NeoAg vaccines impact the immune tumor microenvironment (TME) in comparison to other immunotherapies like anti-PD-1 and anti-CTLA-4 ICT can inform rational use of NeoAg vaccines and combinatorial immunotherapies.</p>", "<p id=\"P3\">To address this, we developed preclinical models to interrogate potential synergies between the mechanisms of action of NeoAg cancer vaccines and ICT. We previously used immunogenomic/mass spectrometry approaches to identify NeoAgs and subsequently demonstrated that therapeutic NeoAg cancer vaccines could provoke tumor rejection in methylcholanthrene (MCA)-induced sarcoma models<sup>##REF##26258412##4##,##REF##25428507##13##</sup>. Others have used similar approaches to identify immunogenic NeoAgs<sup>##REF##26258412##4##,##REF##28678784##6##,##REF##28678778##7##,##REF##23644516##14##, ####REF##22237626##15##, ##REF##25428506##16####25428506##16##</sup>. We further showed that NeoAgs are major targets of T cells reactivated by ICT and that anti-PD-1 and anti-CTLA-4 administered either alone or in combination induces changes in both CD4 and CD8 T cells within the TME<sup>##REF##25428507##13##,##REF##28916749##17##, ####REF##30343900##18##, ##REF##31645760##19##, ##UREF##1##20####1##20##</sup>, consistent with findings from others<sup>##REF##28803728##21##,##REF##31636208##22##</sup>. While both conventional CD4 and CD8 T cells drive immunotherapeutic responses to cancer, cytotoxic CD8 T cells are typically the most potent direct inducers of tumor cell death. In both cancer patients and preclinical models, intratumoral CD8 T cells that express activation markers including inhibitory receptors such as PD-1, LAG-3, and TIM-3 often exist in a terminally differentiated state and may display a range of functional capabilities from short-lived CD8 T effector cells with potent cytotoxicity and cytokine production to dysfunctional or exhausted CD8 T cells that exist in a state of limited or restrained functional capabilities<sup>##REF##30778252##23##</sup>. These dysfunctional or exhausted CD8 T cells also exist on a spectrum of intermediate to terminally dysfunctional/exhausted with progression to terminally dysfunctional/exhausted characterized by high, sustained expression of inhibitory receptors, reduced function, and unique transcriptional and epigenetic profiles, differentiating them from memory T cells and T cells displaying stem-like properties (often referred to as progenitor/precursor exhausted CD8 T cells). These distinct states are driven by key transcription factors, including TCF-1, which promotes stemness or memory-like attributes<sup>##REF##31606264##24##</sup>, and TOX, which plays a crucial role in establishing terminal dysfunction/exhaustion<sup>##REF##31207603##25##, ####REF##31207604##26##, ##REF##34253904##27####34253904##27##</sup>. Although TOX is induced in an NFAT-dependent manner upon T cell activation, chronic antigen exposure and/or signals within the TME promote maintenance of NFAT-independent TOX expression and establishment of a fixed epigenetic landscape in terminal dysfunctional/exhausted CD8 T cells<sup>##REF##25680272##28##</sup>. The increased presence of PD-1<sup>hi</sup> TOX<sup>+</sup> TCF-1<sup>−</sup> CD8 T cells in tumor biopsies correlates with a poorer prognosis in patients treated with ICT and these cells likely do not drastically gain effector function following PD-1/PD-L1 blockade. Instead, stem-like PD-1<sup>+</sup> Tim-3<sup>−</sup> TCF-1<sup>+</sup> CD8 T cells within tumors and lymph nodes expand and differentiate into PD-1<sup>+</sup> Tim-3<sup>+</sup> CD8 T effector-like cells in response to anti-PD-1/PD-L1 ICT<sup>##REF##31827286##29##,##REF##31359002##30##</sup>.</p>", "<p id=\"P4\">While T cells are the major target of NeoAg vaccines and ICT, myeloid cells are a critical component of the TME<sup>##REF##35697799##31##</sup>. Macrophages are amongst the most abundant myeloid cell population within tumors and may comprise both embryonically-derived tissue-resident macrophages and monocyte-derived macrophages<sup>##REF##22437938##32##, ####REF##33637019##33##, ##REF##30718830##34##, ##REF##36792751##35####36792751##35##</sup>. Although macrophages can exhibit anti-tumor effects, macrophages often promote tumor growth. We previously observed major complexity in the ICT-induced changes occurring in the intratumoral macrophage compartment<sup>##REF##30343900##18##, ####REF##31645760##19##, ##UREF##1##20####1##20##</sup>. These included remodeling from M2-like CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages in progressively growing tumors to M1-like iNOS<sup>+</sup> macrophages in tumors that go on to reject in response to ICT. Further, blockade of TREM2 expressed on macrophages using Fc-mutated anti-TREM2 monoclonal antibody (mAb) induced a decline in CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages and induced iNOS<sup>+</sup> macrophages and subsets of macrophages expressing immunostimulatory molecules, with anti-TREM2 dampening tumor growth and augmenting anti-PD-1 efficacy<sup>##REF##32783918##36##</sup>. While tumor immune cell compositions clearly play a major role in response to immunotherapy<sup>##REF##33637019##33##,##REF##30930117##37##</sup>, the heterogeneity and dynamics of immune infiltrates in response to immunotherapies such as NeoAg cancer vaccines is not thoroughly characterized. Further, although much progress has been made towards defining the mechanisms behind ICT efficacy, our understanding is still incomplete and direct comparisons between cancer vaccines and different ICTs used alone or in combination are largely lacking.</p>", "<p id=\"P5\">Here, we systematically compared different immunotherapies that lead to tumor rejection, including NeoAg cancer vaccines, anti-PD-1, anti-CTLA-4, and anti-PD-1 + anti-CTLA-4 ICT using mouse melanoma models expressing defined NeoAgs. NeoAg vaccines induced robust expansion of polyfunctional NeoAg-specific CD8 T cells, including proliferating and stem-like CD8 T cells. Anti-CTLA-4 and/or anti-PD-1 ICT increased the frequency and effector function of intratumoral NeoAg-specific CD8 T cells, with anti-CTLA-4 containing treatments also dramatically altering the CD4 T cell compartment. Both NeoAg vaccines and ICT resulted in an expansion of M1-like iNOS<sup>+</sup> macrophages. Whereas ICT reduced the frequency of intratumoral CX3CR1<sup>+</sup> CD206<sup>+</sup> M2-like macrophages, NeoAg vaccine treated mice instead displayed a higher frequency of CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages. Thus, effective NeoAg cancer vaccines reshape the TME, leading to overlapping as well as distinct alterations when compared to different ICT treatments. To investigate whether the unique impacts of NeoAg vaccines and ICT combine for enhanced tumor control, we tested the efficacy of NeoAg vaccination in combination with either anti-CTLA-4 or anti-PD-1 and found that the window of therapeutic efficacy was extended by combination treatments, further supporting the rationale of combining NeoAg vaccines with ICT.</p>" ]	[ "<title>STAR Methods</title>", "<p id=\"P39\">\n##SUPPL##1##Key resources Table S1##\n</p>", "<title>Mice</title>", "<p id=\"P40\">All mice used were on a C57BL/6 background. WTC57BL/6J mice were purchased from Jackson Labs. All <italic toggle=\"yes\">in vivo</italic> experiments used 8- to 12-week-old male or female mice (to match the sex and strain of the tumors). All mice were housed in a specific pathogen-free animal facility. All animal studies were performed in accordance with, and with the approval of the Institutional Animal Care and Use Committee (IACUC) of The University of Texas MD Anderson Cancer Center (Houston, TX).</p>", "<title>Plasmids</title>", "<p id=\"P41\">Gene blocks for mAlg8, mItgb1, or mLama4 were purchased from Integrated DNA Technologies. Minigene constructs were cloned into the BglII site of pMSCV-IRES GFP (mAlg8 and mItgb1) or pMSCV (mLama4 and mItgb1) using the Gibson Assembly method (New England Biolabs). To generate neoantigen-expressing Y1.7 melanoma cell lines, constructs were transiently transfected into Phoenix Eco cells using Fugene (Promega). After 48 hours, viral supernatants were filtered and subsequently used for transfection of Y1.7 melanoma cell line. Y1.7 mLama4 <sup>MHC-I</sup>.mItgb1<sup>MHC-II</sup> (Y1.7LI) and Y1.7 mAlg8 <sup>MHC-I</sup>.mItgb1<sup>MHC-II</sup> (Y1.7AI) were sorted based on GFP positivity and clones were verified for neoantigen expression.</p>", "<title>Tumor cell lines</title>", "<p id=\"P42\">The <italic toggle=\"yes\">Braf</italic><sup><italic toggle=\"yes\">V600E</italic></sup>\n<italic toggle=\"yes\">Cdkn2a</italic><sup>−/−</sup>\n<italic toggle=\"yes\">Pten</italic><sup>−/−</sup> YUMM1.7 parental line was originally generated in a male GEMM on the C57BL/6 background as described<sup>##REF##27287723##38##</sup>. Parental YUMM1.7 was purchased from ATCC (CRL-3362) and was modified to generate NeoAg-expressing Y1.7 lines. The MC38 line was obtained from B. Schreiber (Washington University in St. Louis School of Medicine). All tumor cell lines were found to be free of common mouse pathogens and Mycoplasma as assessed by IDEXX IMPACT I mouse pathogen testing [PCR evaluation for: Corynebacterium bovis, Corynebacterium sp. (HAC2), Ectromelia, EDIM, Hantaan, K virus, LCMV, LDEV, MAV1, MAV2, mCMV, MHV, MNV, MPV, MTV, MVM, Mycoplasma pulmonis, Mycoplasma sp., Polyoma, PVM, REO3, Sendai, TMEV]. Tumor cell lines from the same cryopreserved stocks that were used in this study tested negative for Mycoplasma and were authenticated and found to be free of non-mouse cells as assessed by mouse cell STR profiling (IDEXX CellCheck mouse 19 plus Mycoplasma spp. testing).</p>", "<title>Tumor transplantation</title>", "<p id=\"P43\">The <italic toggle=\"yes\">Braf</italic><sup><italic toggle=\"yes\">V600E</italic></sup>\n<italic toggle=\"yes\">Cdkn2a</italic><sup>−/−</sup>\n<italic toggle=\"yes\">Pten</italic><sup>−/−</sup> YUMM1.7 parental melanoma line, Y1.7LI or Y1.7AI melanoma line, and the MC38 colorectal cancer line cells were propagated in R-10 plus BME media [RPMI media (HyClone) supplemented with 1% l-glutamine, 1% penicillin–streptomycin, 1% sodium pyruvate, 0.5% sodium bicarbonate, 0.1% 2-mercaptoethanol, and 10% heat-inactivated fetal calf serum (FCS) (HyClone) upon thawing, tumor lines were passaged 3 to 6 times before experimental use. Prior to injection, cells were washed extensively, resuspended at a concentration of 0.5 × 10<sup>6</sup> cells (for YUMM1.7, Y1.7LI, and Y1.7AI) or 1.5 × 10<sup>6</sup> cells (for MC38) in 150 μL of endotoxin-free PBS and 150 μL was injected subcutaneously into the flanks of recipient mice. Tumor cells were >90% viable at the time of injection as assessed by Trypan blue exclusion. Tumor growth was quantified by caliper measurements and expressed as the average of two perpendicular diameters. Lack of survival was defined as mouse death or mean tumor diameter size of 15 mm.</p>", "<title>Tumor rechallenge</title>", "<p id=\"P44\">For tumor rechallenge, mice that rejected primary tumors after treatment with anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, or NeoAg vaccines were then rechallenged with same number of cells used in primary challenge with either the same tumor line used in the primary tumor challenge or a different tumor line as indicated at least 60 days after complete rejection of the primary tumor.</p>", "<title><italic toggle=\"yes\">In vivo</italic> antibody treatments</title>", "<p id=\"P45\">For ICT treatment, YUMM1.7 parental, Y1.7LI, or Y1.7AI tumor-bearing mice were treated intraperitoneally with 200 μg of anti-CTLA-4 and/or anti-PD-1 on d. 3, 6, 9, 12, 18, and 22 or d. 7, 10, 13, 16, 22, and 28; or d. 12, 15, 18, 21, 27 and 33 post-tumor transplant. For controls, mice were injected with 200 μg of IgG2a isotype control antibodies. MC38 tumor-bearing mice were treated intraperitoneally with 200 μg of anti-CTLA-4 and/or anti-PD-1 on d. 12, 15, 18, and 22 post-transplant. For antibody depletion studies, 250 μg of control mAb, anti-CD4, or anti-CD8a was injected intraperitoneally into mice at d. −1 and every 7 days thereafter until day 20. CD4 and CD8 depletion was verified by flow cytometry analysis of surface-stained peripheral blood monocytes (PBMC) and intratumoral immune cells. For <italic toggle=\"yes\">in vivo</italic> experiments, “<italic toggle=\"yes\">In vivo</italic> Platinum”-grade antibodies that were verified to be free of mouse pathogens (IDEXX IMPACT I mouse pathogen testing) were purchased from Leinco Technologies: anti-PD-1 (rat IgG2a clone RMP1–14), anti-CTLA-4 (murine IgG2b clone 9D9), anti-CD4 (rat IgG2b clone GK1.5), anti-CD8a (rat IgG2b clone YTS169.4), and isotype controls (rat IgG2a clone 1–1, mouse lgG2a clone OKT3, or rat IgG2b clone 1–2).</p>", "<title>Peptides</title>", "<p id=\"P46\">Mutant Lama4 8-mer (<underline>V</underline>GFNFRTL), mutant Lama4SLP (QKISFFDGFE<underline>V</underline>GFNFRTLQPNGLLFYYT), mutant AdpgkSLP (HLELASMTN<underline>M</underline>ELMSSIVHQ), mutant Rpl18SLP (KAGGKILTFD<underline>R</underline>LALESPK), mutant Dpagt1 SLP (EAGQSLVISASIIVFNL<underline>L</underline>ELEGDYR), mutant Alg8 8-mer (ITY<underline>T</underline>WTRL), OVA-I<sub>2577–264</sub> (SIINFEKL), mutant Itgb1 SLP (DDCWFYFTYSVNGY<underline>N</underline>EAIVHVVETPDCP), and OVA-II<sub>323–339</sub> (ISQAVHAAHAEINEAGR) peptides were custom ordered from Peptide 2.0. All peptides were HPLC purified to >95% purity.</p>", "<title>Vaccination</title>", "<p id=\"P47\">Y1.7LI or Y1.7AI tumor bearing male mice were vaccinated subcutaneously with 10 μg mLama4 or mAlg8 synthetic long peptide (SLP) in combination with 50 μg of VacciGrade<sup>™</sup> high molecular weight Polyinosinic-polycytidylic acid (pI:C) (InvivoGen) in a total volume of 150 μL diluted in endotoxin-free PBS on d. 3, 9, and 15 or d. 7, 13, and 19 or on d. 12, 18, and 24 post tumor transplant. MC38 tumor bearing female mice were vaccinated subcutaneously with 20 μg of mAdpgk SLP plus 20 μg of mRpl18 SLP plus 20 μg of mDpagt1 plus 50 μg pI:C adjuvant or control vaccine composed of 40 μg of irrelevant HPV SLP + 50 μg of pI:C on d. 12 and 19 post-tumor transplant. For SLP, peptide sequence used for mLama4; QKISFFDGFE<underline>VGFNFRTL</underline>QPNGLLFYYT (epitope underlined), for mAlg8; AVG<underline>ITYTWTRL</underline>YASVLTGSLV (epitope underlined), for mAdpgk; HLELASMTNMELMSSIVHQ, for mRpl18; KAGGKILTFD<bold><italic toggle=\"yes\">R</italic></bold>LALESPK and for mDpagt1; EAGQSLVISASIIVFNLLELEGDYR. mLama4 SLP served as a relevant SLP for the Y1.7LI line and an irrelevant SLP for the Y1.7AI line. mAlg8 served as a relevant SLP for the Y1.7AI line and an irrelevant SLP for the Y1.7LI tumor.</p>", "<title>Tetramers</title>", "<p id=\"P48\">OVA-I (SIINFEKL)-H-2K<sup>b</sup>(irrelevant control tetramer), mutant Alg8-H-2K<sup>b</sup>, and mutant Lama4-H-2K<sup>b</sup> tetramers conjugated to PE or APC fluorophores, were obtained from the Baylor College of Medicine MHC Tetramer Production Facility.</p>", "<title>Tumor and spleen harvest</title>", "<p id=\"P49\">Established tumors were excised from mice, minced, and treated with 1 mg/mL type IA collagenase (Sigma-Aldrich) in HBSS (Hyclone) for 45 minutes at 37°C. Cells were washed thrice. Red blood cells were lysed using ACK lysis buffer (Gibco). To remove aggregates and clumps, cells were passed through a 40-μm strainer. Spleens were harvested, crushed, and vigorously resuspended to make single-cell suspensions. To remove aggregates and clumps, cells were passed through a 70-μm strainer and subsequently through a 40-μm strainer.</p>", "<title>TIL peptide restimulation</title>", "<p id=\"P50\">For peptide and PMA/ionomycin T-cell stimulation, cells from tumors, isolated as described above (see <xref rid=\"S26\" ref-type=\"sec\">tumor and spleen harvest</xref> section), stained, and CD4 and CD8 T cells were sorted. For sorting CD4 and CD8 T cells, tumor cells were stained for 5 min at room temperature with 500 ng of Fc block (anti-CD16/32) and then stained with antibodies to CD45, CD3ε, CD4 or CD8α and Zombie NIR Viability dye in 100 μl of staining buffer. Cells were incubated for 30 minutes at 4°C. Live CD45<sup>+</sup>Cd3ε<sup>+</sup>CD4<sup>+</sup> and live CD45<sup>+</sup>Cd3ε<sup>+</sup>CD8α<sup>+</sup> were then sorted on a BD FACSAria II (BD Biosciences). Splenocytes harvested from naive mice and 100,000 splenocytes were then pulsed with 1 μM of various 8- or 9- or 17- or 28-mer peptides or simulated with 10 ng/mL of PMA (MilliporeSigma) and 1 μg/mL of ionomycin (Fisher) and 100,000 CD4 or CD8 TIL were subsequently added and incubated at 37 °C. Naive splenocytes added with or without CD4 or CD8 TIL, was included as control. After 1 h, BD GolgiPlug (BD Bioscience) was added in, and cells were incubated for an additional 5 h at 37 °C.</p>", "<title>Tetramer staining</title>", "<p id=\"P51\">For tetramer staining, cells were stained for 5 min at room temperature with 500 ng of Fc block (anti-CD16/32). H-2K<sup>b</sup> tetramers conjugated to PE (1:50) or APC (1:100) for mutated Alg8, mutated Lama4, or SIINFEKL were added to cells and incubated for 20 min at 37°C. Tetramer-stained cells were further stained with surface antibody for anti-CD45, anti-Thy1.2, anti-CD8α, anti-CD4, anti-PD-1, anti-TIM-3, and anti-LAG-3 antibody for 20 min at 4 °C.</p>", "<title>Flow cytometry</title>", "<p id=\"P52\">For flow cytometry, cells were stained for 5 minutes at room temperature with rat anti-mouse CD16/32 (mouse BD Fc Block; clone 2.4G2, BD Biosciences) at 1 μg/million cells and then surface stained with flow antibodies for 20 minutes at 4°C. Surface antibodies were diluted in FACS staining buffer (PBS with 2% FCS, 2 mmol/L EDTA, and 0.05% NaN3; Sigma). Anti-mouse CD45-BV605, CD90.2/Thy1.2-PE-Cy7, anti-mouse CD8α-BV786, anti-mouse CD4-BV711, anti-mouse CD19-BV650, anti-mouse CD20-BV421, anti-mouse CD45R/B220-BBUV395, anti-mouse Nkp46/CD335-FITC, anti-mouse γδ TCR-PE-Cy7, anti-mouse PD-1-BV421, anti-mouse TIM-3, anti-mouse LAG-3-PerCP-Cy5.5, anti-mouse CD3ε-APC, anti-mouse CD64-BV421, anti-mouse Ly6G-Alexa Fluor 700, anti-mouse CX3CR1-FITC, anti-mouse I-A/I-E-BV650, anti-mouse CD103-BV421, anti-mouse CD24-BV711, anti-mouse CD11c-BV786, anti-mouse CD11b-APC, anti-mouse F4/80-BUV395, anti-mouse CD64-APC, CD117-FITC, anti-mouse CD11b- PerCP-Cy5.5 , anti-mouse PDCA-1/BST-2 BV650, anti-mouse CD172a APC, anti-mouse PDL1-PE, anti-mouse FcεRI-PE-Cy7 were used for surface staining at the indicated dilutions. Zombie NIR Viability dye was added at 1:500 during surface staining.</p>", "<p id=\"P53\">For intracellular staining, surface-stained cells were fixed and permeabilized with Fixation/Permeabilization Solution Kit (BD Bioscience). Fixed and permeabilized cells were then stained with anti-mouse Mrc1 (CD206)-PE-Cy7 and anti-mouse iNOS/NOS2-PE for 30 minutes at 4°C.</p>", "<p id=\"P54\">For FOXP3 staining, surface-stained cells were fixed and permeabilized using the eBioscience FOXP3/Transcription Factor Staining Buffer Set. Fixed and permeabilized cells were then stained with anti-mouse FOXP3-FITC for 30 minutes at 4°C.</p>", "<p id=\"P55\">For intracellular cytokine staining of lymphocytes, tumor cells were isolated and CD4 and CD8 T cells were sorted and added to peptide pulsed or PMA+Ionomycin stimulated splenocytes and incubated at 37°C for 6 hours with GolgiStop (BD Bioscience). Cells were then washed and stained for 5 minutes at room temperature with Fc block at 1 μg/million cells and then surface stained for 30 minutes at 4°C, and then fixed and permeabilized with BD Fixation and Permeabilization Kit. Fixed and permeabilized cells were then stained with anti-mouse IFNγ-APC, anti-mouse TNF-PE-Cy7 and anti-mouse Granzyme B-PE for 30 minutes at 4°C. All flow cytometry was performed on an BD Fortessa X-20, BD LSR, BD Fortessa, and analyzed using FlowJo software. Gating strategy used is depicted in ##SUPPL##0##Figure S13##.</p>", "<title>scRNAseq</title>", "<title>Antibody hashing</title>", "<p id=\"P56\">For analysis of NeoAg-specific CD8 T cells, cell and nuclei labeling were performed according to an adapted BioLegend cell hashing protocol (TotalSeq<sup>™</sup>-C Antibodies and Cell Hashing with 10x Single Cell 5' Reagent Kit v1.1 Protocol, BioLegend). Briefly, single cell suspensions of harvested tumors from treated mice were resuspended in BioLegend Cell Staining Buffer containing Fc receptor block and stained with mLama4 PE and APC labelled tetramers for 20 min at 37°C. Tetramer-stained cells from control mAb, control VAX, and neo VAX treatment conditions were immediately surface stained by adding anti-CD90.2/Thy1.2-PE-Cy7 and anti-CD8a-BV786 antibodies and incubating for 20 min at 4°C. Tetramer-stained samples from anti-CTLA-4, anti-PD-1, and anti-CTLA-4 plus anti-PD-1 treated groups were incubated with mixture of surface stain (anti-CD90.2/Thy1.2-PE-Cy7 and anti-CD8a-BV786 antibodies) and barcoded antibodies with unique hashtags for each treatment condition [anti-CTLA-4: Hashtag 1 Total Seq<sup>™</sup>-C0301 anti-mouse Hashtag 1 Antibody; anti-PD-1: Hashtag 2 (Total Seq<sup>™</sup>-C0302 anti-mouse Hashtag 2 Antibody); anti-CTLA-4 + anti-PD-1 combination: Hashtag 3 (Total Seq<sup>™</sup>-C0303 anti-mouse Hashtag 3 Antibody)]. Hashtag antibodies were used at a concentration of 1 μg per 2 million cells. Staining with surface antibodies and hashtag antibodies was done for 30 min at 4°C. Cells were then washed 3X with BioLegend Cell Staining Buffer. Sorted mLama4 tetramer-specific CD8 T cells with unique hashtags (anti-CTLA-4, anti-PD-1, and anti-CTLA-4 + anti-PD-1 samples) were pooled for single-cell library generation and CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) through multiplexing. Separate libraries were generated for control mAb, control VAX, and neo VAX samples and, thus, these were not multiplexed.</p>", "<title>scRNAseq library generation</title>", "<p id=\"P57\">Droplet-based 5 end massively parallel scRNAseq was performed by encapsulating sorted live CD45<sup>+</sup> tumor-infiltrating cells into droplets and libraries were prepared using Chromium Next GEM Single-cell 5 Reagent Kit v2 (10x Genomics) according to manufacturer's protocol. The generated scRNAseq libraries were sequenced using an Illumina NovaSeq6000 S2 flow cell.</p>", "<p id=\"P58\">scRNAseq alignment, barcode assignment, and unique molecular identifier counting The Cell Ranger Single-Cell Software Suite available at <ext-link xlink:href=\"https://support.10xgenomics.com/single-cell-gene-expression/software/overview/welcome\" ext-link-type=\"uri\">https://support.10xgenomics.com/single-cell-gene-expression/software/overview/welcome</ext-link> was used to perform sample demultiplexing, barcode processing, and single-cell 5 counting. Cellranger mkfastq was used to demultiplex raw base call files from the NovaSeq6000 sequencer, into sample-specific fastq files. Files were demultiplexed with 81.9% to 97.1% perfect barcode match, and 90%+ q30 reads. Afterward, fastq files for each sample were processed with Cellranger count, which was used to align samples to mm10 genome, filtered, and quantified. For each sample, the recovered cells’ parameter was specified as 10,000 cells that we expected to recover for each individual library.</p>", "<title>Preprocessing analysis with Seurat package</title>", "<p id=\"P59\">The Seurat pipeline was applied to each dataset following tutorial specifications from <ext-link xlink:href=\"https://satijalab.org/seurat/articles/archive\" ext-link-type=\"uri\">https://satijalab.org/seurat/articles/archive</ext-link>; version 3.2 and <ext-link xlink:href=\"https://hbctraining.github.io/scRNA-seq_online/\" ext-link-type=\"uri\">https://hbctraining.github.io/scRNA-seq_online/</ext-link>. Data from all groups were merged into a single Seurat object, and integration was performed using the reciprocal principal component analysis (PCA) workflow to identify integration anchors. After integration, genes that were expressed in fewer than 3 cells and cells that contained fewer than 500 transcripts (unique molecular identifiers; UMI) were excluded. Cells with more than 10%) of mitochondrial transcripts were also excluded from analysis. The cutoffs used were set based on the characteristics of the cell population in each dataset. Data were normalized using LogNormalize method (counts for each cell divided by the total counts for that cell, multiplied by the scale factor of 10<sup>4</sup> and natural-log transformed using log1p). PCA was performed on about 4,000 genes with PCA function. A uniform manifold approximation and projection (UMAP) dimensional reduction was performed on the scaled matrix (with most variable genes only) using the first 30 PCA components to obtain a two-dimensional representation of the cell states. For clustering, we used the function FindClusters that implements SNN (shared nearest neighbor) modularity optimization–based clustering algorithm on 30 PCA components, leading to 33 clusters.</p>", "<p id=\"P60\">Identification of cluster-specific genes and marker-based classification To identify marker genes, the FindAllMarkers function was used with likelihood-ratio test for single-cell gene expression. To characterize clusters, we used ImmGen database. For heatmap representation, mean expression of markers inside each cluster was used. To compare gene expression for the clusters inside cohorts (e.g., T cells, macrophages) we used FindMarkers function to calculate average log2 fold change and identify differentially expressed genes between each pair of experimental conditions using a Wilcoxon rank-sum test for calculating P values and Bonferroni correction for Padj values.</p>", "<title>T cell population analysis</title>", "<p id=\"P61\">To gain more insights into different immunotherapies-induced T cells remodeling in the TME, we subclustered activated T cells (excluding quiescent T cell clusters 10 and 12). Identification of most variable genes, PCA, UMAP, clustering, and marker selection analysis were performed as described above.</p>", "<title>Gene set enrichment analysis (GSEA)</title>", "<p id=\"P62\">To identify if MSigDB hallmark gene sets are up-regulated or down-regulated between clusters and treatments, we performed gene set enrichment analysis. Fold-changes of gene expression between comparisons were calculated using Seurat R package v.4.3.0.1, and normalized enrichment scores as well as p-values of given gene sets were then estimated using the gage R package v.2.46.1.</p>", "<title>Pseudo time trajectory analysis</title>", "<p id=\"P63\">To determine the potential lineage differentiation within CD4 T cell subpopulations, we used the Monocle3 R package to construct CD4 differentiation trajectories after specifying the corresponding cells as root nodes. Subsequently, graph test was used to find the pseudo time trajectory difference genes, and the obtained genes were used to plot the heat map.</p>", "<title>Statistical analysis</title>", "<p id=\"P64\">Samples were compared using an unpaired, two-tailed Student t test, two-way ANOVA, or log-rank (Mantel–Cox) test unless specified otherwise.</p>" ]	[ "<title>RESULTS:</title>", "<title>NeoAg vaccines and ICT induce T cell-dependent long-term tumor protection</title>", "<p id=\"P6\">For this study, we modified the <italic toggle=\"yes\">Braf</italic><sup><italic toggle=\"yes\">V600E</italic></sup>\n<italic toggle=\"yes\">Pten<sup>−/−</sup> Cdkn2a<sup>−/−</sup></italic> YUMM1.7 mouse melanoma line to express different combinations of MHC-I and MHC-II NeoAgs<sup>##REF##27287723##38##</sup>. While GEMMs recapitulate many features of human cancers, GEMM-derived tumors generally nonimmunogenic and lack NeoAgs; however, they can be engineered to express NeoAgs to study tumor-immune interactions<sup>##REF##31645760##19##,##REF##21251614##39##, ####REF##22318517##40##, ##REF##25970248##41##, ##REF##34852236##42##, ##REF##34534464##43####34534464##43##</sup>. To generate a YUMM1.7 cell line expressing known tumor antigens, we engineered it to express minigenes encoding the G1254V mutation in Laminin subunit alpha 4 (mLama4<sup>MHC-I</sup>), the A506T mutation in Alpha-1,3-glucosyltransferase (mAlg8<sup>MHC-I</sup>), and the N710Y mutation in Integrin beta 1 (mItgb1<sup>MHC-II</sup>) NeoAgs in various combinations (##SUPPL##0##Figure S1A##). We generated YUMM1.7 lines expressing minigenes for mLama4<sup>MHC-I</sup> + mItgb1<sup>MHC-II</sup> (Y1.7LI) or mAlg8<sup>MHC-I</sup> + mItgb1<sup>MHC-II</sup> (Y1.7AI). Consistent with prior observations<sup>##REF##27287723##38##,##REF##28630054##44##</sup>, the parental YUMM1.7 melanoma line was insensitive to ICT, even anti-PD-1 and anti-CTLA-4 combination ICT (##SUPPL##0##Figure S1B##). In contrast, enforced expression of mLama4<sup>MHC-I</sup> or mAlg8<sup>MHC-I</sup> NeoAg along with mItgb1<sup>MHCMHC-II</sup> NeoAg rendered YUMM1.7 melanoma lines (Y1.7LI and Y1.7AI) sensitive to anti-CTLA-4 ICT (##FIG##0##Figure 1A##).</p>", "<p id=\"P7\">We next asked whether therapeutic cancer vaccines composed of 10 μg of the SLP containing the minimal MHC-I NeoAg epitope and 50 μg of the adjuvant poly:IC (pI:C) could induce regression of the Y1.7LI and Y1.7AI NeoAg-expressing lines. Tumor bearing mice treated with pI:C alone displayed outgrowth of Y1.7LI or Y1.7AI melanoma, whereas vaccines composed of relevant NeoAg SLP + pI:C (neo VAX) induced complete rejection or delayed outgrowth of both Y1.7 NeoAg expressing variants (##FIG##0##Figure 1B##). Here the NeoAg vaccine-induced tumor rejection was dependent upon specific NeoAg expression, as vaccinating the Y1.7LI (mLama4-expressing) tumor bearing mice with the mAlg8 SLP + pI:C was not able to lead to tumor rejection and vice versa with the Y1.7AI (mAlg8-expressing) tumors (##FIG##0##Figure 1B##). Mice that rejected Y1.7AI or Y1.7LI tumors upon anti-CTLA-4 or neo VAX were rechallenged with the same tumors at least 60 days after rejection of primary tumors in the absence of any additional treatment. Upon secondary challenge, no detectable tumor was observed indicating long-term protection against rechallenge with the same tumor line (##SUPPL##0##Figure S1C##). In contrast, both Y1.7-NeoAg expressing lines grew out when injected in control naïve WT mice in the absence of treatment, indicating cell line preparations used in rechallenge experiments were capable of tumor formation. Additionally, when mice that previously rejected Y1.7LI tumors in response to anti-CTLA-4 or neo VAX therapy were rechallenged with the YUMM1.7 parental line, progressive tumor growth was observed (##SUPPL##0##Figure S1D##), indicating that long-term immunity was likely tumor NeoAg-specific.</p>", "<p id=\"P8\">We next used peptide-MHC (pMHC) tetramers to detect intratumoral CD8 T cells recognizing the mLama4 or mAlg8 NeoAg presented on H-2K<sup>b</sup>. Tumors from anti-CTLA-4 treated mice contained greater frequencies of mAlg8- or mLama4-specific CD8 T cells compared to the frequency of these cells in tumors from mice receiving control mAb (##FIG##0##Figures 1C## and ##SUPPL##0##S1E##). Whereas pI:C alone had little effect on the NeoAg-specific CD8 T cell frequency, neo VAX induced an over 5-fold increase in the frequency of NeoAg-specific CD8 T cells (##FIG##0##Figures 1C## and ##SUPPL##0##S1E##). This was particularly notable with the Y1.7LI tumor treated with NeoVAX, where over 14% of CD8 T cells were specific for mLama4. Neo VAX significantly increased the frequency of NeoAg-specific CD8 T cells co-expressing the inhibitory receptors PD-1 and TIM-3 (##SUPPL##0##Figure S1F##). Although PD-1 and TIM-3 are associated with dysfunction/exhaustion, their co-expression alone does not indicate reduced function and may be indicative of antigen stimulation and Tcell activation state<sup>##REF##24391639##45##,##REF##25257362##46##</sup>.</p>", "<p id=\"P9\">To expand on these observations, we focused on the Y1.7LI line, delayed treatment initiation until day 7, and evaluated anti-CTLA-4 and/or anti-PD-1. As expected, Y1.7LI tumor bearing mice treated with control mAb or control VAX (irrelevant mAlg8 SLP + pI:C) starting on day 7 post-transplant displayed progressive tumor outgrowth (##FIG##0##Figure 1D##). In contrast, anti-CTLA-4, anti-PD-1, combination anti-PD-1 plus anti-CTLA-4, or neo VAX induced tumor rejection in a majority of mice. ICT- and neo VAX-induced tumor rejection was dependent on both CD4 and CD8 T cells, as mAb depletion of either T cell subset completely abolished ICT efficacy (##SUPPL##0##Figure S2A##). Mice that rejected Y1.7LI tumors upon anti-PD-1 and/or anti-CTLA-4 or neo VAX initiated on day 7 were rechallenged with Y1.7LI at least 60 days after rejection of primary tumors in the absence of any additional treatment. Upon secondary challenge, no detectable tumor was observed under any of the conditions (##SUPPL##0##Figure S2B##). In contrast, Y1.7LI grew out when injected in control naïve WT mice in the absence of treatment.</p>", "<title>scRNAseq analysis of tumor microenvironment remodeling induced by NeoAg vaccines and ICT</title>", "<p id=\"P10\">We next used an unbiased approach to assess whether effective tumor-specific NeoAg vaccines induced TME alterations that are distinct or overlapping with different forms of ICT. Groups of Y1.7LI tumor bearing WT mice were treated with (1) control mAb, (2) anti-CTLA-4, (3) anti-PD-1, (4) anti-CTLA-4 + anti-PD-1, (5) control VAX (irrelevant SLP + pI:C), or (6) neo VAX (mLama4 SLP + pI:C) beginning on day 7 (##FIG##1##Figure 2A##). Tumors were harvested on day 15 (a critical timepoint prior to tumor rejection during ICT or neo VAX in this model) and live CD45<sup>+</sup> cells were sorted and processed for 10X single cell 5' library generation and sequencing for scRNAseq. We performed unsupervised graph-based clustering and noted clusters of myeloid cells and lymphocytes (##FIG##1##Figures 2B## and ##FIG##1##2C##). scRNAseq and flow cytometry both indicated that immunotherapy altered the proportions of different myeloid and lymphoid subsets and in some cases these alterations were dependent upon the specific treatment employed (##SUPPL##0##Figure S3A##).</p>", "<p id=\"P11\">To gain more insights into how the different immunotherapies altered T cells in the TME, we chose clusters containing activated T cells for subclustering and identified multiple clusters of conventional CD4 and CD8 T cells, Foxp3<sup>+</sup> CD4<sup>+</sup> T regulatory cells (Tregs), gamma delta T cells (γδT), and innate lymphoid cells (ILCs) (##FIG##1##Figures 2D##, ##SUPPL##0##S3B##-##SUPPL##0##S3D##, ##SUPPL##0##S4##, and ##SUPPL##0##S5##). Specific clusters of CD4 and CD8 T cells were annotated based on expression of select transcripts (##FIG##1##Figures 2E##, ##SUPPL##0##S4##, and ##SUPPL##0##S5##). We identified 5 exclusively CD8 T cell clusters, although this analysis did not distinguish their antigen specificity (##FIG##1##Figures 2D##, ##FIG##1##2E##, ##SUPPL##0##S4##, ##SUPPL##0##S5##, and ##SUPPL##0##S6A##-##SUPPL##0##S6F##). Overall, these clusters of CD8 T cells spanned a range of activation states including proliferating (Cd8<sub>Cycling</sub>), CD69<sup>hi</sup> IFN stimulated [Cd8<sub>iSTIM</sub> (<underline>i</underline>nterferon <underline>STIM</underline>ulated)], PD-1<sup>+</sup> TCF7<sup>+</sup> plastic/stem-like or progenitor exhausted (Cd8<sub>PE</sub>), and PD-1<sup>+</sup> TCF7<sup>−</sup> terminal effectors or dysfunctional/exhausted CD8 T cells (Cd8<sub>Eff/Ex</sub>) (##FIG##1##Figures 2E##, ##SUPPL##0##S4##, ##SUPPL##0##S5##, and ##SUPPL##0##S6A##-##SUPPL##0##S6F##).</p>", "<title>NeoAg vaccines and ICT induce CD8 T cells with proliferative transcriptional signature</title>", "<p id=\"P12\">While most clusters contained either CD4 or CD8 T cells, cluster Cd4/8<sub>cycling</sub> contained a mix of Tregs, CD4T cells, and CD8T cells and displayed a cell proliferation transcript signature (##FIG##1##Figures 2D##-##FIG##1##2F##\n##SUPPL##0##S4## and ##SUPPL##0##S5##). Not only did tumors from neo VAX, anti-PD-1, or anti-CTLA-4 treated mice have a greater frequency of cells within Cd4/8<sub>Cycling</sub>, but the ratio of cycling conventional CD4 and CD8 T cells to Tregs was higher as compared to control mAb or control VAX (##FIG##1##Figures 2G##-##FIG##1##2K##). Anti-CTLA-4 with or without anti-PD-1 reduced proliferating Tregs and expanded CD4 T cells within Cd4/8<sub>Cycling</sub>, while the ratio of proliferating CD8 T cells to Tregs or CD4 T cells was higher with anti-PD-1. Interestingly, neo VAX contained the greatest ratio of cycling CD8 T cells to other T cells in this cluster.</p>", "<p id=\"P13\">Cd8<sub>Cycling</sub> also exhibited features of proliferation/cycling but was exclusively composed of CD8 T cells which displayed a more activated phenotype compared to Cd4/8<sub>Cycling</sub>, along with enrichment in gene sets associated with glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid metabolism were enriched as manifested by Gene Set Enrichment Analysis (GSEA) (##SUPPL##0##Figures S4##, ##SUPPL##0##S5##, ##SUPPL##0##S6A##, and ##SUPPL##0##S6B##). Whereas the percentage of Cd8<sub>Cycling</sub> cells increased modestly with anti-CTLA-4 or anti-PD-1 ICT, neo VAX drove ~2-fold increase in the frequency of cells within this cluster (##SUPPL##0##Figure S6B##). These results suggest that while either neo VAX or ICT induce proliferating CD8 T cells, neo VAX more robustly expands subsets of proliferating CD8 T cells.</p>", "<p id=\"P14\">Cluster Cd8<sub>Eff/Ex</sub> displayed little detectable <italic toggle=\"yes\">Tcf7</italic> (encoding TCF-1) expression and elevated transcript expression of multiple inhibitory receptors and other genes associated with T cell activation, effector function, and also exhaustion/dysfunction including <italic toggle=\"yes\">Tox</italic> (##SUPPL##0##Figures S5##, ##SUPPL##0##S6A##, and ##SUPPL##0##S6C##). Cd8<sub>PE</sub> expressed <italic toggle=\"yes\">Pdcd1</italic> (PD-1), but to less of an extent than Cd8<sub>Eff/Ex</sub>, and additionally expressed <italic toggle=\"yes\">Slamf6</italic> and <italic toggle=\"yes\">Tcf7</italic>, indicating a phenotype consistent with progenitor/precursor exhausted T cells that display plastic/stem-like properties (##SUPPL##0##Figures S5##, ##SUPPL##0##S6A##, and ##SUPPL##0##S6D##). neo VAX or monotherapy with anti-CTLA-4 or anti-PD-1 reduced the frequency of cells within Cd8<sub>Eff/Ex</sub> and Cd8<sub>PE</sub>, whereas combination anti-CTLA-4 plus anti-PD-1 stood out as the only treatment to not decrease the frequency of Cd8<sub>Eff/Ex</sub> (##SUPPL##0##Figures S6C## and ##SUPPL##0##S6D##).</p>", "<p id=\"P15\">Within Cd8<sub>Cycling</sub>, Cd8<sub>PE</sub>, Cd8<sub>iSTIM</sub>, and Cd8<sub>Ccr7</sub>, the highest expression of <italic toggle=\"yes\">Lag3, Cd39</italic>, and <italic toggle=\"yes\">Gzmb</italic> within each respective cluster was observed with combination anti-CTLA-4 + anti-PD-1 ICT (##SUPPL##0##Figures S5##, ##SUPPL##0##S6A##, ##SUPPL##0##S6B##, and ##SUPPL##0##S6D##-##SUPPL##0##S6F##). Additionally, <italic toggle=\"yes\">Prf1</italic> was most robustly induced by combination ICT in all CD8 clusters, except for Cd8<sub>Ccr7</sub>, where neo VAX induced the highest expression (##SUPPL##0##Figures S5## and ##SUPPL##0##S6A##-##SUPPL##0##S6F##). Further, a pattern emerged within CD8 T cells whereby in each cluster, anti-CTLA-4 (alone or in combination with anti-PD-1), as well as neo VAX to some extent, drove higher expression of <italic toggle=\"yes\">Cd226</italic> encoding the co-activating receptor CD226/DNAM-1. CD226 counteracting the actions of the inhibitory receptor TIGIT by competing for binding to ligands such as CD155<sup>##UREF##2##47##</sup>. Expression of <italic toggle=\"yes\">Tigit</italic> followed an inverse pattern as <italic toggle=\"yes\">Cd226</italic> with anti-CTLA-4 containing treatments and neo VAX reducing <italic toggle=\"yes\">Tigit</italic> expression within clusters expressing the highest levels of <italic toggle=\"yes\">Tigit</italic> (Cd8<sub>Eff/Ex</sub>, Cd8<sub>Cycling</sub>, Cd8<sub>Ccr7</sub>) (##SUPPL##0##Figures S5##, ##SUPPL##0##S6A##, ##SUPPL##0##S6B##, ##SUPPL##0##S6C##, and ##SUPPL##0##S6F##).</p>", "<title>Anti-PD-1 expands PD-1<sup>+</sup> TCF7<sup>−</sup> NeoAg-specific Teff/Tex, with combination anti-PD-1 + anti-CTLA-4 ICT inducing robust expansion of Bhlhe40<sup>hi</sup> PD-1<sup>+</sup> TCF7<sup>−</sup> NeoAg-specific Teff/Tex</title>", "<p id=\"P16\">We and others have demonstrated that tumor antigen-specific CD8 T cells have unique features as compared to bystander CD8 T cells and that immunotherapy primarily affects tumor antigen-specific versus bulk CD8 T cells<sup>##REF##25428507##13##,##REF##28916749##17##,##REF##34290406##48##, ####UREF##3##49##, ##REF##35113651##50####35113651##50##</sup>. Therefore, we monitored CD8 T cells specific for the mLama4 NeoAg in the setting of neo VAX or ICT (##FIG##2##Figure 3A##). neo VAX, anti-CTLA-4, anti-PD-1, or combination ICT all increased the overall frequency of intratumoral CD8 T cells (##FIG##2##Figure 3B##). Anti-CTLA-4 alone or in combination with anti-PD-1 drove a significant increase in the frequency of mLama4-specific CD8 T cells (##FIG##2##Figures 3C##, ##FIG##2##3D##, and ##SUPPL##0##S7A##). Although anti-PD-1 did not alter mLama4-specific CD8 T cells as a percentage of CD8 T cells (##FIG##2##Figures 3C## and ##SUPPL##0##S7A##), mLama4-specific CD8 T cells were significantly increased with anti-PD-1 when analyzed as a percentage of CD45<sup>+</sup> cells (##FIG##2##Figure 3D##). Notably, neo VAX drove the greatest increase in mLama4-specific CD8 T cells from less than 2% of CD8 T cells in control mAb or control VAX to over 20% in mice treated with neo VAX, which corresponds to over 4% of all intratumoral CD45<sup>+</sup> cells in mice treated with neo VAX (##FIG##2##Figures 3C##, ##FIG##2##3D##, and ##SUPPL##0##S7A##). Since the scRNAseq profiling of intratumoral CD45<sup>+</sup> cells did not distinguish NeoAg-specific CD8 T cells from other CD8 T cells, we profiled NeoAg-specific CD8 T cells by sorting intratumoral mLama4 tetramer positive CD8 T cells from mice treated with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 plus anti-PD-1, control VAX, or neo VAX (##FIG##2##Figure 3E##). We profiled between 937 to 1762 mLama4-specific CD8 T cells for each of the different ICT treatment conditions and 4459, 6723, and 7646 mLama4-specific CD8T cells for control mAb, control VAX, and neo VAX, respectively. The two smallest clusters contained contaminating stromal cells, with the remaining clusters expressing transcripts consistent with CD8 T cells (##FIG##2##Figure 3F##, ##FIG##2##3G##, ##SUPPL##0##S7B##, ##SUPPL##0##S7C##, and ##SUPPL##0##S8##). Apart from these two small clusters, this analysis uncovered multiple clusters of NeoAg-specific CD8 T cells that enabled us to distinguish features that were not evident when profiling bulk CD8 T cells.</p>", "<p id=\"P17\">Clusters nAg.Cd8<sub>Eff/Ex</sub> and nAg.Bhlhe40<sup>Hi</sup>Cd8 both highly expressed <italic toggle=\"yes\">Pdcd1, Havcr2, Lag3, Tigit</italic>, and <italic toggle=\"yes\">Ccl5</italic> as well as effector transcripts (<italic toggle=\"yes\">Nkg7, Gzmb, Gzmk, Prf1, Cxcr6</italic>) and <italic toggle=\"yes\">Tox</italic> and exhibited little to no detectable expression of <italic toggle=\"yes\">Tcf7</italic> (##FIG##2##Figures 3G##-##FIG##2##3I##, ##FIG##3##4A##, ##SUPPL##0##S7B## and ##SUPPL##0##S7C##). neo VAX most notably reduced the proportion of nAg.Cd8<sub>Eff/Ex</sub> cells, whereas the proportion of cells in this cluster increased with anti-PD-1 alone or in combination with anti-CTLA-4 (##FIG##3##Figure 4B##). The top defining marker of cluster nAg.Bhlhe40<sup>Hi</sup>Cd8 was <italic toggle=\"yes\">Bhlhe40</italic> (##FIG##2##Figures 3G##, ##FIG##2##3H##, and ##SUPPL##0##S8##), which we previously demonstrated was upregulated in tumor-specific T cells and required for CD4 and/or CD8 T cell effector function and response to ICT<sup>##UREF##1##20##</sup>. In addition to <italic toggle=\"yes\">Bhlhe40</italic> (as well as <italic toggle=\"yes\">Pdcd1, Havcr2</italic>, and <italic toggle=\"yes\">Lag3</italic>) this cluster also expressed other transcripts induced by TCR activation, including <italic toggle=\"yes\">Ctla4, Cd69</italic>, as well as <italic toggle=\"yes\">Nr4a1</italic> (Nur77) and <italic toggle=\"yes\">Nr4a3</italic> suggesting recent activation and/or TCR stimulation (##FIG##2##Figures 3H##, ##FIG##3##4A##, and ##SUPPL##0##S7B##). nAg.Bhlhe40<sup>Hi</sup>Cd8 displayed the highest expression of <italic toggle=\"yes\">Tbx21</italic> and <italic toggle=\"yes\">Ifng</italic> amongst all the mLama4-specific CD8 T cells (##SUPPL##0##Figure S7B##). As compared to control mAb treatment, all other conditions (including control VAX) displayed a higher frequency of cells within this cluster, with the frequency of nAg.Bhlhe40<sup>Hi</sup>Cd8 increased from 2.4% of mLama4-specific CD8 T cells under control mAb conditions to 6.2% under anti-PD-1 treatment conditions (##FIG##3##Figure 4B##). Strikingly, anti-CTLA-4 and anti-PD-1 combination ICT increased this cluster to over 28% of mLama4-specific CD8 T cells.</p>", "<title>Anti-CTLA-4 alone or in combination with anti-PD-1 reduces expression of <italic toggle=\"yes\">Tox</italic> and inhibitory receptors and promotes <italic toggle=\"yes\">Il7r</italic> expression in PD-1<sup>+</sup>TCF7<sup>−</sup> Teff/Tex NeoAg-specific CD8 T cells</title>", "<p id=\"P18\">In addition to increasing the frequency of cells with in PD-1<sup>+</sup> TCF7<sup>−</sup> Teff/Tex clusters (nAg.Cd8<sub>Eff/Ex</sub> and nAg.Bhlhe40<sup>Hi</sup>Cd8), combination ICT increased expression of <italic toggle=\"yes\">Bhlhe40, Fasl, Il7r, Icos</italic>, and <italic toggle=\"yes\">Cd28</italic>, while decreasing <italic toggle=\"yes\">Tox, Pdcd1, Lag3, Entpd1</italic>, and <italic toggle=\"yes\">Tigit</italic> expression within both of these clusters (##FIG##3##Figures 4A##, ##SUPPL##0##S7B##, and ##SUPPL##0##S7C##). Further, combination ICT decreased expression on <italic toggle=\"yes\">Havcr2</italic> and increased expression of <italic toggle=\"yes\">Cd69</italic> within nAg.Bhlhe40<sup>Hi</sup>Cd8. While some of the features observed in combination ICT were distinct from either anti-CTLA-4 or anti-PD-1, within both these clusters the decrease in <italic toggle=\"yes\">Tox, Pdcd1, Lag3, Entpd1</italic>, and <italic toggle=\"yes\">Tigit</italic> (and <italic toggle=\"yes\">Havcr2</italic> in nAg.Bhlhe40<sup>Hi</sup>Cd8) with combination ICT was also observed with anti-CTLA-4 ICT (but not with anti-PD-1) (##FIG##3##Figures 4A##, ##SUPPL##0##S7B##, and ##SUPPL##0##S7C##), suggesting that these specific changes included by combination therapy were primarily driven by anti-CTLA-4. In contrast, increased expression of <italic toggle=\"yes\">Bhlhe40</italic> was most prominently observed in the presence of anti-PD-1. Other features (e.g., increased <italic toggle=\"yes\">Icos, Cd28</italic>, and <italic toggle=\"yes\">Fasl</italic> expression) were unique to the anti-CTLA-4 and anti-PD-1 combination ICT treatment conditions.</p>", "<title>NeoAg vaccination preferentially increases NeoAg-specific stem-like PD-1<sup>+</sup>TCF7<sup>+</sup>CD8 T cells and proliferating NeoAg-specific CD8 T cells</title>", "<p id=\"P19\">Amongst the most prominent NeoAg vaccine-driven features observed, NeoAg vaccines drove an over 3-fold increase in the frequency of mLama4-specific CD8 T cells within cluster nAg.PD-1<sup>+</sup> TCF7<sup>+</sup> Cd8 as compared to control mAb and over 8-fold increase as compared to control VAX (##FIG##3##Figure 4B##). Cluster nAg.PD-1<sup>+</sup> TCF7<sup>+</sup> Cd8 displayed high expression of <italic toggle=\"yes\">Slamf6</italic> and <italic toggle=\"yes\">Pdcd1</italic> amongst others; low to moderate expression of <italic toggle=\"yes\">Ifng, Gzmk, Prf1</italic>, and <italic toggle=\"yes\">Cd226</italic>; and no detectable expression of <italic toggle=\"yes\">Havcr2</italic> (TIM-3) or <italic toggle=\"yes\">Entpd1</italic> (CD39) (##FIG##2##Figures 3G##, ##FIG##2##3H##, ##FIG##3##4A##, and ##SUPPL##0##S7B##). nAg.PD-1<sup>+</sup> TCF7<sup>+</sup> Cd8 also expressed transcripts encoding molecules related to T cell homing such as <italic toggle=\"yes\">Ccr7</italic>, as well as <italic toggle=\"yes\">Bach2</italic><sup>##REF##33574619##51##</sup> and <italic toggle=\"yes\">Tcf7</italic>. These features are consistent with CD8 T cells with plastic or stem-like properties or progenitor exhausted CD8 T cells. While NeoAg vaccines promoted this population, the proportion of NeoAg-specific CD8 T cells within this cluster was largely unchanged with anti-CTLA-4, reduced slightly with anti-PD-1, and even further reduced with combination anti-CTLA-4 and anti-PD-1 (##FIG##3##Figure 4B##). Anti-CTLA-4 containing treatments displayed decreased expression of <italic toggle=\"yes\">Pdcd1, Lag3, Tigit</italic> and increased expression of transcripts encoding molecules related to T cell quiescence and homing such as <italic toggle=\"yes\">S1pr1, Sell</italic> (Cd62l), and <italic toggle=\"yes\">Klf2</italic>, as well as the IL-7 receptor transcript <italic toggle=\"yes\">Il7r</italic> (##FIG##3##Figures 4A##, ##SUPPL##0##S7B##, and ##SUPPL##0##S7C##).</p>", "<p id=\"P20\">We annotated 5 clusters of NeoAg-specific CD8 T cells as “cycling”. NeoAg vaccination increased the frequency of cells in all 5 cycling NeoAg-specific CD8 T cell clusters displaying a range of activation states and proliferation signatures (##FIG##3##Figures 4A##, ##SUPPL##0##S7B##, ##SUPPL##0##S7C##, and ##SUPPL##0##S8##). Each of the 5 cycling clusters also displayed a greater frequency of cells under control VAX conditions as compared to control mAb (##FIG##3##Figure 4B##). This suggests that although far more NeoAg-specific CD8 T cells are observed within tumors treated with neo VAX as compared to control VAX (##FIG##2##Figures 3C## and ##FIG##2##3D##), within NeoAg-specific CD8 T cells, pI:C contained in both control VAX and neo VAX likely promotes cycling of tumor-specific CD8T cells. These 5 cycling clusters together represented 20.9% of all mLama4-specific CD8 T cells under control mAb treatment, 54.1% under control VAX treatment, and 61.3% under neo VAX treatment (##FIG##3##Figure 4C##). Within nAg.Cd8<sub>Cycling</sub>_1, nAg.Cd8<sub>Cycling</sub>_2, and nAg.Cd8<sub>Cycling</sub>_6, either control VAX or neo VAX increased the frequency of NeoAg-specific CD8 T cells to about the same level (##FIG##3##Figure 4B##). In contrast, nAg.Cd8<sub>Cycling</sub>_3 represented 10.6% of NeoAg-specific CD8 T cells under control VAX conditions, whereas under neo VAX conditions, the frequency of cells within this cluster increased to 19.2% of NeoAg-specific CD8 T cells (##FIG##3##Figure 4B##). As compared to the other cycling clusters, nAg.Cd8<sub>Cycling</sub>_3 expressed higher <italic toggle=\"yes\">Xcl1, Tnfrsf4</italic> (OX40), <italic toggle=\"yes\">Tnfrsf9</italic> (4-1BB), <italic toggle=\"yes\">Prf1</italic>, and <italic toggle=\"yes\">Ifng</italic> (##FIG##3##Figures 4A##, ##SUPPL##0##S7B## and ##SUPPL##0##S8##). The frequency of total cells within cycling clusters was modestly increased by anti-CTLA-4 or anti-PD-1 ICT, whereas anti-CTLA-4 plus anti-PD-1 combination ICT decreased the frequency by almost half.</p>", "<title>NeoAg vaccines induce robust expansion of NeoAg-specific IFN-γ<sup>+</sup> CD8 T cells expressing PD-1 and LAG-3 and/or TIM-3</title>", "<p id=\"P21\">Since we noted that mice treated with neo VAX displayed a greater frequency of PD-1<sup>+</sup> TIM-3<sup>+</sup> NeoAg-specific CD8 T cells as compared to other treatments when treatment was initiated on d. 3 post-tumor transplant (##SUPPL##0##Figure S1F##), we assessed surface expression of PD-1, TIM-3, and additionally LAG-3 on intratumoral mLama4 NeoAg-specific CD8 T cells from mice when treatment initiation occurred on d. 7 post-transplant (as in our scRNAseq experiments). As expected, a majority of NeoAg-specific CD8 T cells expressed PD-1, with similar frequencies of PD-1<sup>+</sup> TIM-3<sup>+</sup> or PD-1<sup>+</sup> LAG-3<sup>+</sup> NeoAg-specific CD8 T cells observed between control mAb, control VAX, and the different ICT treatment conditions (##FIG##3##Figure 4D##). However, the expression level of PD-1, TIM-3, and LAG-3 on a per cell basis was lower in ICT treated groups. In contrast, a dramatic increase in the percentage of PD-1<sup>+</sup> TIM-3<sup>+</sup> or PD-1<sup>+</sup> LAG-3<sup>+</sup> mLama4-specific CD8 T cells was observed in mice treated with neo VAX and amongst PD-1<sup>+</sup>, TIM-3<sup>+</sup>, or LAG-3<sup>+</sup> NeoAg-specific CD8 T cells, PD-1, TIM-3, and LAG-3, respectively, was expressed higher in the neo VAX treated group (##FIG##3##Figure 4D##). These results were consistent with the discordance between effective NeoAg vaccines and ICT in PD-1 and TIM-3 surface expression on NeoAg-specific CD8 T cells observed when treatment was initiated on day 3 (##SUPPL##0##Figure S1F##). Intracellular cytokine staining (ICS) on isolated intratumoral CD8 T cells restimulated with the mLama4 NeoAg peptide revealed anti-CTLA-4 increased the frequency of IFN-γ<sup>+</sup> or TNFα<sup>+</sup> CD8 T cells, while neo VAX induced the greatest expansion of more than 5-fold of IFN-γ<sup>+</sup> or TNFα<sup>+</sup> CD8 T cells (##FIG##3##Figures 4E## and ##FIG##3##4F##). Amongst IFN-γ<sup>+</sup> CD8 T cells, expression of IFN-γ on a per cell basis increased significantly with anti-CTLA-4 and/or anti-PD-1, with the most robust increase occurring in mLama4 NeoAg-stimulated IFN-γ<sup>+</sup> CD8 T cells isolated from neo VAX treated mice (##FIG##3##Figure 4E##).</p>", "<title>Anti-CTLA-4 promotes IFNγ<sup>+</sup> Th1-like CD4 T cells expressing ICOS and Bhlhe40, while combination anti-CTLA-4 and anti-PD-1 ICT induces a small subset of Th2-like CD4 T cells</title>", "<p id=\"P22\">Since we observed that neo VAX or anti-CTLA-4/anti-PD-1 ICT required not only CD8 T cells, but also CD4 T cells for efficacy (##SUPPL##0##Figure S2A##), we examined CD4 T cells from our scRNAseq performed on sorted CD45<sup>+</sup> cells (##FIG##1##Figure 2A##). Conventional CD4 T cells and Tregs were significantly altered by anti-CTLA-4, with anti-CTLA-4 inducing a higher frequency of CD4 T cells and reducing the percentage of Tregs as assessed by both scRNAseq and flow cytometry (##FIG##1##Figures 2G##-##FIG##1##2I##, ##FIG##1##2K##, ##SUPPL##0##S3A##, and ##SUPPL##0##S3B##). Anti-CTLA-4 (+/− anti-PD-1) induced notable increases in proliferating CD4 T cells and a decrease in proliferating Tregs within cluster Cd8/4<sub>Cycling</sub> (##FIG##1##Figures 2H##, ##FIG##1##2I##, and ##FIG##1##2K##), further indicating that anti-CTLA-4 containing treatments dramatically affect the intratumoral CD4 T cell compartment. Most notably, anti-CTLA-4 (+/− anti-PD-1) induced subpopulations of Th1-like cells expressing <italic toggle=\"yes\">Ifng</italic> and <italic toggle=\"yes\">Bhlhe40</italic>, including cluster ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> CD4<sub>Th1</sub> that also highly expressed <italic toggle=\"yes\">Icos</italic> (##FIG##1##Figures 2E##, ##FIG##4##5A##, ##FIG##4##5B##, ##SUPPL##0##S5## and ##SUPPL##0##S9A##). ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> CD4<sub>Th1</sub> expressed transcripts indicative of highly activated T cells including high expression of <italic toggle=\"yes\">Pdcd1, Ctla4</italic>, and the <italic toggle=\"yes\">Furin</italic> transcript encoding a proprotein convertase, whose expression is regulated by TCR signaling and IL-12 signaling through STAT4<sup>##REF##16627761##52##</sup> (##FIG##4##Figures 5A##, ##SUPPL##0##S4##, and ##SUPPL##0##S5##). This cluster also expressed <italic toggle=\"yes\">Cxcr6, Csf2, Fasl</italic>, and <italic toggle=\"yes\">Tnfaip3</italic>, which encodes the A20 protein that regulates TCR/CD28-mediated NF-κB activation and TCR-mediated survival<sup>##REF##19494296##53##</sup> (##SUPPL##0##Figure S5##). ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> CD4<sub>Th1</sub> displayed enrichment in IL-2 STAT5 and IL-6 JAK STAT3 signaling, TNFa signaling via NF-κB, and IFN-γ response gene sets amongst others (##SUPPL##0##Figure S9A##). neo VAX also exhibited a greater frequency of cells within this cluster as compared to control VAX (##FIG##4##Figure 5B##). Bhlhe40<sup>+</sup> Cd4<sub>Th1</sub>_a also expressed <italic toggle=\"yes\">Icos</italic> and <italic toggle=\"yes\">Bhlhe40</italic>, but to less of an extent than ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> CD4<sub>Th1</sub> (##FIG##4##Figures 5A## and ##SUPPL##0##S5##). Bhlhe40<sup>+</sup> Cd4<sub>Th1</sub>_a was further distinguished from ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> CD4<sub>Th1</sub> by lower <italic toggle=\"yes\">Csf2, Runx3, Tnfaip3, Cxcr6, Furin, Pdcd1, Havcr2</italic>, and <italic toggle=\"yes\">Lag3</italic> expression and higher <italic toggle=\"yes\">Tbx21</italic> (Tbet) expression. Anti-CTLA-4 dramatically increased the frequency of Bhlhe40<sup>+</sup> CD4<sub>Th1</sub>_a, with anti-PD-1 also increasing cells within this cluster (##FIG##4##Figure 5B##). Likewise, neo VAX increased the frequency of Bhlhe40<sup>+</sup> Cd4<sub>Th1</sub>_a cells but to much less of an extent (##FIG##4##Figure 5B##). Although both clusters expressed glycolytic enzyme transcripts, greater expression of several of these transcripts was seen in ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> CD4<sub>Th1</sub>, while Bhlhe40<sup>+</sup> Cd4-<sub>Th1</sub>_a displayed gene set enrichment in Fatty Acid Metabolism (##SUPPL##0##Figures S5##, ##SUPPL##0##S9A##, and ##SUPPL##0##S9B##). Additionally, both clusters displayed significant enrichment in TGF beta signaling gene sets (##SUPPL##0##Figures S9A## and ##SUPPL##0##S9B##). Cluster Bhlhe40<sup>+</sup> CD4<sub>Th1</sub>_b was the smallest cluster of Th1-like cells and exhibited high <italic toggle=\"yes\">Ifng, Pdcd1, Tigit, Havcr2</italic>, and <italic toggle=\"yes\">Lag3</italic> expression (##FIG##4##Figures 5A##, ##SUPPL##0##S5##, and ##SUPPL##0##S9C##). This cluster also expressed the lowest level of <italic toggle=\"yes\">Icos</italic> and the highest level of <italic toggle=\"yes\">Tox</italic> amongst all CD4 clusters (##FIG##4##Figures 5A## and ##SUPPL##0##S5##). While only subtle changes to the frequency of cells within this cluster were seen with treatments apart from control VAX and combination anti-CTLA-4 and anti-PD-1, with the latter displaying the highest frequency of cells within this cluster amongst all groups (##FIG##4##Figure 5B##).</p>", "<p id=\"P23\">Amongst all treatment conditions, mice treated with anti-CTLA-4 alone or in combination with anti-PD-1 displayed the highest expression of <italic toggle=\"yes\">Bhlhe40</italic> and least expression of <italic toggle=\"yes\">Tnfrsf18 (GITR)</italic> (##FIG##4##Figures 5A##, ##SUPPL##0##S5##, ##SUPPL##0##S9A##-##SUPPL##0##S9E##, and ##SUPPL##0##S9G##). As observed within CD8 T cell clusters, within multiple CD4 clusters, anti-CTLA-4 alone or in combination drove an increase in <italic toggle=\"yes\">Cd226</italic> expression and a decrease in <italic toggle=\"yes\">Tigit</italic> expression, with neo VAX also following this same pattern but to less of an extent.</p>", "<p id=\"P24\">The increase in IFN-γ expressing Th1-like cells most prominently induced by anti-CTLA-4 was reflected by ICS on isolated intratumoral CD4 T cells restimulated <italic toggle=\"yes\">ex vivo</italic> with the mItgb1 MHC-II NeoAg peptide. Anti-CTLA-4 +/− anti-PD-1 induced the most dramatic increase in both the overall frequency of conventional CD4 T cells, with anti-CTLA-4 and/or anti-PD-1 increasing the frequency of IFN-γ<sup>+</sup> CD4 T cells upon restimulation with mItgb1 peptide (##FIG##4##Figures 5C## and ##FIG##4##5D##). This is in contrast to neo VAX, where only subtle changes were observed. Altogether, these findings indicate that while mice treated with anti-CTLA-4, alone or in combination with anti-PD-1, display the most dramatic increase in IFN-γ-producing Th1-like CD4 T cells within the tumor, anti-PD-1 also provokes IFN-γ<sup>+</sup> CD4 T cells (##FIG##4##Figure 5D##). This is supported by comparing the expression of <italic toggle=\"yes\">Ifng</italic> transcript within <italic toggle=\"yes\">Ifng</italic><sup>+</sup> CD4 T cells clusters, where anti-PD-1 induced increased <italic toggle=\"yes\">Ifng</italic> expression in these clusters, even those whose frequency was unaltered by anti-PD-1 (i.e., ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> Cd4<sub>Th1</sub>, Bhlhe40<sup>+</sup> Cd4<sub>Th1</sub>_b, Cd4<sub>Tfh</sub>) (##FIG##4##Figures 5A##, ##SUPPL##0##S5##, and ##SUPPL##0##S9A##-##SUPPL##0##S9D##).</p>", "<p id=\"P25\">Interestingly, combination ICT induced a small population of cells found in Cd4<sub>Th2</sub>, which also expressed <italic toggle=\"yes\">Icos</italic> and <italic toggle=\"yes\">Bhlhe40</italic>, but unlike the other ICOS<sup>+</sup> Bhlhe40<sup>+</sup> clusters the transcripts for <italic toggle=\"yes\">Ifng, Tim3</italic>, and <italic toggle=\"yes\">Lag3</italic> transcript were barely detectable (##FIG##4##Figures 5A##, ##SUPPL##0##S5##, and ##SUPPL##0##S9E##). Amongst CD4 clusters, Cd4<sub>Th2</sub> expressed the highest level of <italic toggle=\"yes\">Cxcr6</italic>, as well as <italic toggle=\"yes\">Tnfaip3</italic> (##SUPPL##0##Figure S5##). In addition to low <italic toggle=\"yes\">Ifng</italic> expression, many cells within Cd4<sub>Th2</sub> expressed <italic toggle=\"yes\">Gata3, Il4, Il5</italic>, and <italic toggle=\"yes\">Il13</italic>, indicative of a Th2-like cluster (##FIG##4##Figures 5A##, ##SUPPL##0##S5##, and ##SUPPL##0##S9F##). Although cluster Cd4<sub>Th2</sub> expressed Th2 cytokine transcripts and <italic toggle=\"yes\">Gata3</italic>, both Cd4<sub>Th2</sub> and ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> CD4<sub>Th1</sub> highly expressed <italic toggle=\"yes\">Furin</italic> and <italic toggle=\"yes\">Bhlhe40</italic> (##FIG##4##Figures 5A## and ##SUPPL##0##S5##). ICOS<sup>hi</sup> Bhlhe40<sup>hi</sup> CD4<sub>Th1</sub> also displayed enrichment in TNFa signaling via NFkB and IFN-γ response gene sets, along with Kras signaling up, whereas Cd4<sub>Th2</sub> displayed enrichment in Kras signaling down (##SUPPL##0##Figures S9A## and ##SUPPL##0##S9E##).</p>", "<p id=\"P26\">To gain insight into the temporal dynamics of the observed changes in CD4T cells, we used Monocle to analyze scRNAseq data<sup>##REF##24658644##54##</sup>. Monocle suggested that the starting point for conventional CD4 T cells corresponds to cells within either the Cd4<sub>Naive/Mem</sub> cluster (expressing <italic toggle=\"yes\">Tcf7, Il7r</italic>, and <italic toggle=\"yes\">S1pr1</italic>, indicative of naïve or memory phenotype) or CD4 T cells within the Cd4/8<sub>Cycling</sub> cluster (##FIG##4##Figure 5E##) with Cd4<sub>Tfh</sub> connecting Cd4/8<sub>Cycling</sub> CD4 T cells to the main trajectory towards Cd4<sub>Naive/Mem</sub> and the branch to more activated, polarized CD4T cells. Notably, a pseudotime trajectory branch point occurs whereby activated CD4 T cells occupy Th1-like ICOS<sup>hi</sup>Bhlhe40<sup>hi</sup>Cd4<sub>Th1</sub> driven by anti-CTLA-4 (+/− anti-PD-1) (and to a lesser extent by neo VAX) or encounter another branch whereby they assume one of two fates: they either become Th1-like CD4 T cells within Bhlhe40<sup>+</sup>Cd4<sub>Th1</sub>_a or become Th2-like Cd4<sub>Th2</sub>, with Bhlhe40<sup>+</sup> Cd4-<sub>Th1</sub>_a being induced by anti-CTLA-4 and/or anti-PD-1 or neo VAX and Cd4<sub>Th2</sub> primarily being driven by combination anti-CTLA-4 + anti-PD-1.</p>", "<title>Features of intratumoral Treg subpopulations during NeoAg vaccine or ICT treatment</title>", "<p id=\"P27\">We also identified three CD4 Foxp3<sup>+</sup> Treg clusters (##SUPPL##0##Figures S3B##). Treg_1 and Treg_3 appeared to be the most activated with Treg_3 expressing the highest level of <italic toggle=\"yes\">Ctla4, Havcr2</italic>, and <italic toggle=\"yes\">Klrg1</italic> (##SUPPL##0##Figure S5##). Mice treated with anti-CTLA-4 alone or in combination with anti-PD-1 experienced a decrease in frequency of Treg_1 and Treg_3 (##SUPPL##0##Figures S3B##), which is consistent with previous results that the anti-CTLA-4 mAb we used (mouse IgG2b; clone 9D9) partially depletes Tregs, especially those highly expressing CTLA-4<sup>##REF##35181783##55##</sup>. Treg_2 expressed lower amounts of <italic toggle=\"yes\">Ctla4, Havcr2, Tigit</italic>, and <italic toggle=\"yes\">Klrg1</italic> with the frequency of these Tregs not being affected by anti-CTLA-4, whereas anti-PD-1 with or without anti-CTLA-4, control VAX, or neo VAX displaying a greater frequency of cells in this cluster (##SUPPL##0##Figure S3B##). As compared to control VAX, the cellular density of Treg_1 and Treg_2 decreased in tumors from mice treated with neo VAX (##SUPPL##0##Figures S3B##). Further, transcript expression of <italic toggle=\"yes\">Foxp3</italic> in Treg_2 was lower in the neo VAX group (##SUPPL##0##Figure S3B##). These alterations to the overall frequency of Tregs most prominently observed in the presence of anti-CTLA-4 are also corroborated by flow cytometry analysis (##SUPPL##0##Figure S3A##).</p>", "<title>Intratumoral myeloid cell compartment during NeoAg vaccines or ICT treatment</title>", "<p id=\"P28\">We first noted that neutrophils represented a small proportion of the overall immune infiltrate as more reliably shown by flow cytometry (##FIG##1##Figures 2B## and ##SUPPL##0##S3A##). Consistent with previous observations in sarcoma models<sup>##REF##30343900##18##</sup>, anti-CTLA-4 (+/− anti-PD-1) increased the proportion of neutrophils to just under 1.5% of CD45<sup>+</sup> intratumoral cells (##SUPPL##0##Figure S3A##). To comprehensively characterize the signatures of intratumoral macrophages and DCs, we subclustered the myeloid component excluding the single neutrophil cluster (##SUPPL##0##Figure S10A##). In addition to a cluster of plasmacytoid DCs (pDCs), four other DC clusters were identified (CD103<sup>+</sup> cDC1, CD63<sup>+</sup> Ccr7<sup>+</sup> cDC, Ccr7<sup>+</sup> cDC, and Mgl2<sup>+</sup> DC) (##SUPPL##0##Figures S10A##-##SUPPL##0##S10G##). Cluster CD103<sup>+</sup> cDC1 expressed multiple classical DC (cDC) 1 transcripts including <italic toggle=\"yes\">Itgae</italic> (<italic toggle=\"yes\">Cd103</italic>), <italic toggle=\"yes\">Xcr1</italic>, and <italic toggle=\"yes\">Clec9a</italic> (##SUPPL##0##Figures S10A## and ##SUPPL##0##S10B##). CD63<sup>+</sup> Ccr7<sup>+</sup> cDC and Ccr7<sup>+</sup> cDC expressed <italic toggle=\"yes\">Ccr7, Cd1d1, Cd200, Fscn1, Cd274</italic> (PD-L1), and <italic toggle=\"yes\">Pdcd1lg2</italic> (PD-L2). These two migratory cDC clusters are likely composed of mregDCs, which describes a maturation state of cDC1s and cDC2s upon uptake of tumor antigen and although they express immunoregulatory molecules, they are not necessarily immunosuppressive<sup>##REF##32269339##56##,##REF##34343496##57##</sup> (##SUPPL##0##Figures S10B##, ##SUPPL##0##S10D## and ##SUPPL##0##S10E##). CD63<sup>+</sup> Ccr7<sup>+</sup> cDC expressed higher <italic toggle=\"yes\">Cd63, Cd40, Cd70</italic>, and <italic toggle=\"yes\">Btla</italic> as compared to Ccr7<sup>+</sup> cDC (##SUPPL##0##Figures S10B## and ##SUPPL##0##S10D##).</p>", "<title>Distinct Macrophage Remodeling Induced by NeoAg Vaccines and ICT</title>", "<p id=\"P29\">We observed multiple intratumoral monocyte/macrophage clusters in Y1.7LI displaying a range of phenotypic states<sup>##REF##35690521##58##,##UREF##4##59##</sup> (##FIG##5##Figures 6A##, ##FIG##5##6B##, and ##SUPPL##0##S11##). Ccr2<sup>+</sup> M_c1 displayed transcripts consistent with monocytes, including <italic toggle=\"yes\">Ccr2</italic> and <italic toggle=\"yes\">Chil3</italic>, and the frequency of cells within this cluster only increased slightly with anti-PD-1 or neo VAX (##FIG##5##Figures 6B##, ##FIG##5##6C##, and ##SUPPL##0##S11##). <italic toggle=\"yes\">Chil3</italic><sup><italic toggle=\"yes\">+</italic></sup> monocytes were previously shown to be reduced by a NeoAg vaccine in preclinical models<sup>##REF##36302380##60##</sup>; however, the NeoAg vaccine and adjuvant used in that setting differed from ours.</p>", "<p id=\"P30\">We previously demonstrated that anti-CTLA-4 and/or anti-PD-1 induces macrophage TME remodeling characterized by a reduction in M2-like macrophages co-expressing the fractalkine receptor (CX3CR1) and the CD206 pattern recognition receptor and an increase in M1-like iNOS<sup>+</sup> macrophages in mouse MCA sarcoma models<sup>##REF##30343900##18##,##UREF##1##20##</sup>. We noted a similar ICT-induced remodeling trend in the Y1.7LI melanoma model. Whereas a slight decrease in the frequency of CX3CR1<sup>+</sup> CD206<sup>hi</sup> M_c2 cells expressing high levels of <italic toggle=\"yes\">Cx3cr1, Mrc1 (Cd206), Trem2, Vcam1, Cd63</italic>, and <italic toggle=\"yes\">Cd72</italic> was observed with anti-CTLA-4 and/or anti-PD-1 ICT, expression of <italic toggle=\"yes\">Cx3cr1</italic> and frequency of <italic toggle=\"yes\">Cx3cr1</italic><sup>+</sup> macrophages within this cluster was notably decreased under all ICT treatment conditions (##FIG##5##Figures 6B##-##FIG##5##6D##). The frequency of cells expressing <italic toggle=\"yes\">Cx3cr1</italic> within this cluster under control VAX treatment was equal to or higher than with control mAb (##FIG##5##Figure 6D##). neo VAX reduced the proportion of cells within this cluster expressing <italic toggle=\"yes\">Cx3cr1</italic> (##FIG##5##Figure 6D##). CX3CR1<sup>+</sup> CD206<sup>+</sup> M_c3 also expressed <italic toggle=\"yes\">Cx3cr1</italic>, as well as <italic toggle=\"yes\">Mrc1 (Cd206), Trem2, Vcam1</italic>, and <italic toggle=\"yes\">Cd72</italic> with the latter transcripts being expressed less than in CX3CR1<sup>+</sup> CD206<sup>hi</sup> M_c2.CX3CR1<sup>+</sup> CD206<sup>+</sup>M_c3 also displayed a cell proliferation transcript signature that included high expression of <italic toggle=\"yes\">Mki67</italic> and exhibited lower <italic toggle=\"yes\">Mertk</italic> expression as compared to CX3CR1<sup>+</sup> CD206<sup>hi</sup> M_c2 (##FIG##5##Figure 6B##). Anti-CTLA-4 alone reduced the frequency of CX3CR1<sup>+</sup> CD206<sup>+</sup> M_c3 (##FIG##5##Figures 6C## and ##FIG##5##6D##). Although the aforementioned two clusters expressed the highest levels of <italic toggle=\"yes\">Cx3cr1</italic> and <italic toggle=\"yes\">Mrc1</italic>, M_c8 and M_c9 macrophages also expressed <italic toggle=\"yes\">Cx3cr1</italic> and <italic toggle=\"yes\">Mrc1</italic> under control mAb conditions with ICT reducing expression of <italic toggle=\"yes\">Cx3cr1</italic> within these clusters (##FIG##5##Figures 6B## and ##FIG##5##6D##). Comparable expression levels of <italic toggle=\"yes\">Cx3cr1</italic> was observed in M_c8 under control VAX and neo VAX conditions, with neo VAX increasing the frequency of cells within this cluster (##FIG##5##Figures 6B##, ##FIG##5##6C##, and ##FIG##5##6D##). Under either control VAX or neo VAX conditions, M_c11 expressed both <italic toggle=\"yes\">Cx3cr1</italic> and <italic toggle=\"yes\">Mrc1</italic> and the frequency of cells within this cluster dramatically increased in mice treated with either control VAX or neo VAX, with ICT reducing this population (##FIG##5##Figures 6B##-##FIG##5##6D##). Overall, cells within all monocyte/macrophage clusters from mice treated with control VAX and neo VAX displayed higher expression of <italic toggle=\"yes\">Cx3cr1</italic> as compared to ICT groups, with neo VAX also displaying similar expression of <italic toggle=\"yes\">Mrc1</italic> as control mAb (##FIG##5##Figure 6E##).</p>", "<p id=\"P31\">Several monocyte/macrophage clusters expressed high levels of <italic toggle=\"yes\">Nos2</italic> (iNOS); other clusters expressed varying levels of <italic toggle=\"yes\">Nos2</italic>, with expression of <italic toggle=\"yes\">Nos2</italic> being highly correlated with ICT treatment as well as neo VAX, but to less of an extent (##FIG##5##Figures 6B## and ##FIG##5##6F##). Further, expression of <italic toggle=\"yes\">Cd274</italic> (PD-L1) also correlated with expression of <italic toggle=\"yes\">Nos2</italic> within macrophage clusters, in particular under ICT treatment conditions (##FIG##5##Figure 6B##). While the overall frequency of these iNOS<sup>+</sup> M1-like clusters often only modestly increased with ICT, the frequency of cells within these clusters expressing <italic toggle=\"yes\">Nos2</italic> and/or <italic toggle=\"yes\">Nos2</italic> expression on a per cell basis dramatically increased under all ICT conditions (##FIG##5##Figures 6B##, ##FIG##5##6C##, and ##FIG##5##6F##). Nos2<sup>hi</sup>M_c4 and Nos2<sup>hi</sup> M_c6 both manifested high expression of <italic toggle=\"yes\">Nos2, Il1a, Il1b, Cxcl2, Inhba</italic>, and <italic toggle=\"yes\">Nfkb1</italic>, signatures of inflammatory macrophages<sup>##UREF##5##61##</sup> (##FIG##5##Figure 6B##). While Nos2<sup>hi</sup>M_c4 displayed classic features of M1-like macrophages including low <italic toggle=\"yes\">Mrc1</italic> expression, Nos2<sup>hi</sup> M_c6 moderately expressed <italic toggle=\"yes\">Mrc1</italic> as well as higher <italic toggle=\"yes\">F13a1, Trem2</italic>, and <italic toggle=\"yes\">Il1a</italic><sup>##REF##35690521##58##,##REF##33033253##62##</sup>, along with lower <italic toggle=\"yes\">Il1r2</italic> compared to Nos2<sup>hi</sup>M_c4 (##FIG##5##Figure 6B##). Nos2<sup>hi</sup>M_c4 displayed high expression of <italic toggle=\"yes\">Cxcl9</italic> and <italic toggle=\"yes\">Spp1</italic>, with expression of the latter diminished with ICT or neo VAX. Higher expression of <italic toggle=\"yes\">CXCL9</italic> and lower <italic toggle=\"yes\">SPP1</italic> expression was found to be correlated with macrophage prognostic score in cancer patients<sup>##REF##37535729##63##</sup>. Nos2<sup>hi</sup>M_c5 highly expressed <italic toggle=\"yes\">Nos2</italic> in the presence of ICT, with ICT also increasing the frequency of macrophages within this cluster (##FIG##5##Figures 6B##, ##FIG##5##6C##, and ##FIG##5##6F##). This cluster also expressed moderate levels of <italic toggle=\"yes\">Mki67</italic> and other cell cycle related transcripts, indicative of iNOS<sup>+</sup> macrophages with proliferative capabilities (##FIG##5##Figure 6B##). Nos2<sup>hi</sup> M_c7 was the smallest iNOS<sup>+</sup> macrophage cluster and in addition to <italic toggle=\"yes\">Nos2</italic> expression, displayed highest expression of interferon-stimulated genes (ISGs) and also expressed high levels of <italic toggle=\"yes\">Cxcl9, Cxcl10, Cd274, Cd72, Cd81</italic>, and <italic toggle=\"yes\">Ms4a4c</italic> (##FIG##5##Figures 6B## and ##FIG##5##6F##). Although M_c8 and M_c9 expressed modest levels of <italic toggle=\"yes\">Cx3cr1</italic> under control mAb conditions, its expression was reduced by ICT along with induction of <italic toggle=\"yes\">Nos2</italic> expression within these clusters (##FIG##5##Figures 6B##, ##FIG##5##6D##, and ##FIG##5##6F##). These same overall patterns were manifested at the protein level where in anti-CTLA-4 and/or anti-PD-1 treated mice, the frequency of intratumoral CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages decreased with a concomitant increase in iNOS<sup>+</sup> macrophages induced by ICT (##FIG##5##Figures 6G## and ##FIG##5##6H##). In contrast, while neo VAX treated mice also displayed a greater frequency of iNOS<sup>+</sup> macrophages, CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages were only slightly reduced by neo VAX as compared to control VAX, but nonetheless were maintained at a similar frequency as seen in control mAb treated mice (##FIG##5##Figures 6F## and ##FIG##5##6G##). Since the frequency of CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages in both control VAX and neo VAX treated mice were similar or even greater than in control mAb treated mice, induction or maintenance of this macrophage subpopulation was likely linked to the pI:C adjuvant used in both control Vax and neo VAX. These results reveal that despite a relatively a similar abundance of M2-like CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages that were previously associated with progressively growing tumors in untreated or control mAb treated mice<sup>##REF##30343900##18##,##UREF##1##20##</sup>, tumors in mice treated with neo VAX regress equivalently to ICT treated mice.</p>", "<title>ICT Broadens Therapeutic Window for Neoantigen Vaccines</title>", "<p id=\"P32\">We noted changes that were not only shared between treatment conditions, but also distinct depending upon which treatment strategy was employed. Principle Component Analysis (PCA) further illustrated that neo VAX induces distinct changes to the immune TME as compared to anti-CTLA-4 and/or anti-PD-1 (##SUPPL##0##Figure S12##). This, together with our findings that neo VAX induces robust expansion of NeoAg-specific CD8 T cells that produce IFN-γ and appear functional, yet highly express PD-1/TIM-3/LAG-3 (##FIG##2##Figures 3C##, ##FIG##2##3D##, ##FIG##3##4D##, ##FIG##3##4E##, and ##SUPPL##0##S7A##), prompted us to asked whether neo VAX could synergize with ICT. While neo VAX or ICT led to robust rejection of Y1.7LI when initiated on d. 7 post-transplant, a majority of tumor bearing mice displayed tumor outgrowth when treatment with anti-CTLA-4, anti-PD-1, or neo VAX was initiated on d. 12 post-transplant. We therefore used a d. 12 treatment start timepoint to assess whether combining neo VAX with anti-CTLA-4 or anti-PD-1 improved efficacy (##FIG##6##Figure 7A##). Mice treated with neo VAX in combination with anti-CTLA-4 or anti-PD-1 displayed enhanced tumor control as compared to control VAX (irrelevant SLP + pI:C) + anti-PD-1 or control VAX + anti-CTLA-4 (##FIG##6##Figure 7A##). Further, neo VAX used in combination with anti-CTLA-4 or anti-PD-1 provided superior tumor growth inhibition compared to combination anti-CTLA-4 and anti-PD-1 ICT. To extend our findings to a distinct tumor model, we assessed our vaccine protocol and combination treatment using the MC38 tumor model, which has several known endogenous MHC-I tumor NeoAgs<sup>##REF##25428506##16##,##REF##32923109##64##,##REF##36969213##65##</sup>. Since it has been reported that expression of these NeoAgs varies depending on the source of the MC38 cell line, we previously confirmed in our MC38 line the presence of point mutations that form NeoAgs (mAdpgk, mRpl18, and mDpagt1)<sup>##REF##25428506##16##,##REF##32923109##64##</sup>. We assessed combinatorial treatments in MC38 tumor bearing mice by choosing an injection dose of cells (see <xref rid=\"S16\" ref-type=\"sec\">Methods</xref>) and treatment schedule where monotherapy with anti-CTLA-4, anti-PD-1, or neo VAX alone is largely ineffective (##FIG##6##Figure 7B##). PBS, control VAX, or neo VAX was administered to MC38 tumor bearing mice on d. 12 and 19 post-transplant with or without anti-CTLA-4 or anti-PD-1 given on d. 12, 15, 18, and 22. Similar to results in the Y1.7LI model, neo VAX in combination with anti-CTLA-4 or anti-PD-1 provided superior protection versus monotherapy (##FIG##6##Figure 7B##). These findings in two distinct models complement ongoing NeoAg vaccine clinical trials and further support the rationale for combination NeoAg-based therapies.</p>" ]	[ "<title>Discussion</title>", "<p id=\"P33\">In this study, we compared different immunotherapies that lead to tumor rejection (NeoAg SLP vaccines, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, or NeoAg SLP cancer vaccines) and pertinent control treatments where tumor progression occurs using mouse melanoma models expressing defined NeoAgs and melanoma-relevant gain-of-function and loss-of-function genetic perturbations<sup>##REF##27287723##38##</sup>. Although prior studies have examined NeoAg vaccines<sup>##REF##36302380##60##</sup>, few (if any) studies have performed extensive comparisons between anti-PD-1, anti-CTLA-4, combination ICT, and NeoAg vaccines in the same robust experimental system. Further, while the focus of most prior studies involving ICT or NeoAg vaccines was on either lymphoid or myeloid cells<sup>##REF##28803728##21##,##REF##35393580##66##</sup>, our work has provided insights into both categories of cells and how different immunotherapies differentially affect these cells within the TME. Our treatment schedule and analyses were initially performed so that the NeoAg cancer vaccines or ICT we used lead to complete tumor rejection in a majority of mice; thus, we could compare and contrast the molecular and cellular changes that occur as a consequence of NeoAg vaccines or different forms of ICT and link them to outcomes. We specifically chose to study an SLP NeoAg vaccine as SLP vaccines are highly relevant with many clinical trials employing SLPs usually in combination with the adjuvant polyIC:LC vaccines are being conducted<sup>##REF##28678778##7##,##REF##33064988##9##,##REF##33479501##67##</sup>.</p>", "<p id=\"P34\">The current study makes several key observations. First, NeoAg vaccines and ICT work by several overlapping mechanisms related to the CD8 T cell response, with key differences in the overall magnitude of the response and phenotype of NeoAg-specific CD8T cells observed. NeoAg vaccines induce the greatest expansion of functional intratumoral NeoAg-specific CD8T cells including proliferating T cells and PD-1<sup>+</sup> TCF-1<sup>+</sup> stem-like CD8 T cells and require not only CD8 T cells, but also CD4 T cells for efficacy. However, anti-CTLA-4 and/or anti-PD-1 also increased the frequency of intratumoral CD8 T cells, including NeoAg-specific CD8 T cells with enhanced production of IFN-γ. Anti-PD-1 alone, or most dramatically when administered in combination with anti-CTLA-4 ICT, induced a subset of Bhlhe40<sup>hi</sup> NeoAg-specific CD8 T cells also display high expression of <italic toggle=\"yes\">Tbx21</italic> and <italic toggle=\"yes\">Ifng</italic>. Additionally, this subset expressed <italic toggle=\"yes\">Ctla4, Cd69</italic>, as well as <italic toggle=\"yes\">Nr4a1</italic> (Nur77) and <italic toggle=\"yes\">Nr4a3</italic>, which suggest recent activation and/or TCR stimulation due to their known pattern of rapid and transient expression following T cell stimulation. Interestingly, a recent study identified Bhlhe40 as modulating a key differentiation point between progenitor and intermediate subsets of exhausted T cells in an in vitro exhaustion model and chronic LCMV infection<sup>##REF##37595022##68##</sup>. While some of the features observed with combination ICT were distinct from either anti-CTLA-4 or anti-PD-1, the decrease in <italic toggle=\"yes\">Tox, Pdcd1, Lag3, Havcr2, Entpd1</italic>, and <italic toggle=\"yes\">Tigit</italic> with combination ICT was also observed with anti-CTLA-4 ICT, whereas the increased expression of Bhlhe40 within several NeoAg-specific CD8 T cell subsets was often more akin to the level of increase observed with anti-PD-1. These findings add to the accumulating evidence that the enhanced anti-tumor activity of combination anti-CTLA-4 and anti-PD-1 ICT is likely mediated by not only additive effects, but also through mechanisms distinct from the monotherapies<sup>##REF##30343900##18##,##REF##31636208##22##</sup>. In addition to modulating the CD8 T cell compartment, ICT notably impacted the CD4 T cell compartment as well. Anti-CTLA-4 reduced the frequency of Tregs and induced ICOS<sup>+</sup> Th1-like conventional CD4 T cells displaying high expression of Bhlhe40, a transcription factor that we previously documented regulates T cell effector function during ICT<sup>##UREF##1##20##</sup>. Interestingly, subsets of Th1-like CD4 T cells with high expression of Bhlhe40 were previously found to be enriched in patients with microsatellite instability (MSI) colorectal cancer, who display favorable outcomes in response to anti-CTLA-4<sup>##REF##24777852##69##, ####REF##19202079##70##, ##REF##30479382##71####30479382##71##</sup>. Further, studies in both preclinical models and human melanoma patients have revealed that anti-CTLA-4 induces ICOS<sup>+</sup> CD4 T cells expressing IFN-γ<sup>##REF##19202079##70##,##REF##24687957##72##</sup>. Anti-PD-1 also increased the frequency of overall IFN-γ<sup>+</sup> Th1-like CD4 T cells, but to less of an extent as compared to anti-CTLA-4. Combination anti-CTLA-4 and anti-PD-1 ICT induced a small, but significant subpopulation of Th2-like CD4 T cells (Cd4-<sub>Th2</sub>) expressing <italic toggle=\"yes\">Il4, Il13, Gata3</italic>.</p>", "<p id=\"P35\">While vaccines targeting MHC-I NeoAgs predominately affected CD8 T cells, we found that these MHC-I NeoAg vaccines require CD4 T cells for efficacy. In MHC-II positive tumors, cytotoxic CD4 T cells have been show to directly kill tumor cells<sup>##REF##34910940##73##</sup>; however, even with tumors lacking MHC-II expression, CD4 T cells are often required for anti-tumor immunity<sup>##REF##31645760##19##,##REF##34852236##42##,##REF##25901682##74##</sup>. The importance of CD4 T cells may be due to their ability to produce cytokines such as IFN-γ and IL-2 and also likely stems from their ability to and their ability to be primed by cDC1s presenting tumor antigens and their CD40-dependent licensing of cDC1s that is critical for priming and activation of CD8 T cells<sup>##REF##32788723##75##,##REF##36271147##76##</sup>. Further, CD4T cell reprogramming of the myeloid compartment towards IFN-activated, iNOS-expressing tumoricidal and antigen-presenting phenotypes has also been implicated in tumor destruction<sup>##REF##29752262##77##,##REF##37316667##78##</sup>. The detailed mechanisms regarding the contribution of CD4 T cells in NeoAg vaccines targeting MHC-I NeoAgs remains to be fully elucidated by future studies and may entail multiple functions of CD4 T cells within both the lymph nodes and tumor. Although MHC-II NeoAgs are critical components of anti-tumor immunity, we specifically chose to utilize an SLP vaccine against a single MHC-I NeoAg in order to definitively link the MHC-I NeoAg vaccine to specific defined NeoAgs. Further, since MHC-II NeoAgs are more difficult to predict than MHC-I NeoAgs, we wanted to study the effects of an MHC-I NeoAg vaccine and whether this NeoAg vaccine approach in combination with anti-CTLA-4 or anti-PD-1 ICT could provoke rejection of larger, established tumors. SLPs offer several advantages over short peptides including the ability to specifically target professional APCs, stability, and the capacity to provoke both CD4 and CD8 T cells responses<sup>##REF##23836147##79##, ####REF##26214521##80##, ##REF##33907315##81####33907315##81##</sup>; however, most immunogenic NeoAgs are either MHC-I or MHC-II NeoAgs, even when using SLPs. In our study, the SLP NeoAgs (mAlg8 or mLama4) provoked only NeoAg-specific CD8 T cell responses. Recent work revealed that physically linked MHC-I and MHC-II SLP vaccines provoked tumor growth inhibition in a preclinical squamous cell tumor model<sup>##UREF##6##82##</sup>. Determining whether incorporating an MHC-II NeoAg such as mItgb1 or even a shared, non-mutant antigen will enhance the efficacy of MHC-I NeoAg vaccines in our models is of future interest.</p>", "<p id=\"P36\">Beyond the T cell compartment, we noted a more divergent impact of NeoAg vaccines on the myeloid compartment than ICT. Both ICT and neo VAX increased M1-like iNOS<sup>+</sup> macrophages, while ICT exclusively reduced the frequency of intratumoral CX3CR1<sup>+</sup> CD206<sup>+</sup> M2-like macrophages. Although less than in control VAX (irrelevant SLP + pI:C) treated mice, neo VAX (NeoAg SLP + pI:C) treated mice displayed a greater frequency of CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages as compared to control mAb or ICT treated mice. The detailed mechanisms by which control VAX and NeoAg vaccines induce CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages and the ability of NeoAg vaccines to provoke tumor regression in an environment that is partially distinct from that exhibited with ICT is yet to be fully delineated. In MCA sarcoma models, we previously found that intratumoral macrophage subpopulations displayed the spectrum of activation states ranging from an M2-like CX3CR1<sup>+</sup> CD206<sup>+</sup> phenotype in progressively growing tumors to a proinflammatory iNOS<sup>+</sup> phenotype in tumors that will reject in response to ICT<sup>##REF##30343900##18##</sup>, consistent with findings herein. Whereas induction of iNOS<sup>+</sup> macrophages was dependent upon IFN-γ, ICT-driven depletion of CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages was partially independent of IFN-γ<sup>##REF##30343900##18##</sup>. In our vaccine setting, we hypothesize that neo VAX comprising MHC-I NeoAg SLP and p:IC favors the induction of T cell-derived IFN-γ and other signals that drives monocyte polarization to iNOS<sup>+</sup> macrophages upon entering the tumor, but other signals promote expansion or induction of CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages as well. These details of these signals are yet unknown but are likely induced by the pI:C (contained in both the control VAX and neo VAX), which acts as a TLR3 agonist in the endosome to potently induce a type IIFN response and can also activate RIG-I/MDA-5 in the cytosol to promote IL-12 production<sup>##REF##11607032##83##,##REF##22449776##84##</sup>. Although we and others use the term “M1-like” and “M2-like” to describe features that at least partially overlap with M1 or ‘classically’ activated and M2 or ‘alternatively’ activated macrophages, this is an oversimplification due to the complexity of activation and functional states of intratumoral macrophages<sup>##REF##35690521##58##</sup>. Further, it is also important to note that although CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages display expression patterns consistent with immunosuppressive macrophages, CD206 alone is not sufficient to distinguish macrophages as immunosuppressive<sup>##UREF##4##59##</sup>, as we observed CD206 expression on some macrophages expressing iNOS. Nevertheless, it is tempting to speculate that combining NeoAg vaccines that maintain or promote CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages expressing high levels of <italic toggle=\"yes\">Trem2</italic> with treatments targeting this macrophage population might enhance the efficacy of NeoAg vaccines.</p>", "<p id=\"P37\">Lastly, in both the Y1.7LI melanoma model and MC38 model, neo VAX combined with either anti-CTLA-4 or anti-PD-1 enhanced anti-tumor efficacy. Our rationale for assessing these combinations resulted from our observation that while some of the changes induced by neo VAX, as well as by ICT overlapped, distinct alterations were also noted. The unique features of each immunotherapy therefore prompted us to assess combining anti-CTLA-4 or anti-PD-1 with neo VAX and comparing efficacy to monotherapy or combination anti-CTLA-4 and anti-PD-1 ICT. We now find that combining anti-CTLA-4 or anti-PD-1 with neo VAX leads to better anti-tumor immune responses than even combination anti-CTLA-4 and anti-PD-1. While up to 20-30% of patients treated with anti-CTLA-4 or anti-PD-1 may experience durable cancer control, ~50% of metastatic melanoma patients treated with the combination of anti-CTLA-4 plus anti-PD-1 experience durable cancer control; however, immune related adverse events remain a problem<sup>##REF##33811120##85##,##REF##34818112##86##</sup>. As NeoAg vaccines have demonstrated favorable safety profiles thus far, combining NeoAg vaccines with single agent ICT may yield robust anti-tumor immunity with less toxicity than anti-CTLA-4 and anti-PD-1 combination ICT. While we find that anti-CTLA-4 or anti-PD-1 can synergize with neo VAX in different tumor models when we give the first NeoAg vaccine and ICT mAb at the same time, the timing of treatment may impact the response in different settings, as it has been shown that blockade of PD-1 in sub-primed CD8 T cells provokes PD-1<sup>+</sup> CD38<sup>+</sup> T cells that contribute to resistance to anti-PD-1 in other models and vaccine settings<sup>##REF##31358999##87##</sup>. Although our approach of targeting a single NeoAg has revealed important insights, it is likely that targeting multiple NeoAgs and possibly even shared, non-mutant antigens will be required in patients due to tumor heterogeneity and therapy induced-immunoediting, with at least some of the antigens targeted by the vaccine needing to be clonal NeoAgs<sup>##REF##26940869##88##,##REF##35594163##89##</sup>.</p>", "<p id=\"P38\">This study provides key insights into the transcriptional, molecular, and functional changes that occur within major immune cell populations within the TME following different forms of cancer immunotherapy and compliments ongoing human clinical studies of NeoAg vaccines. Although we did not fully elaborate on every specific immune cell population we profiled, our analyses were designed to interrogate the entire immune TME, and thus our study should additionally provide an important resource. Therefore, the myeloid and lymphoid cell subsets and potential biomarkers we have described herein should inform the development of improved personalized NeoAg vaccines and combinatorial therapies in human patients.</p>" ]	[]	[ "<title>SUMMARY</title>", "<p id=\"P1\">The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining intratumoral T cells with enhanced anti-tumor capabilities. However, whether therapeutic cancer vaccination and ICT achieve enhanced anti-tumor immunity by distinct or somewhat overlapping immunological mechanisms remains unclear. Considering increasing interest in combining these two types of treatment to improve efficacy rates, a better understanding of how these treatments are similar and different is needed. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) cancer vaccines with anti-PD-1, anti-CTLA-4, or anti-CTLA-4 plus anti-PD-1 combination ICT in preclinical models. We found that both NeoAg vaccines and anti-CTLA-4 and/or anti-PD-1 ICT induced robust expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was more substantial following NeoAg vaccine compared to ICT. Further, we found that NeoAg vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. Additionally, anti-CTLA-4 notably induced ICOS<sup>+</sup> Th1-like CD4 T cells expressing the transcription factor Bhlhe40 and, interestingly, when combined with anti-PD-1 a small subset of Th2-like CD4 T cells was observed. Conversely, we observed a more divergent effect on certain subsets of intratumoral macrophages induced by NeoAg vaccines as compared to ICT. Although effective NeoAg vaccines or ICT expanded M1-like iNOS<sup>+</sup> macrophages, NeoAg vaccines expanded rather than suppressed (as observed with ICT) distinct subpopulations of M2-like CX3CR1<sup>+</sup> CD206<sup>+</sup> macrophages, associated with the poly I:C adjuvant used in the vaccine. Considering the similarities and difference we identified in how NeoAg vaccines versus ICT reshaped the TME, we hypothesized that combining ICT with NeoAg vaccines would expand the therapeutic window for efficacy in these preclinical models. Indeed, we found the combination NeoAg vaccine plus ICT induced superior anti-tumor control compared to either therapy in isolation, highlighting the utility of combining these modalities to eliminate cancer.</p>" ]	[ "<title>Data and software availability</title>", "<p id=\"P65\">Data files for the sequencing data reported in this article will be deposited in the Gene Expression Omnibus (GEO) database and made publicly available at the time of publication. Software used in this study is available online: current version of Cell Ranger: <ext-link xlink:href=\"https://support.10xgenomics.com/single-cell-gene-expression/software/downloads/latest\" ext-link-type=\"uri\">https://support.10xgenomics.com/single-cell-gene-expression/software/downloads/latest</ext-link>; Seurat 4.0: <ext-link xlink:href=\"https://satijalab.org/seurat/\" ext-link-type=\"uri\">https://satijalab.org/seurat/</ext-link>; ggplot2 3.3.3: <ext-link xlink:href=\"https://ggplot2.tidyverse.org/index.html\" ext-link-type=\"uri\">https://ggplot2.tidy verse.org/index.html</ext-link>; and ImmGen: <ext-link xlink:href=\"https://www.immgen.org\" ext-link-type=\"uri\">https://www.immgen.org</ext-link>. All other data generated in this study are available within the article and its Supplementary Data files, will be provided upon request at the time of publication, and/or will made publicly available at the time of publication via deposition in appropriate databases.</p>", "<title>Supplementary Material</title>" ]	[ "<title>Acknowledgements</title>", "<p id=\"P79\">S. Keshari was a Balzan Postdoctoral Research Fellow supported by The International Balzan Prize Foundation. M.M. Gubin is a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and an Andrew Sabin Family Fellow. This work was supported by CPRIT (Recruitment of First-Time Tenure-Track Faculty Members; RR190017), an Andrew Sabin Family Foundation Fellowship, Parker Institute for Cancer Immunotherapy (PICI) Bridge Scholar Award, University of Texas (UT) Rising Stars Award, and the University of Texas MD Anderson Cancer Center (MDACC) Support Grant (CCSG) New Faculty Award supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) (P30CA016672) to M.M. Gubin; and NIH/NCI U01CA247760 to K. Chen. K.H. Hu is a CPRIT Scholar in Cancer Research and a PICI Bridge Scholar. K.E. Pauken is supported by an Andrew Sabin Family Foundation Fellowship, a Melanoma SPORE Developmental Research Program Grant, and a UT Rising STARs Award. The Flow Cytometry and Cellular Imaging Core Facility was supported in part by MDACC and NIH/NCI Core grant P30CA016672. scRNAseq was performed by the MDACC Advanced Technology Genomics Core (ATGC) Facility supported by an NCI Core grant [CA016672 (ATGC)]. We would like to thank David Pollock at MDACC ATGC Facility for assistance with scRNAseq. We would like to thank the Baylor College of Medicine MHC Tetramer Core and thank the core director, X. Lily Wang for production of MHC tetramers used in this study. We would like to thank Prachi Sao (MDACC) for assistance with deconvolution of multiplexed hashtagged scRNAseq samples. We would like to thank Mehdi Chaib, (MDACC) for providing feedback to the manuscript. The authors thank all members of the Gubin lab for helpful discussions and technical support.</p>", "<title>Authors’ Disclosures</title>", "<p id=\"P80\">K.H. Hu reports grants from Cancer Prevention and Research Institute of Texas (CPRIT), grants from Parker Institute for Cancer Immunotherapy (PICI). K. Chen reports grants from the NIH/NCI during the conduct of this study. M.M. Gubin reports grants from CPRIT (RR190017), PICI, and The University of Texas MD Anderson Cancer Center Support Grant (CCSG) New Faculty Award supported by the NIH/NCI (P30CA016672) during the conduct of the study; and a personal honorarium of $1000.00 USD per year from Springer Nature Ltd for his role as an Associate Editor for the journal Nature Precision Oncology. No disclosures were reported by the other authors.</p>" ]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1.</label><caption><title>Therapeutic NeoAg Vaccines or ICT Inhibit Tumor Growth in Mice Bearing NeoAg-Expressing <italic toggle=\"yes\">Braf</italic><sup><italic toggle=\"yes\">V600E</italic></sup>\n<italic toggle=\"yes\">Pten</italic><sup>−/−</sup>\n<italic toggle=\"yes\">Cdkn2a</italic><sup>−/−</sup> Melanoma.</title><p id=\"P81\"><bold>(A)</bold> Tumor growth and percent tumor rejection in WT C57BL/6J mice transplanted with Y1.7 mA<sup>MHC-I</sup>.mI<sup>MHC-II</sup> (Y1.7AI) and Y1.7 mL<sup>MHC-I</sup>.mI<sup>MHC-II</sup> (Y1.7LI) melanoma cells and treated with control mAb or anti-CTLA-4 immune checkpoint therapy (ICT) starting on d. 3 post tumor-transplant, and subsequently on d. 6, 9, 12, 18, 24. (<bold>B</bold>) Tumor growth, cumulative mouse survival, and percent tumor rejection in WT C57BL/6J mice transplanted with Y1.7AI and Y1.7LI melanoma cells and treated with mAlg8 or mLama4 NeoAg synthetic long peptide (SLP) plus poly I:C (pI:C) vaccines or pI:C alone starting on d. 3 post tumor-transplant and given every 6 days for total 3 doses. (<bold>C</bold>) Representative graphs displaying mAlg8 or mLama4 tetramer-specific CD8 T cells in Y1.7AI and Y1.7LI tumors treated with control mAb, anti-CTLA-4, pI:C, mAlg8 SLP + pI:C NeoAg vaccine (for Y1.7AI) or mLama4 SLP + pI:C NeoAg vaccine (for Y1.7LI) as in <bold>A</bold> and <bold>B</bold> and harvested on d. 16 post-tumor transplant. mAlg8-H2-K<sup>b</sup>, mLama4-H2-K<sup>b</sup>, or SIINFEKL-H2-K<sup>b</sup> (irrelevant control) tetramers were labeled with PE and APC. Dot plots are gated on live CD45<sup>+</sup> Thy1.2<sup>+</sup> CD8 T cells. (<bold>D</bold>) Tumor growth, cumulative mouse survival, and percent tumor rejection in WT C57BL/6J mice transplanted with Y1.7LI melanoma cells and treated with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) starting on d. 7 post tumor-transplant, and subsequently on d. 10, 13, 16, 22, 28 for ICT and d. 13, 19 for NeoAg vaccines. Tumor growth data in (<bold>A</bold>), (<bold>B</bold>), and (<bold>D</bold>) are presented as individual mouse tumor growth as mean tumor diameter and are representative of (<bold>A</bold>) five, (<bold>B</bold>) three, or (<bold>D</bold>) four independent experiments. Tumor rejection graphs display cumulative percentage of mice with complete tumor rejection from independent experiments. Cumulative survival curves and tumor rejection graphs include mice from three independent experiments (<italic toggle=\"yes\">P < 0.01, P < 0.001</italic>, log-rank (Mantel–Cox) test). Bar graphs in (<bold>C</bold>), display mean ± SEM and are representative of at least three independent experiments (<italic toggle=\"yes\">P</italic> < 0.05, <italic toggle=\"yes\">P</italic> < 0.01, <italic toggle=\"yes\">P</italic> < 0.005, NS, not significant; unpaired, two-tailed Student’s <italic toggle=\"yes\">t</italic> test).</p></caption></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2.</label><caption><title>scRNAseq of Intratumoral Immune Cells from Y1.7LI Tumor Bearing Mice Treated with NeoAg Vaccines or ICT.</title><p id=\"P82\">(<bold>A</bold>) WT C57BL/6J mice were injected with Y1.7LI melanoma cells and subsequently treated beginning on d. 7 with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) and harvested on d. 15 post-tumor transplant. Intratumoral live CD45<sup>+</sup> cells were sorted and analyzed by scRNAseq. (<bold>B</bold>) UMAP plot from scRNAseq of intratumoral CD45<sup>+</sup> cells. Cell types were annotated based on lineage marker expression. (<bold>C</bold>) Feature plot showing lineage-specific transcripts defining lymphoid and myeloid cell types. (<bold>D</bold>) Feature plots displaying subclustering of activated T cell containing clusters and subclustered T cell/ILC cluster annotations (middle plot) and <italic toggle=\"yes\">Cd4</italic> and <italic toggle=\"yes\">Cd8</italic> expression (bottom plot). (<bold>E</bold>) Table showing select genes describing each CD8 and CD4 T cell cluster. (<bold>F</bold>) Gene set enrichment analysis (GSEA) displaying significantly enriched gene sets in cluster Cd4/8<sub>Cycling</sub>. (<bold>G</bold>) Proliferating T cells in cluster Cd4/8<sub>Cycling</sub> by treatment condition represented as percentage of subclustered T cells. (<bold>H</bold>) Dot plot depicting expression level and percent of cells expressing <italic toggle=\"yes\">Foxp3, Cd4, Cd8, Ifng</italic> in Cd4/8<sub>Cycling</sub> by treatment condition. (<bold>I</bold>) Percentage of Foxp3<sup>+</sup> CD4 Tregs, conventional CD4 T cells, or CD8 T cells in Cd4/8<sub>Cycling</sub> by treatment condition. (<bold>J</bold>) Graph displaying CD8 T cells from cluster Cd4/8<sub>Cycling</sub> represented as percentage of total subclustered T cells. (<bold>K</bold>) Graph displaying CD4 T cells from cluster Cd4/8<sub>Cycling</sub> represented as percentage of total subclustered T cells.</p></caption></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3.</label><caption><title>scRNAseq Profiling of mLama4 NeoAg-Specific CD8 T cells from Y1.7LI Tumor Bearing Mice Treated with NeoAg Vaccines or ICT.</title><p id=\"P83\">(<bold>A</bold>) WT C57BL/6J mice were injected with Y1.7LI melanoma cells and subsequently treated beginning on d. 7 with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) and harvested on d. 15 post-tumor transplant. single cell suspensions of harvested tumors from treated mice were stained with SIINFEKL or mLama4 PE and APC labelled tetramers and surface stained with flow antibodies. (<bold>B</bold>) Graph displaying CD8 T cells as a percentage of intratumoral live CD45<sup>+</sup> cells in Y1.7LI tumors treated with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) and harvested on d. 15 post-tumor transplant. Graph displaying, (<bold>C</bold>) mLama4 tetramer-specific CD8 T cells and <bold>(D)</bold> mLama4 tetramer-specific CD45+ cells in Y1.7LI tumors treated with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) and harvested on d. 15 post-tumor transplant. mLama4-H2-K<sup>b</sup> or SIINFEKL-H2-K<sup>b</sup> (irrelevant control) tetramers were labeled with PE and APC. <bold>(E)</bold> WT C57BL/6J mice were injected with Y1.7LI melanoma cells and subsequently treated beginning on d. 7 with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) and harvested on d. 15 post-tumor transplant. Sorted mLama4 tetramer positive CD8 T cells were analyzed by scRNAseq. <bold>(F)</bold> UMAP plot from scRNAseq of mLama4 NeoAg-specific CD8 T cells. Cell types were annotated based on transcriptional activation states of NeoAg-specific CD8 T cells. <bold>(G)</bold> Feature plots displaying expression of select subtype or functional state defining genes. <bold>(H)</bold> Violin plots denoting expression level of select genes per neoAg-specific CD8 T cell. <bold>(I)</bold> Table showing select genes describing each NeoAg-specific CD8 T cells cluster.</p></caption></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4.</label><caption><title>NeoAg Vaccines Promote Cycling and PD-1<sup>+</sup> TCF-7<sup>+</sup> Stem-Like NeoAg-Specific CD8 T Cells and Anti-CTLA-4 and/or Anti-PD-1 ICT Induce Distinct Effects on NeoAg-Specific CD8 T Cells.</title><p id=\"P84\">(<bold>A</bold>) Heat map displaying normalized expression of select genes in each NeoAg-specific CD8 T cell cluster by treatment condition. (<bold>B</bold>) Bar graphs displaying mLama4 NeoAg-specific CD8 T cells within each cluster by treatment condition. (<bold>C</bold>) <monospace>The frequency of total</monospace> mLama4 NeoAg-specific CD8 T <monospace>cells within the combined 5 cycling clusters</monospace> by treatment condition. <bold>(D)</bold> Representative flow cytometry plots displaying PD-1<sup>+</sup> and/or TIM-3<sup>+</sup>/LAG-3<sup>+</sup> after gating on mLama4 tetramer positive CD8 T cells and graphs displaying percent of PD-1<sup>+</sup> TIM-3<sup>+</sup>/LAG-3<sup>+</sup> or expression level of PD-1, TIM-3, or LAG-3 on PD-1<sup>+</sup>, TIM-3<sup>+</sup>, or LAG-3<sup>+</sup> mLama4-specific CD8 T cells in Y1.7LI tumors treated with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, Control VAX, or neo VAX and harvested on d. 15 post-tumor transplant. Graph displaying <bold>(E)</bold> IFNγ<sup>+</sup> mLama4-specific CD8 T cells and <bold>(F)</bold> TNFα<sup>+</sup> mLama4-specific CD8 T cells assessed by intracellular cytokine staining of CD8 T cells isolated from Y1.7LI tumors under different treatment conditions and harvested on d. 15 post-tumor transplant. Bar graphs in <bold>(D), (E)</bold>, and <bold>(F)</bold> display mean ± SEM and are representative of at least three independent experiments (<italic toggle=\"yes\">P</italic> < 0.05, <italic toggle=\"yes\">P</italic> < 0.01, <italic toggle=\"yes\">P</italic> < 0.005, *** <italic toggle=\"yes\">P</italic> < 0.0001; NS, not significant, unpaired t test).</p></caption></fig>", "<fig position=\"float\" id=\"F5\"><label>Figure 5.</label><caption><title>Anti-CTLA-4 Induces an ICOS<sup>+</sup> Bhlhe40<sup>+</sup> Th1-Like Subpopulation of CD4 T Cells and when Combined with Anti-PD-1, a Small Th2-Like Subpopulation.</title><p id=\"P85\"><bold>(A)</bold> Heat map displaying normalized expression of select genes in each CD4 T cell cluster. <bold>(B)</bold> Bar graphs depicting frequency of CD4 T cells within each cluster by treatment condition. <bold>(C)</bold> Graph displaying CD4 T cells as a percentage of intratumoral live CD45<sup>+</sup> cells as determined by flow cytometry in Y1.7LI tumors under different treatment conditions and harvested on d. 15 post-tumor transplant. <bold>(D)</bold> Graph displaying IFNγ<sup>+</sup> CD4 T cells as assessed by intracellular cytokine staining on CD4 T cells isolated from Y1.7LI tumors under different treatment conditions and harvested on d. 15 post-tumor transplant. <bold>(E)</bold> Monocle 3-Guided Cell Trajectory of CD4 T Cell Clusters. UMAP plot displaying exclusively CD4 T cell-containing clusters (left) of all experimental conditions, CD4 T cell trajectory graph overlaid on UMAP (middle) where the origin of the inferred pseudotime is indicated by the red arrow and assigned with pseudotime score 0, and geodesic distances and pseudotime score among other CD4 T cells are calculated from there based on transcripts associated cell states. CD4 T cell clusters overlaid on Monocle3 pseudotime plot (right). Bar graphs in <bold>(C)</bold> and <bold>(D)</bold> display mean ± SEM and are representative of at least three independent experiments (<italic toggle=\"yes\">P</italic> < 0.05, <italic toggle=\"yes\">P</italic> < 0.01, <italic toggle=\"yes\">P</italic> < 0.005, <italic toggle=\"yes\">P</italic> < 0.0001, NS, not significant, unpaired t test).</p></caption></fig>", "<fig position=\"float\" id=\"F6\"><label>Figure 6.</label><caption><title>NeoAg Vaccines Promote Partially Distinct Macrophage Remodeling from ICT.</title><p id=\"P86\"><bold>(A)</bold> UMAP displaying sub-clustering of select myeloid clusters from CD45<sup>+</sup> scRNAseq analysis (See ##FIG##1##Figure 2A##). <bold>(B)</bold> Heatmap displaying normalized expression of select genes in each monocyte/macrophage cluster by treatment condition. <bold>(C)</bold> Percent monocytes/macrophages in each cluster by condition and treatment represented as percent of live CD45<sup>+</sup> cells. <bold>(D)</bold> Violin plots denoting expression level of <italic toggle=\"yes\">Cx3cr1</italic> transcript per cell in each monocyte/macrophage cluster by treatment condition. <bold>(E)</bold> scRNAseq dot plot depicting expression level/percent of cells expressing <italic toggle=\"yes\">Mrc1</italic> and <italic toggle=\"yes\">Cx3cr1</italic> within all monocytes/macrophages clusters by treatment condition. <bold>(F)</bold> Representative flow cytometry plots and graph displaying CX3CR1<sup>+</sup>CD206<sup>+</sup> macrophages in Y1.7LI tumors under different treatment conditions and harvested on d. 15 post-tumor transplant. <bold>(G)</bold> Violin plots denoting expression level of <italic toggle=\"yes\">Nos2</italic> (iNOS) transcript per cell in each monocyte/macrophage cluster by treatment condition. <bold>(H)</bold> Representative flow cytometry plots and graph displaying iNOS<sup>+</sup> macrophages in Y1.7LI tumors under different treatment conditions and harvested on d. 15 post-tumor transplant. For flow cytometry analysis in <bold>(F)</bold> and <bold>(H)</bold>, dot plot displaying CX3CR1<sup>+</sup>CD206<sup>+</sup> and iNOS<sup>+</sup> macrophages are gated on macrophages using a gating strategy previously described (39). Bar graphs in <bold>(F)</bold> and <bold>(H)</bold> display mean ± SEM and are representative of at least three independent experiments (<italic toggle=\"yes\">P</italic> < 0.01, ***<italic toggle=\"yes\">P</italic> < 0.0001, NS, not significant, unpaired <italic toggle=\"yes\">t</italic> test).</p></caption></fig>", "<fig position=\"float\" id=\"F7\"><label>Figure 7.</label><caption><title>NeoAg Vaccines Broaden the Therapeutic Window for Anti-CTLA-4 or Anti-PD-1 ICT when Used in Combination Against Y1.7LI and MC38 Tumors.</title><p id=\"P87\"><bold>(A)</bold> Tumor growth and cumulative survival of WT C57BL/6J mice transplanted with Y1.7LI melanoma cells on d. 0 and treated beginning on d. 12 with different monotherapies: control mAb, anti-CTLA-4, anti-PD-1, irrelevant SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX); or combination therapies: anti-CTLA-4 + anti-PD-1 combination ICT, anti-CTLA-4 + control VAX, anti-CTLA-4 + neo VAX, anti-PD-1 + control VAX, or anti-PD-1 + neo VAX. (B) Tumor growth and cumulative survival of WT C57BL/6J mice transplanted with MC38 cells on d. 0 and treated beginning on d. 12 with different monotherapies: control mAb, anti-CTLA-4, anti-PD-1, irrelevant HPV SLP + pI:C (Control VAX), or relevant mAdpgk SLP + mRpl18 SLP + mDpagt1 SLP + pI:C (neo VAX); or combination therapies: anti-CTLA-4 + anti-PD-1 combination ICT, anti-CTLA-4 + control VAX, anti-CTLA-4 + neo VAX, anti-PD-1 + control VAX, or anti-PD-1 + neo VAX. Tumor growth data in <bold>(A)</bold> and <bold>(B)</bold> are presented as individual mouse tumor growth as mean tumor diameter with fraction indicating # of mice rejecting tumor/# of mice used in experiment and are representative of three independent experiments. Cumulative survival curves in <bold>(A)</bold> and <bold>(B)</bold> include mice from three independent experiments (<italic toggle=\"yes\">P < 0.01</italic>, <italic toggle=\"yes\">P < 0.05</italic>, *<italic toggle=\"yes\">P < 0.001</italic>, log-rank (Mantel–Cox) test).</p></caption></fig>" ]	[]	[]	[ "<boxed-text id=\"BX1\" position=\"float\"><caption><title>Highlights</title></caption><list list-type=\"bullet\" id=\"L2\"><list-item><p id=\"P88\">Neoantigen vaccines utilize distinct cellular mechanisms from anti-CTLA-4 or anti-PD-1 immune checkpoint therapy.</p></list-item><list-item><p id=\"P89\">Neoantigen vaccines preferentially induce PD-1+ TCF1+ stem-like and proliferating neoantigen-specific CD8 T cells</p></list-item><list-item><p id=\"P90\">Anti-PD-1 expands PD-1+ TCF-7- NeoAg-specific Teff/Tex, with combination anti-PD-1 + anti-CTLA-4 ICT inducing robust expansion of Bhlhe40hi PD-1+ TCF-7- NeoAg-specific Teff/Tex.</p></list-item><list-item><p id=\"P91\">Anti-CTLA-4 promotes Th1-like ICOS+ Bhlhe40+ CD4 T cells, while combination anti-CTLA-4 and anti-PD-1 ICT induces a small subset of Th2-like CD4 T cells</p></list-item><list-item><p id=\"P92\">Neoantigen vaccines induce partially distinct intratumoral macrophage remodeling from immune checkpoint therapy</p></list-item><list-item><p id=\"P93\">Neoantigen vaccines in combination with anti-CTLA-4 or anti-PD-1 provides enhanced tumor protection equivalent to or even exceeding protection seen with combination anti-CTLA-4 and anti-PD-1</p></list-item></list></boxed-text>" ]	[]	[]	[]	[ "<supplementary-material id=\"SD1\" position=\"float\" content-type=\"local-data\"><label>Supplement 1</label><caption><p id=\"P66\"><bold>Supplementary Figure 1. NeoAg Vaccines and ICT Induces Long-Term Tumor Protection in Y1.7AI and Y1.7LI Melanoma Models. (A)</bold> Depiction of minigene NeoAgs used to express NeoAgs in the parental <italic toggle=\"yes\">Braf</italic><sup><italic toggle=\"yes\">V600E</italic></sup>\n<italic toggle=\"yes\">Pten</italic><sup>−/−</sup>\n<italic toggle=\"yes\">Cdkn2a</italic><sup>−/−</sup> YUMM1.7 melanoma line. mLama4 or mAlg8 and mItgb1 NeoAgs were separated by 2A peptides that induce ribosomal skipping during translation. <bold>(B)</bold> Tumor growth in WT C57BL/6J mice transplanted with parental <italic toggle=\"yes\">Braf</italic><sup><italic toggle=\"yes\">V600E</italic></sup>\n<italic toggle=\"yes\">Pten</italic><sup>−/−</sup>\n<italic toggle=\"yes\">Cdkn2a</italic><sup>−/−</sup> YUMM1.7 melanoma cells and treated with control mAb, anti-CTLA-4, anti-PD-1 or anti-CTLA4 + anti-PD-1 combination immune checkpoint therapy (ICT) on d. 3, 6, 9, 12, 18, 24 post tumor-transplant. <bold>(C)</bold> WT C57BL/6J mice were transplanted with Y1.7 mA<sup>MHC-I</sup>.mI<sup>MHC-II</sup> (Y1.7AI) and Y1.7 mL<sup>MHC-I</sup>.mI<sup>MHC-II</sup> (Y1.7LI) melanoma cells and treated with control mAb or anti-CTLA-4 on d. 3, 6, 9, 12, 18, 24 or mAlg8 NeoAg (relevant for Y1.7AI) synthetic long peptide (SLP) + poly I:C (pI:C) or mLama4 NeoAg (relevant for Y1.7LI) synthetic long peptide (SLP) + pI:C on d. 3, 9, 15. mice were rechallenged with same tumor used for initial tumor challenge at least 60 days post-rejection of primary tumor. Naïve WT C57BL/6J mice transplanted with Y1.7AI or Y1.7LI tumor without any treatment was included as control indicating cell line preps used in rechallenge experiments were capable of tumor formation. <bold>(D)</bold> WT C57BL/6J mice were transplanted with Y1.7LI melanoma cells and treated with anti-CTLA-4 ICT on d. 3, 6, 9, 12, 18, 24 or with mLama4 NeoAg SLP + pI:C on d. 3, 9, 15. Mice were rechallenged with either with same tumor used for initial tumor challenge (Y1.7LI) or parental <italic toggle=\"yes\">Braf</italic><sup><italic toggle=\"yes\">V600E</italic></sup>\n<italic toggle=\"yes\">Pten</italic><sup>−/−</sup>\n<italic toggle=\"yes\">Cdkn2a</italic><sup>−/−</sup> YUMM1.7 at least 60 days post-rejection of primary tumor. Naïve WT C57Bl6J mice transplanted with either Y1.7 LI or parental <italic toggle=\"yes\">Braf</italic><sup><italic toggle=\"yes\">V600E</italic></sup>\n<italic toggle=\"yes\">Pten</italic><sup>−/−</sup>\n<italic toggle=\"yes\">Cdkn2a</italic><sup>−/−</sup> YUMM1.7 without any treatment was included as control indicating cell line preps used in rechallenge experiments were capable of tumor formation. <bold>(E)</bold> Representative flow cytometry plots displaying mAlg8 or mLama4 tetramer-specific CD8 T cells in Y1.7AI and Y1.7LI tumors treated with control mAb, anti-CTLA-4, pI:C, mAlg8 SLP + pI:C NeoAg vaccine (for Y1.7AI) or mLama4 SLP + pI:C NeoAg vaccine (for Y1.7LI) and harvested on d. 16 post-tumor transplant. mAlg8-H2-K<sup>b</sup>, mLama4-H2-K<sup>b</sup>, or SIINFEKL-H2-K<sup>b</sup> (irrelevant control) tetramers were labeled with PE and APC. Dot plots are gated on live CD45<sup>+</sup> Thy1.2<sup>+</sup> CD8 T cells. <bold>(F)</bold> Co-expression of PD-1 and TIM-3 on mAlg8- or mLama4-specific CD8 T cells in Y1.7AI and Y1.7LI tumors treated with control mAb, anti-CTLA-4, pI:C, mAlg8 SLP + pI:C NeoAg vaccine (for Y1.7AI), or mLama4 SLP + pI:C NeoAg vaccine (for Y1.7LI). Tumor growth data in <bold>(B), (C)</bold> and <bold>(D)</bold> are presented as individual mouse tumor growth as mean tumor diameter and are representative of three independent experiments.</p><p id=\"P67\"><bold>Supplementary Figure 2. NeoAg Vaccines and ICT Induce Long-Term Tumor Protection in Y1.7LI Melanoma Models in a T Cell-Dependent Manner. (A)</bold> Y1.7LI tumor growth in WT C57BL/6J mice treated with control mAb, anti-CD4 or anti-CD8α mAbs on d. −1, 6, 13, 20 and anti-CTLA-4 or anti-PD-1 on d. 7, 10, 13, 16, 22, 28 or Irrelevant mAlg8 SLP + pI:C (Control VAX) or relevant mLama4 SLP + pI:C (neo VAX) on d. 7, 13, 19. <bold>(B)</bold> WT C57BL/6J mice transplanted with Y1.7LI melanoma cells and treated with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) starting on d. 7 post tumor-transplant, and subsequently on d. 10, 13, 16, 22, 28 for ICT and d. 13, 19 for NeoAg vaccines. Following post 60 days of primary tumor injection, mice were rechallenged with tumor used for initial tumor challenge. Naïve WT C57BL/6J mice transplanted with Y1.7 LI tumor without any treatment was included as control indicating cell line preps used in rechallenge experiments were capable of tumor formation. Tumor growth data in <bold>(A)</bold> and <bold>(B)</bold> are presented as individual mouse tumor growth as mean tumor diameter and are representative of three independent experiments.</p><p id=\"P68\"><bold>Supplementary Figure 3. scRNAseq Analysis of NeoAg Vaccines or ICT Induced Intratumoral Lymphoid and Myeloid Remodeling. (A)</bold> Graph of flow cytometry data displaying intratumoral lymphoid and myeloid cells as a percentage of intratumoral live or live CD45<sup>+</sup> cells in Y1.7LI tumors treated with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) beginning on d. 7 post-tumor transplant and harvested on d. 15. <bold>(B)</bold> Dot plot depicting expression level and percent of cells expressing <italic toggle=\"yes\">Foxp3, Ctla4, Icos, Tigit, Havcr2, Klrg1, Gzmb</italic> and graph displaying frequency of regulatory T cell (Treg) clusters by treatment condition. <bold>(C)</bold> Graph displaying mixed T cell clusters represented as percentage of total subclustered T cells; GSEA displaying significantly enriched gene sets; and percentage of Foxp3<sup>+</sup> CD4 Tregs, conventional CD4 T cells, or CD8 T cells in clusters T_1, T_2; and T_3 by treatment condition. <bold>(D)</bold> Graph displaying γδ T cell clusters represented as percentage of total subclustered T cells by treatment condition. <bold>(E)</bold> Graph displaying ILC clusters represented as percentage of total subclustered T cells by treatment condition. Bar graphs in <bold>(A)</bold> display mean ± SEM and are representative of at least three independent experiments (<italic toggle=\"yes\">P</italic> < 0.05, <italic toggle=\"yes\">P</italic> < 0.01, <italic toggle=\"yes\">P</italic> < 0.005, **<italic toggle=\"yes\">P</italic> < 0.0001, NS, not significant, unpaired t test).</p><p id=\"P69\"><bold>Supplemental Figure 4. Heatmap displaying normalized expression per cell of top 10 cluster-defining genes for each T cell/ILC Cluster</bold> (see ##FIG##1##Figure 2D##).</p><p id=\"P70\">Supplemental Figure 5. Heatmap displaying normalized expression of select genes in each T cell/ILC cluster by treatment condition.</p><p id=\"P71\">Supplemental Figure 6. scRNAseq Analysis of Bulk CD8 T cells from Y1.7LI Tumor Bearing Mice Treated with NeoAg Vaccines or ICT. <bold>(A)</bold> Heat map displaying normalized expression of select genes in each bulk CD8 T cell clusters (see ##FIG##1##Figure 2A## and ##FIG##1##2D##). <bold>(B-F)</bold> scRNAseq dot plot depicting expression level/percent of cells expressing select transcripts, GSEA displaying significantly enriched gene sets, and bar graphs depicting frequency of bulk CD8 T cells within each cluster by treatment condition.</p><p id=\"P72\">Supplemental Figure 7. scRNAseq and Flow Cytometry Profiling of mLama4 NeoAg-Specific CD8 T cells from Y1.7LI Tumor Bearing Mice Treated with NeoAg Vaccines or ICT. <bold>(A)</bold> Representative flow cytometry plots displaying mLama4 tetramer-specific CD8 T cells in Y1.7LI tumors treated with control mAb, anti-CTLA-4, anti-PD-1, anti-CTLA-4 + anti-PD-1, irrelevant (for Y1.7LI) mAlg8 SLP + pI:C (Control VAX), or relevant mLama4 SLP + pI:C (neo VAX) and harvested on d. 15 post-tumor transplant. mLama4-H2-K<sup>b</sup> or SIINFEKL-H2-K<sup>b</sup> (irrelevant control) tetramers were labeled with PE and APC. Dot plots are gated on live CD45<sup>+</sup> Thy1.2<sup>+</sup> CD8 T cells. <bold>(B)</bold> Heatmap displaying normalized expression of select genes in each NeoAg-specific CD8 T cell clusters (see ##FIG##2##Figure 3E##). <bold>(C)</bold> scRNAseq dot plot depicting expression level/percent of cells expressing select transcripts within each cluster by treatment condition.</p><p id=\"P73\">Supplemental Figure 8. Heatmap displaying normalized expression per cell of top 10 cluster-defining genes for each NeoAg-specific CD8 T cells cluster (see ##FIG##2##Figure 3E##).</p><p id=\"P74\">Supplemental Figure 9. scRNAseq Profiling od CD4 T cells indicates Anti-CTLA-4 Induces an ICOS<sup>+</sup> Bhlhe40<sup>+</sup> Th1-Like Subpopulation of CD4 T Cells and when Combined with Anti-PD-1, a Small Th2-Like Subpopulation. <bold>(A-E and G)</bold> scRNAseq dot plots depicting expression level/percent of cells expressing select transcripts and GSEA displaying significantly enriched gene sets within each CD4 T cells cluster by treatment condition (see ##FIG##1##Figure 2D##). <bold>(F)</bold> Violin plots denoting expression level of expression level of select genes per CD4 T cells.</p><p id=\"P75\">Supplemental Figure 10. Dendritic Cell (DC) Changes Induced by ICT and NeoVAX in Y1.7LI Tumors. <bold>(A)</bold> UMAP displaying myeloid cell sub-clustering and DC annotations (See ##FIG##1##Fig. 2A## and ##FIG##5##6A##). <bold>(B)</bold> Heatmap displaying normalized expression of select genes in each DC cluster. <bold>(C-G)</bold> scRNAseq dot plot depicting expression level/percent of cells expressing select transcripts and bar graphs depicting frequency of DCs within each cluster by treatment condition.</p><p id=\"P76\">Supplemental Figure 11. Heatmap displaying normalized expression of select genes in each monocyte/macrophage cluster by treatment condition.</p><p id=\"P77\"><bold>Supplemental Figure 12. Principal Component Analysis of Subclustered T Cells/ILCs.</bold> Each dot represents individual sample from different treatment conditions (see ##FIG##1##Figure 2A## and ##FIG##1##2D##).</p><p id=\"P78\">Supplemental Figure 13. Gating Strategy for Identifying Intratumoral Immune Cells. Flow cytometry dot plots and gating of intratumoral myeloid and lymphoid populations.</p></caption></supplementary-material>", "<supplementary-material id=\"SD2\" position=\"float\" content-type=\"local-data\"><label>Supplement 2</label></supplementary-material>" ]	[]	[ "<graphic xlink:href=\"nihpp-2023.12.20.570816v1-f0001\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.20.570816v1-f0002\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.20.570816v1-f0003\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.20.570816v1-f0004\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.20.570816v1-f0005\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.20.570816v1-f0006\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.20.570816v1-f0007\" position=\"float\"/>" ]	[ "<media xlink:href=\"media-1.pdf\" id=\"d64e3259\" position=\"anchor\"/>", "<media xlink:href=\"NIHPP2023.12.20.570816v1-supplement-2.pdf\" id=\"d64e3262\" position=\"anchor\"/>" ]	[{"label": ["5"], "surname": ["Carreno"], "given-names": ["B. M."], "article-title": ["A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells"], "source": ["Science"], "pub-id": ["10.1126/science.aaa3828"], "year": ["2015"]}, {"label": ["20"], "surname": ["Salmon"], "given-names": ["A. J."], "article-title": ["BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint-Therapy Efficacy"], "source": ["Cancer Immunol Res"], "pub-id": ["10.1158/2326-6066.CIR-21-0129"], "year": ["2022"]}, {"label": ["47"], "surname": ["Chiang", "Mellman"], "given-names": ["E. Y.", "I."], "article-title": ["TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy"], "source": ["J Immunother Cancer"], "volume": ["10"], "pub-id": ["10.1136/jitc-2022-004711"], "year": ["2022"]}, {"label": ["49"], "surname": ["Pauken"], "given-names": ["K. E."], "article-title": ["Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment"], "source": ["J Exp Med"], "volume": ["218"], "pub-id": ["10.1084/jem.20200920"], "year": ["2021"]}, {"label": ["59"], "surname": ["Ray"], "given-names": ["A"], "article-title": ["Critical role of CD206+ macrophages in organizing anti-tumor immunity"], "source": ["bioRxiv"], "pub-id": ["10.1101/2023.10.31.560822"], "year": ["2023"]}, {"label": ["61"], "surname": ["Kemp"], "given-names": ["S. B."], "article-title": ["Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages"], "source": ["Life Sci Alliance"], "volume": ["4"], "pub-id": ["10.26508/lsa.202000935"], "year": ["2021"]}, {"label": ["82"], "surname": ["Dolina"], "given-names": ["J. S."], "article-title": ["Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression"], "source": ["J Clin Invest"], "volume": ["133"], "pub-id": ["10.1172/JCI164258"], "year": ["2023"]}]	{ "acronym": [], "definition": [] }	89	CC BY	no	2024-01-13 00:14:50	bioRxiv. 2023 Dec 22;:2023.12.20.570816	oa_package/4d/ca/PMC10769249.tar.gz
PMC10769253	38187726	[ "<title>INTRODUCTION</title>", "<p id=\"P4\">As of November 2023, the COVID-19 pandemic has claimed approximately 7 million lives globally, and the emergence of new SARS-CoV-2 variants continues to be a challenge (##UREF##0##1##). Neutralizing antibodies (nAbs) from active immunization remain protective immune correlates against SARS-CoV-2 infection (##REF##36507702##2##–##REF##33412089##7##). The target for nAbs against SARS-CoV-2 is the spike (S) protein on the virion surface (##UREF##1##8##, ##REF##32991844##9##). The SARS-CoV-2 S is a trimeric type I fusion protein (##REF##32991844##9##–##REF##34611326##13##) cleaved by proteases into S1 and S2 domains. The receptor binding domain (RBD), located within the S1 domain of spike, engages the viral receptor ACE2 on target cells (##REF##32694201##14##). The S2 domain mediates fusion with the target cell membrane (##REF##35087058##11##–##REF##32694201##14##). The spike trimer has a dynamic structure, where the receptor binding domain can adopt various positions (##UREF##2##15##). When engaging the host receptor ACE2, the RBD is in the “up” conformation. The RBD stochastically samples the “up” and “down” positions (##UREF##3##16##, ##REF##32699321##17##). Hence, the RBD on individual protomers of the trimeric S protein can adopt different positions where all three or only a subset of RBDs can be in the up position (##REF##32991844##9##, ##REF##32075877##10##).</p>", "<p id=\"P5\">Over half a billion doses of mRNA encapsulated in lipid nanoparticle (Mrna-LNP) vaccines from Pfizer and Moderna have been administered in the United States (##UREF##4##18##). Initially, each of these vaccines encoded the S protein from the ancestral Wuhan Hu-1 or WA-1 isolates that was presumed to be stabilized in the prefusion state by including diproline substitutions K986P and V987P (S-2P) (##REF##34133867##19##). These same substitutions improved neutralizing antibody elicitation of SARS-CoV-1 and MERS-CoV, and thus were thought to function similarly in the context of SARS-CoV-2 (##REF##28807998##20##, ##REF##32703906##21##). However, side-by-side biochemical analyses revealed the 2P mutations did not increase expression of trimeric SARS-CoV-2 Spike protein, thermostability, or antigenicity (##REF##33417835##22##). Moreover, cryo-electron microscopy studies showed the overall structures of S with or without the diproline substitutions to be highly similar with an overall root mean square deviation of 0.54(##REF##33417835##22##). In mice, the 2P substitutions were not required for potent immunogenicity of SARS-CoV-2 spike (##REF##37085495##23##). It should also be noted that the Oxford-AstraZeneca COVID-19 vaccine developers chose to express from an adenoviral vector spike without the 2P substitutions for their vaccine (##REF##33306990##24##, ##REF##33306989##25##). Thus, despite the successes of the authorized mRNA-LNP vaccines encoding S-2P, the effects of the 2P substitutions on immunogenicity of SARS-CoV-2 S remains unclear.</p>", "<p id=\"P6\">The relationship between immunogenicity of RBD relative to its conformational dynamics has yet to be fully explored but could inform the design of next generation COVID-19 vaccines (##REF##37085495##23##). Cryo-electron microscopy structures of S protein with or without 2P substitutions showed particles with either 1 RBD up or 3 RBDs up (##REF##32075877##10##, ##REF##32699321##17##, ##REF##32703906##21##, ##REF##33417835##22##, ##REF##32155444##26##, ##REF##35654847##27##). Previously, we designed a spike with a <italic toggle=\"yes\">de novo</italic> disulfide bond that prevented the RBD from transitioning to the up state (##REF##32699321##17##). Structural studies of this stabilized version of SARS-CoV-2 S showed all three RBDs were most frequently in the down position (##REF##32699321##17##). While RBD neutralizing antibodies such as DH1041 (RBD-1 community) or the RBD inner face Ab DH1047 (RBD-6/7 community), which spans across RBD-6 and 7 epitopes, bind to the up conformation of RBD, it is unknown if an S with RBDs usually in the down state would elicit RBD neutralizing antibody responses.</p>", "<p id=\"P7\">Sarbecoviruses circulating in bats that have the ability to infect primary airway human cells <italic toggle=\"yes\">in vitro</italic> are considered pre-emergent threats for zoonotic transmission (##REF##28214731##28##, ##REF##26552008##29##). <italic toggle=\"yes\">Sarbecovirus</italic> cross-nAb DH1047 protects against bat coronavirus infection (##REF##34726473##30##,##REF##34242577##31##), but is unable to neutralize Omicron VOCs (##REF##35732171##32##). The escape of the Omicron sublineage from the RBD-6/7 community antibody DH1047 raises the question of whether vaccination or infection can elicit a single antibody that simultaneously neutralizes multiple zoonotic SARS-related Sarbecoviruses as well as recent SARS-CoV-2 VOCs.</p>", "<p id=\"P8\">Here, we show that 2P stabilization of transmembrane spike was not required for mRNA-LNP elicitation of either broad sarbecovirus or broad SARS-CoV-2 VOC nAbs. Rather both types of SARS-CoV-2 bnAbs were induced by mRNA-encoded spike lacking 2P substitutions. Such a polyclonal response provides one mechanism for how SARS-CoV-2 spike can induce broad protective antibodies against SARS-CoV-2 VOCs as well as bat zoonotic pre-emergent Sarbecoviruses.</p>" ]	[ "<title>MATERIALS AND METHODS</title>", "<title>Rhesus macaques and immunizations</title>", "<p id=\"P22\">Rhesus macaques used in this study were housed and treated in AAALAC-accredited institutions. The study protocol and all veterinarian procedures were approved by the Bioqual IACUC per a memorandum of understanding with the Duke IACUC and were performed based on standard operating procedures. Nucleoside-modified messenger RNA encapsulated in lipid nanoparticles (mRNA-LNP) encoding different versions of SARS-CoV-2 spike or RBD was prepared as previously stated(##REF##32783919##33##). Rhesus macaques were on average 8 or 9 years old, and their body weights ranged from 2.75 to 8 kg. 8 rhesus macaques were allocated into each group and immunized intramuscularly with 50μg of mRNA-LNP encoding the monomer receptor-binding domain (RBD), full-length spike protein stabilized with K986P/V987P mutations (Spike 2P), full-length spike protein stabilized with S483C/D985C/K986P/V987P (Spike 2C 2P), or wild-type spike without any stabilization mutations. Balance of male and female animals per group was considered when macaque availability permitted. Studies were performed unblinded. Animals were observed and evaluated by Bioqual veterinary staff throughout immunizations and no significant abnormalities were noted in obtained CBCs and chemistries.</p>", "<title>SARS-CoV-2 intranasal and intratracheal challenge</title>", "<p id=\"P23\">Infectious dose of 10<sup>5</sup> PFU of SARS-CoV-2 (2019-nCoV/USA-WA1/2020) was selected to challenge all animals. Aliquots of virus were stored at −80°C and thawed by hand and placed immediately on wet ice. Prior to inoculation, the stock was diluted to 2.5×10<sup>4</sup> PFU/mL in PBS and vortexed for 5 seconds and 3mL of diluted virus were administered to animals in combined intratracheal and intranasal routes. Nasal swabs, bronchoalveolar lavage (BAL), plasma, and serum samples were collected at 0, 2, 4, 7 days post-challenge. Animals were necropsied and lungs were harvested on Day 7 post-challenge for histopathology and immunohistochemistry (IHC) analysis.</p>", "<title>SARS-CoV-2 pseudovirus neutralization</title>", "<p id=\"P24\">Neutralization of SARS-CoV-2 Omicron Spike-pseudotyped virus was performed by adopting an infection assay described previously (##REF##32697968##49##). Mutations for BA.1, BA.4/5, BA.4.6, BA.2.75.2, BF.7, BQ.1., XBB.1, or XBB.1.5 were introduced into an expression plasmid encoding codon-optimized full-length spike of the Wuhan-1 isolate (VRC7480) VRC7480 by site-directed mutagenesis and confirmed by full-length spike gene sequencing by Sanger Sequencing. Pseudovirions were produced in HEK293T/17 cells following a co-transfection of spike plasmid, lentiviral backbone plasmid (pCMV ΔR8.2) and firefly Luc reporter gene plasmid (pHR’ CMV Luc) in a 1:17:17 ratio in Opti-MEM. Transfection mixtures were then added to pre-seeded HEK 293 T/17 cells and incubated for 16–20 hours at 37°C. After the incubation, medium was removed and replaced with fresh growth medium. A pre-determined dose of virus was incubated with serially diluted monoclonal antibodies or heat inactivated serum. HEK 293T/17 cells expressing ACE2 were suspended using TrypLE express enzyme solution and immediately added to all wells. Control wells received HEK 293T/17 cells and virus control and another set received cells only and was assessed as background control. After 66–72 h of incubation of cells and monoclonal antibodies, medium was removed, 1x lysis was added and incubated for 10 minutes at room temperature. At the end of the incubation, Bright- Glo luciferase reagent was added to all wells. After 1–2 minutes, luminescence was measured using a luminometer. Neutralization titers were quantified as serum dilution (ID50/ID80) at which relative luminescence units (RLU) were reduced by 50% and 80% compared to virus control wells after subtraction of background.</p>", "<p id=\"P25\">For pseudovirus assays with SARS-CoV-2 WA-1, D614G, B1.1.7, B.1.351, P.1, B.617.2, B.617.1, B.1.429, B.1.526, 50 μL of SARS-CoV-2 S pseudovirions were pre-incubated with an equal volume of medium containing serum at varying dilutions at room temperature for 1 h, then virus-antibody mixtures were added to 293T-ACE2 (WA-1 and B.1.351 assays) or 293-ACE2-TMPRSS2 (WA-1 and P.1 assays) cells in a 96-well plate. After a 3 h incubation, the inoculum was replaced with fresh medium. Cells were lysed 24 h later, and luciferase activity was measured using luciferin. Controls included cell only control, virus without any antibody control and positive control sera. Neutralization titers are the serum dilution (ID50/ID80) at which relative luminescence units (RLU) were reduced by 50% and 80% compared to virus control wells after subtraction of background RLUs.</p>", "<title>Live virus neutralization assays</title>", "<p id=\"P26\">Live virus assays were performed with SARS-CoV-1 Urbani, SARS-CoV-2 D614G, and RsSHC014 designed to express nanoluciferase (nLuc) (##REF##32540900##50##, ##REF##32454512##51##). For the live virus neutralization assays, cells were plated at 20,000 cells per well in clear bottom, black-walled 96-well plates the day prior to the assay. On the day of the assay, monoclonal antibodies were serially diluted 3-fold for eight dilutions. Serially diluted antibody was added at a 1:1 volume with diluted virus and incubated for 1hr. Antibody-virus dilutions were then added to cells and incubated at 37°C with 5% CO2. Following a 24hr incubation, luminescence was generated by adding 25 μL of Nano-Glo Luciferase Assay System (Promega). Spectramax M3 plate readers (Molecular Devices) were used to measure luminescence. The inhibitory concentration that resulted in a fifty percent reduction in luminescence virus was calculated using GraphPad Prism via four-parameter dose-response curves.</p>", "<title>Serum and antibody binding ELISA</title>", "<p id=\"P27\">For direct binding assays, 384-well plates were coated with 15μl/well of diluted antigen in 0.1 M sodium bicarbonate and stored at 4°C overnight. On the following day, plates were washed with PBS +0.05% Tween 20 (Superwash) and subsequently blocked with 40μl/well using PBS containing 4% (w/v) whey protein, 15% Normal Goat Serum, 0.5% Tween-20, and 0.05% Sodium Azide (SuperBlock) for 1 hour at room temperature. Purified monoclonal antibodies were serially diluted (3-fold). Positive and negative controls for each antigen were included for each plate. The starting concentration of the purified monoclonal antibodies was typically 100μg/ml and for serum 1:30. After 1 hour of blocking, plates were washed with Superwash and serially diluted samples and controls were added to the plate at 10μl/well and incubated plates for 1 hour at room temperature. After the incubation, plates were washed with Superwash and 10 μl/well of HRP-conjugated secondary antibody diluted in Superblock without Sodium Azide was added to the plates and incubated for 1 hour at room temperature.</p>", "<p id=\"P28\">After incubation, plates were washed with Superwash and TMB substrate was added at 20μl/well and incubated at room temperature for 15 minutes. After the incubation, the reaction was stopped using 1% HCl solution at 20μl/well. Absorbance values were read at 450nm using SoftmaxPro ELISA microplate reader.</p>", "<title>ACE2 and neutralizing antibody blocking assay</title>", "<p id=\"P29\">Recombinant ACE-2 protein was diluted to 2 μg/mL in filtered 0.1M sodium bicarbonate. 384 well ELISA plates were coated with 15 μL/well of coating solution and incubated overnight at 4°C. Following day, plates were washed and blocked with 40 μL/well using 3% BSA in PBS. Plates were then incubated for 1 hour at room temperature. In a separate tube, SARS-CoV-2 spike was diluted to 0.4 μg/ml in 1% BSA/0.05% Tween-20 in PBS. Macaque sera were diluted to 1:25. If purified antibodies were used, the serial dilution of antibodies was performed and the starting concentration was 100 μg/ml, titrated 3-fold in 1% BSA/0.05% Tween-20 in PBS. Spike-2P protein was mixed with the diluted sera or antibodies at a final Spike concentration equal to the EC50 at which spike binds to ACE-2 protein. The mixture was incubated at room temperature for 1 hour.</p>", "<p id=\"P30\">After the blocking step, plates were washed, and the antibody-spike mixture was added to ACE2 coated wells and incubated for 1 hour at room temperature. Plates were washed and a polyclonal rabbit serum against SARS-CoV-2 spike was added and incubated for 1 hour following a wash step and detection of binding with goat anti rabbit-HRP (Abcam catalog # ab97080). TMB substrate was added to the plates for detection of HRP. Hydrochloric acid was added to the plat to stop the detection reaction. Well absorbance was read at 450 nm. Percent blocking was calculated as follows: blocking % = (100 − (Optical Density of antibody plus Spike/Optical Density of Spike only)*100)</p>", "<title>Plasma and IgG blocking of RBD monoclonal antibody binding.</title>", "<p id=\"P31\">Blocking assays for DH104, DH1042, DH1044, DH1047, DH1073, DH1235, DH1284, DH1193, DH50.1, DH1052, S409, CR3022, SP1–77 were performed as stated above for ACE2, except plates were coated with the binding antibody of interest instead of ACE2 and used biotinylated version of the binding antibody as detection antibody.</p>", "<title>Subgenomic RNA real time PCR quantification</title>", "<p id=\"P32\">The measuring of SARS-CoV-2 E gene and N gene subgenomic mRNA was done using one-step RT-qPCR. The assay was adapted from previously described methods as described previously (##REF##32697968##49##).</p>", "<title>Histopathology and immunohistochemistry</title>", "<p id=\"P33\">Lung specimen from individual animals were fixed in 10% neutral-buffered formalin, processed, and blocked in paraffin for histology analyses. All tissues were sectioned at 5 μm and stained with hematoxylin-eosin (H&E) to assess histopathology. Stained sections were evaluated by a board-certified veterinary pathologist in a blinded manner. Olympus BX51 microscope and Olympus DP73 camera were used to obtain the photographs. The representative images for each group are shown.</p>", "<p id=\"P34\">For immunohistochemistry (IHC) staining for SARS-CoV-2 nucleocapsid antigen, Bond RX automated system with the Polymer Define Detection System (Leica) was used following the manufacturer’s protocol. Briefly, tissue sections were dewaxed with Bond Dewaxing Solution (Leica) at 72°C for 30 minutes. At the end of incubation, the sections were rehydrated with graded alcohol washes and 1x Immuno Wash (StatLab). Heat-induced epitope retrieval (HIER) was performed using Epitope Retrieval Solution 1 (Leica) and along with heating the tissue section to 100°C for 20 minutes. To quench endogenous peroxidase activity prior to applying the SARS-CoV-2 nucleocapsid antibody, a peroxide block (Leica) was applied for 5 min (1:2000, GeneTex, GTX135357). To minimize the background, antibodies were diluted in Background Reducing Antibody Diluent (Agilent) and subsequently incubated with an anti-rabbit HRP polymer (Leica) and colorized with 3,3’-Diaminobenzidine (DAB) chromogen for 10 minutes, and at the end slides were counterstained with hematoxylin.</p>", "<title>Antigen-specific single B cell sorting</title>", "<p id=\"P35\">Antigen-specific single macaque B cell sorting was performed as described previously with modifications (##REF##36070369##52##). Briefly, cryopreserved peripheral blood mononuclear cells (PBMC) were processed and stained with natural killer (NK), T, and B cell surface markers and fluorophore- labeled SARS-CoV-2 Spike and RBD proteins. Antibodies used for staining were CD20 fluorescein isothiocyanate (FITC) clone L27 (BD Biosciences Cat No. 347673), CD3 peridinin chlorophyll protein (PerCP) Cy5.5 clone SP34-2 (BD Biosciences Cat No. 552852), IgD phycoerythrin (PE) polyclonal (Southern Biotech Cat No. 2030–09), CD8 PE Texas Red clone 3B5 (Invitrogen Cat No. MHCD0817), IgM PE Cy5 clone G20–127 (BD Biosciences Cat No. 551079), CD16 PE Cy7 clone 3G8 (BD Biosciences Cat No. 557744), Live / Dead Aqua (Invitrogen Cat No. L34957), CD14 brilliant violet (BV) 570 clone M5E2 (BioLegend Cat No. 301832), and CD27 allophycocyanin (APC) Cy7 clone O323 (BioLegend Cat No. 302816). SARS-CoV-2 Spike and/or RBD reactive, live, IgD- single B cells were sorted into 96-well PCR plate where each B cell is separated into a single well that contained cell lysis buffer and 5X first-strand synthesis buffer and subjected to reverse transcription of RNA.</p>", "<title>Antibody gene RT-PCR.</title>", "<p id=\"P36\">Antibody gene RT-PCR was performed as detailed before with modifications (##REF##36070369##52##). Briefly, Superscript III (Thermo Fisher Scientific Cat No. 18080044) and immunoglobulin constant region-specific reverse primers were used to reverse transcribe B cell RNA. Two rounds of nested PCR were performed using 5 μL of complementary DNA (cDNA) to amplify immunoglobulin heavy and light chain variable regions and yielding variable regions were confirmed by using 96 well E-gel agarose electrophoresis (Thermo Fisher Scientific). Purified PCR amplicons were then sequenced with forward and reverse primers and contigs of the amplified immunoglobulin sequences were made by the Duke automated sequence analysis pipeline (Duke ASAP). Immunogenetics of rhesus macaque and human immunoglobulin genes were determined with the macaque reference library using Cloanalyst. Simultaneously, to express antibodies in small scall that are required for binding screens, purified PCR amplicon was used for overlapping PCR and generated a linear expression cassette. The expression cassette was transfected into Expi293F cells (Thermo Fisher Scientific, Cat No. A14527) supernatant of the cell culture media were tested for binding to distinct SARS-CoV-2 spike antigens. Based on the positive binding data, antibodies were down selected for gene synthesis. The synthesized heavy and light chains were cloned into gamma, kappa, or lambda expression vectors (GenScript) and subjected to transient transfection of Expi293F cells purify immunoglobulin heavy and light chain plasmids.</p>", "<title>Recombinant antibody expression.</title>", "<p id=\"P37\">Recombinant antibody expression was performed as described elsewhere (##REF##36070369##52##). Briefly, Expi293F cells were co-transfected with heavy and light chain plasmid using Expifectamine (Thermo Fisher Scientific, Cat No. A14526) per the manufacturer’s protocol. Cells were harvested and centrifuged post 5 days transfection, and the cell culture supernatant was concentrated and incubated with protein A beads overnight at 4 °C. The mixture of protein A beads (Thermo Fisher Scientific) and supernatant was centrifuged. Protein A resin was washed by resuspending it in 25 mL of Tris-buffered saline pipetted into an empty gravity flow column followed by an elution step using 2% glacial acetic acid. The pH was neutralized by adding 1M Tris pH8.0 to a final pH of 6. The eluate was concentrated and buffer exchanged into 25 mM sodium citrate pH6, 150 mM NaCl pH6. The purified IgG monoclonal antibodies were run in SDS-PAGE followed by Coomassie blue staining and western blot to confirm correct molecular weights.</p>", "<title>SARS-CoV-2 protein production</title>", "<p id=\"P38\">The human and animal coronavirus ectodomain constructs were produced and purified as described previously (##REF##32075877##10##, ##REF##34242577##31##). The full-length spike proteins were stabilized by introducing 2 prolines at amino acid positions 986 and 987 (Spike 2P) and transiently transfected in FreeStyle 293-F cells using Turbo293 (SpeedBiosystems) or 293Fectin (ThermoFisher). The constructs contained an HRV3C-cleavage site followed by His and/or streptagII tags for purification purposes. Post 6-days transfection, protein was purified using cell-free culture supernatant by StrepTactin resin (IBA) and by size-exclusion chromatography using Superdex 200 (RBD and NTD) or Superose 6 (S-2P) column (GE Healthcare) in 10 mM Tris pH8, 500 mM NaCl. In some cases, after affinity chromatography, the tag sequences were cleaved by HRV3C digestion prior to size exclusion chromatography. ACE2-Fc was expressed by transient transfection of Freestyle 293-F cells and purified from cell culture supernatant by HiTrap protein A column chromatography followed by Superdex200 size-exclusion chromatography in 10 mM Tris pH8,150 mM NaCl.</p>", "<title>Negative stain electron microscopy</title>", "<p id=\"P39\">Antibody-spike complexes with DH1329 and DH1333 were made by mixing the corresponding full-length IgG with D614G 2P spike at a 1.5 to 1 molar ratio; Fab-spike complexes with DH1047, DH1193, DH1328, DH1337, and DH1338 were made by mixing the corresponding Fab with Hexapro spike at a 9 to 1 molar ratio; and Fab-spike complex of DH1044 was made by mixing Fab with 2P spike at a 9 to 1 molar ratio. All complexes were incubated for one hour at 37 °C then processed for NSEM. For NSEM, complexes were brought to room temperature and crosslinked by diluting with HBS-buffer containing 20 mM HEPES, 150 mM NaCl, and 8 mM glutaraldehyde, pH 7.4, with sufficient buffer added for a nominal final spike concentration of 0.2 mg/ml. After crosslinking for five minutes at room temperature, excess glutaraldehyde was quenched by adding sufficient 1 M Tris stock, pH 7.4 for a final Tris concentration of 80 mM and incubating for 5 minutes at room temperature. Quenched samples were then applied directly to a glow-discharged carbon-coated EM grid for 10–12 second, then blotted and stained with 2 g/dL uranyl formate for 1 min, blotted and air-dried. Grids were examined on a Philips EM420 electron microscope operating at 120 kV. Dataset were collected for DH1044 and DH1047 at a nominal magnification of 82,000x and recorded on a 4 Mpix CCD at 4.02 Å/pixel. All subsequent datasets were collected at a nominal magnification of 49,000x and recorded on a 76 Mpix CCD camera at 2.4 Å/pixel. Images were analyzed by 2D class averages, 3D classifications, and final 3D reconstructions calculated using standard protocols with Relion 3.0 (69).</p>", "<title>Cryo-Electron microscopy of antibody-Spike complexes</title>", "<p id=\"P40\">Purified SARS-CoV-2 spike ectodomains were diluted to a concentration of ~ 1.5 mg/mL in 2 mM Tris pH 8.0, 200 mM NaCl and 0.02% NaN3 and 0.5% glycerol was added. A 2.4-μL drop of protein was deposited on a Quantifoil-1.2/1.3 grid (Electron Microscopy Sciences, PA) that had been glow discharged for 10 s using a PELCO easiGlow Glow Discharge Cleaning System. After a 30 s incubation in >95% humidity, excess protein was blotted away for 2.5 s before being plunge frozen into liquid ethane using a Leica EM GP2 plunge freezer (Leica Microsystems). Frozen grids were imaged using a Titan Krios (Thermo Fisher) equipped with a K3 detector (Gatan). The cryoSPARC (##REF##28165473##53##) software was used for data processing. Phenix (##REF##31588918##54##, ##REF##29872004##55##), Coot (##REF##20383002##56##), Pymol (##UREF##6##57##), Chimera (##REF##15264254##58##), ChimeraX (##REF##28710774##59##) and Isolde (##REF##29872003##60##) were used for model building and refinement.</p>", "<title>Mouse passive protection experiments</title>", "<p id=\"P41\">Twelve-month old female immunocompetent BALB/c mice purchased from Envigo (stock# 047) were used for passive immunization protection experiments. Mice were housed in groups of five animals per cage and fed standard chow diets. Mice were anesthetized with ketamine and xylazine prior to performing viral inoculations. Anesthetized mice were intranasally infected at 1×10<sup>4</sup> PFU with RsSHC014-MA15 as described previously (##REF##34237773##40##). For prophylaxis passive immunization experiments, mice were intraperitoneally injected with DH1338 at 15mg/kg or with flu IgG (CH65) at 15mg/kg 12 hours before infection. For the therapy passive immunization experiments, mice were intraperitoneally injected with DH1338 at 15mg/kg six hours post infection. Each treatment group contained N=9–10 mice. Following infection, mice were monitored daily for signs of disease. Ninety-six hours post infection, mice were sacrificed, lungs were harvested, and infectious virus replication was measured by plaque assays. All mouse studies were carried out in accordance with the recommendations for care and use of animals by the Office of Laboratory Animal Welfare (OLAW), National Institutes of Health and the Institutional Animal Care. Mouse studies performed at the University of North Carolina at Chapel Hill (Animal Welfare Assurance #A3410–01) using approved protocols by the Institutional Animal Care and Use Committee (IACUC). Mouse passive immunization and virus challenge experiments were performed in a biosafety level 3 (BSL3) facility at UNC Chapel Hill.</p>", "<title>Statistics Analysis</title>", "<p id=\"P42\">Data were plotted using Prism GraphPad 9.0. When appropriate, the area under the curve (AUC) was calculated using the linear trapezoidal method for longitudinal data (weeks 0–12). Wilcoxon rank-sum exact tests were performed to make comparisons between groups with an alpha level set at 0.05. The statistical analysis was performed using SAS 9.4 (SAS Institute). No adjustments were made to the alpha level for multiple comparisons, thus p < 0.05 is considered significant.</p>" ]	[ "<title>RESULTS</title>", "<title>Immunogenicity of engineered and wildtype SARS-CoV-2 spike</title>", "<p id=\"P9\">To investigate the effects of spike stabilization on immunogenicity and protection from infection in non-human primates, we generated nucleoside-modified mRNA-LNP vaccines encoding Wuhan-Hu-1 full-length transmembrane spike with two different potential stabilization strategies. First, the spike was stabilized with the diproline substitutions and termed S-2P. Second, the diproline substitutions were introduced into spike in combination with S483C and D985C (S-2C 2P)substitutions. Recombinant S-2C 2P has been previously shown to have RBDs predominantly in the down position (##REF##32699321##17##). For comparison, transmembrane spike lacking any stabilization substitutions (S-tm) was also designed as an mRNA. Each of the three spike designs had the furin cleavage site replaced with a glycine-serine-alanine linker. We also generated an mRNA-LNP encoding the Wuhan-Hu-1 RBD to compare bnAb elicitation to non-stabilized (##REF##32783919##33##) and stabilized full-length spike (##FIG##0##Fig. 1A##). As a negative control, we produced mRNA-LNP vaccines expressing firefly luciferase (Luc) protein instead of coronavirus S protein. Groups of eight rhesus macaques were immunized 2 times four weeks apart with 100 mcg of mRNA-LNPs encoding one of the spike proteins or the control mRNA encoding Luc (##FIG##0##Fig. 1B##). All rhesus macaques, except those in the control group, elicited IgG responses to Wuhan-Hu-1 S-2P, RBD, spike N-terminal domain (NTD), and S2 domain after one immunization, with titers being boosted by the second immunization (##FIG##0##Fig. 1C##, ##SUPPL##0##fig. S1##). Significantly lower S-2P IgG was present for the monomeric RBD mRNA-LNP group after the first immunization (##FIG##0##Fig. 1C##; Exact Wilcoxon <italic toggle=\"yes\">P</italic><0.05 n = 8 macaques), which may indicate a low level of <italic toggle=\"yes\">in vivo</italic> expression upon vaccination. RBD-specific serum IgG binding was highest for S-tm after one immunization (Exact Wilcoxon <italic toggle=\"yes\">P</italic><0.05 n = 8 macaques), but after two immunizations binding magnitudes were similar in all full-length S and monomer RBD mRNA-LNP groups (##FIG##0##Fig. 1C##). Similarly, after two immunizations, the serum dilution that neutralized 50% (ID<sub>50</sub>) of SARS-CoV-2 Wuhan-Hu1 live virus or pseudovirus replication was comparable across the different spike-immunized groups (##FIG##0##Fig. 1D##). We next performed competitive ELISA binding assays in which macaque plasma was used to block the binding of ACE2, RBD nAbs, and N-terminal domain nAbs. Each S-immunized group demonstrated comparable plasma blocking of ACE-2 (##FIG##0##Fig. 1E##). Compared to RBD mRNA-LNP immunization, S-tm mRNA-LNP elicited significantly higher antibodies that blocked ancestral SARS-CoV-2-specific RBD nAb DH1041 that target the RBD-1 community epitope, RBD inner face, <italic toggle=\"yes\">Sarbecovirus</italic> cross-nAb DH1047 that binds across RBD-6 and 7 epitopes (##FIG##0##Fig. 1E## and ##SUPPL##0##fig. S2##, Exact Wilcoxon P= P<0.05 for each antibody). SARS-CoV-2 VOCs broadly neutralizing antibody DH1193, which binds the RBD-4 community epitope (##SUPPL##0##fig. S2##), was also blocked to similar magnitudes by plasma antibodies from the various spike mRNA-LNP vaccinated macaques (##FIG##0##Fig. 1E##). The S-2P and S-2P 2C groups were not significantly different from each other (Exact Wilcoxon <italic toggle=\"yes\">P</italic>>0.05 n = 8 macaques) (##FIG##0##Fig. 1E##). Similarly, macaque plasma from S-tm-immunized macaques blocked ancestral SARS-CoV-2 NTD nAb DH1050.1 and non-neutralizing NTD antibody DH1052 significantly better than plasma from other immunization groups (Exact Wilcoxon <italic toggle=\"yes\">P</italic><0.05 n = 8 macaques, ##FIG##0##Fig. 1E##). Thus, nucleoside-modified mRNA LNP vaccines encoding various forms of transmembrane S protein elicited similar serum neutralization responses, with S-tm generating superior antibodies that block neutralizing epitopes (Exact Wilcoxon <italic toggle=\"yes\">P</italic><0.05 n = 8 macaques).</p>", "<title>Spike vaccination protected against SARS-CoV-2 challenge in rhesus macaques</title>", "<p id=\"P10\">To compare the protective efficacy of mRNA-LNP vaccines, we challenged macaques vaccinated with either the S-tm, the S-2P or the S-2C,2P mRNA-LNP with SARS-CoV-2 WA-1/2020 via intratracheal and intranasal routes six weeks after the second immunization (##FIG##0##Fig. 1B##). We quantified SARS-CoV-2 replication in bronchoalveolar lavage (BAL) fluid and nasal swab samples by measuring SARS-CoV-2 envelope (E) and nucleocapsid (N) gene subgenomic RNA (sgRNA). Two and four days following challenge, levels of E and N gene sgRNA in BAL samples from macaques administered each of the spike or RBD vaccines were significantly decreased as compared to Luc mRNA-LNP-immunized macaques (Exact Wilcoxon <italic toggle=\"yes\">P</italic><0.05 n = 8 macaques) (##FIG##0##Fig. 1F## and ##SUPPL##0##S3##). Macaques administered the S-2P mRNA-LNP were the only macaques to exhibit undetectable E and N gene sgRNA on day 4 and 7 in BAL fluid, while macaques in other groups had detectable BAL E and N gene sgRNA (##SUPPL##0##fig. S3##). Immunohistochemistry detected N antigen in the lungs of most Luc mRNA-LNP-immunized macaques on day 7 post-infection (##FIG##0##Fig. 1G##) with some macaques showing undetectable N antigen on day 7 (##SUPPL##0##fig. S3##). In contrast, N antigen was not detected in the lungs in either S or RBD-immunized macaques (##FIG##0##Figs. 1G## and ##SUPPL##0##S3B##). Haematoxylin and eosin staining seven days post-challenge showed Luc mRNA-LNP-immunized macaques had the highest inflammation score (##FIG##0##Fig. 1G##). Thus, S-2P, S-tm, and RBD mRNA-LNP vaccine-mediated immunity each controlled SARS-CoV-2 lung virus replication and lung pathology caused by infection.</p>", "<p id=\"P11\">In contrast to the lower airway, E and N sgRNA concentrations in nasal swab fluid for all S or RBD-vaccinated groups were not significantly different from the Luc control group. (Exact Wilcoxon <italic toggle=\"yes\">P</italic>>0.05) (##FIG##0##Fig. 1F## and ##SUPPL##0##S3##). Plasma IgG binding magnitude across all spike or RBD groups did not increase after SARS-CoV-2 challenge, hence viral antigen from replication was not sufficient to boost serum IgG responses (##FIG##0##Fig. 1C##). Thus, each Spike-based mRNA-LNP vaccine provided protective immunity for control of lower-airway SARS-CoV-2 replication but had minimal effects on upper respiratory tract sgRNA levels.</p>", "<title>S-tm mRNA-LNP vaccination elicited cross-Sarbecovirus nAbs</title>", "<p id=\"P12\">Given the increased magnitude of plasma blocking of Sarbecovirus and SARS-CoV-2 nAbs in S-tm-immunized macaques(##FIG##0##Fig. 1E##), we isolated monoclonal antibodies from three S-tm mRNA-LNP-vaccinated macaques (##SUPPL##0##fig. S4##). We sorted single memory B cells that bound to full-length SARS-CoV-2 spike protein and/or RBD (##SUPPL##0##fig. S4##). From the sorted B cells, 88 paired V<sub>H</sub> and V<sub>L</sub> immunoglobulin genes were sequenced. The distribution of V<sub>H</sub>, V, and V gene segment usage, mutation frequencies, and CDR3 lengths recapitulated the expected distributions typically seen in the macaque repertoire (##SUPPL##0##Fig. S5##) (##REF##35419009##34##). Each antibody was expressed in small-scale and assessed for binding to a panel of SARS-CoV-2, SARS-CoV-1, MERS-CoV, endemic cold coronavirus, and zoonotic coronavirus antigens in ELISA (##FIG##1##Fig. 2A##, ##SUPPL##0##S6##). We selected 57 SARS-CoV-2-specific antibodies based on their breadth and potency of CoV S or RBD binding for further analysis (##FIG##1##Figs. 2A##, ##SUPPL##0##S6## and ##SUPPL##0##S7##). Eighteen of these antibodies bound to the RBDs of various subsets of SARS-CoV-1, SARS-related bat CoV (RaTG13, RsSHC014, HKU3–1), and SARS-CoV-2-related pangolin CoV (GXP4L) (##FIG##1##Fig. 2##). More than half of the RBD antibodies bound to both Wuhan-Hu1 and BA.5 Spike proteins (##FIG##1##Fig. 2##). None of the RBD-specific antibodies bound to human endemic coronavirus (OC43, HKU1, 220E, NL63) or MERS-CoV S antigens (##FIG##1##Fig. 2A## and ##SUPPL##0##S7##). Among the remaining 39 antibodies, twelve were SARS-CoV-2-specific RBD antibodies (##SUPPL##0##fig. S7##). Fifteen were NTD-directed, with eleven of these antibodies exhibiting cross-reactivity with animal zoonotic coronavirus isolates GXP4L, RsSHC014, and RaTG13 (##SUPPL##0##fig. S7##). Twelve of the selected antibodies bound to an unidentified epitope outside of the RBD and NTD and cross-reacted with at least one animal coronavirus spike protein (##SUPPL##0##fig. S7##).</p>", "<title>Vaccine-induced broadly neutralizing monoclonal Abs that targeted the RBD outer face</title>", "<p id=\"P13\">Next, we performed competitive binding ELISA assays with a subset of 22 cross-reactive or SARS-CoV-2-specific vaccine-induced RBD mAbs and structurally-defined human CoV nAbs. We identified 7 RBD antibodies that blocked >50% of RBD outer face nAbs DH1044 and/or DH1193 (##REF##35419009##34##) binding at ng/mL concentrations (##FIG##2##Fig. 3A## and ##SUPPL##0##S8A##). Two of these outer face antibodies (DH1329and DH1333) blocked SP1–77, a potent neutralizing antibody against SARS-CoV-2 VOCs (##REF##35951767##35##). All seven rhesus antibodies that blocked DH1044 or DH1193 were broad neutralizers of SARS-CoV-2 VOCs, and DH1341, DH1343, DH1344, and DH1345 neutralized all tested SARS-CoV-2 VOCs including Omicron sublineage pseudoviruses (##FIG##2##Fig. 3B##–##FIG##2##D##, and ##SUPPL##0##S8##). Three additional antibodies blocked DH1044, but were minimally neutralizing or non-neutralizing (##SUPPL##0##fig. S8##). Similar to DH1044, no outer face antibodies exhibited cross-neutralization of SHC014 or SARS-CoV-1 (##FIG##2##Fig. 3B##). Finally, we confirmed the epitopes of the outer face nAbs by performing negative stain electron microscopy of the antigen binding fragments (Fabs) or the full-length IgG in complex with SARS-CoV-2 S-2P. The SARS-CoV-2 nAbs DH1333, DH1329, and DH1345 bound to the outer face of the RBD (##FIG##3##Fig. 4A##), explaining their competition with DH1044 or DH1193 for binding to spike (##FIG##2##Fig. 3A##). DH1333 and DH1329 bound down RBDs with a binding mode similar to DH1044 (##FIG##3##Fig. 4B##); whereas DH1345 bound up RBDs at a site most similar to the RBD-4 community epitope recognized by DH1193 (##FIG##3##Fig. 4C## and ##SUPPL##0##S2##).</p>", "<title>Vaccine-induced cross-sarbecovirus nAbs that targeted the inner face of RBD</title>", "<p id=\"P14\">Among the subset of 22 cross-reactive or SARS-CoV-2-specific vaccine-induced RBD mAbs tested, six antibodies blocked cross-nAbs DH1047 and DH1235 which bind to the inner face of the RBD and broadly neutralize Sarbecoviruses (##REF##34726473##30##–##REF##35732171##32##, ##REF##37749254##36##) (##FIG##2##Fig. 3A##). The six macaque antibodies also blocked CR3022 binding to spike (##FIG##2##Fig. 3A##). CR3022 is a SARS-CoV-1 nAb that cross-reacts with SARS-CoV-2 (##REF##32065055##37##, ##REF##32245784##38##). Consistent with targeting the DH1047 inner face epitope, RBD nAbs DH1338 and DH1337 neutralized SARS-CoV-2, SARS-CoV, and bat CoV RsSCH014 (##FIG##2##Fig. 3B##). A third antibody, DH1328 neutralized replication-competent SARS-CoV-2 D614G and BatCoV RsSHC014 (##FIG##2##Fig. 3B##). One additional antibody blocked outer face antibodies, but was non-neutralizing (##SUPPL##0##fig. S8##). Like DH1047, none of the inner face antibodies neutralized BA.4/5 virus (##FIG##2##Fig. 3C##). Thus, mRNA-LNP S-tm vaccination generated cross-Sarbecovirus nAbs that were distinct from the Omicron sublineage broad nAbs.</p>", "<p id=\"P15\">Negative stain electron microscopy of the antibody-spike protein complexes confirmed that the cross-Sarbecovirus nAbs (DH1338, DH1337, DH1328) bound to the inner face of RBD similar to DH1047 (##FIG##3##Figs. 4D##–##FIG##3##E## and ##SUPPL##0##S6D##). DH1328 targeted the same epitope as DH1047 but had a slightly different binding angle of approach compared to DH1338, DH1337, and DH1047 (##FIG##3##Fig. 4D##–##FIG##3##E##). Thus, NSEM analysis demonstrated that vaccine-induced inner face antibodies bound an epitope overlapping with RBD-6 and7 community epitopes just like human nAb, DH1047.</p>", "<title>Dynamic SARS-CoV-2 VOCs sensitivity to neutralizing monoclonal RBD Abs</title>", "<p id=\"P16\">Neutralization resistance mutations have accumulated in SARS-CoV-2 since the beginning of the COVID-19 pandemic (##REF##33684923##39##–##REF##36535326##45##). Next, we examined how vaccine-induced RBD nAbs neutralized SARS-CoV-2 VOCs that arose at various points during the COVID-19 pandemic. First, six of the nAbs, including DH1338, neutralized 8 of the variants but lacked neutralization of either BA.1 or BA.4/5 (##FIG##2##Fig. 3B## and ##FIG##2##C##). Second, antibodies like DH1329 and DH1330 neutralized early variants, lost neutralization activity against Delta, but also neutralized Omicron BA.1 (##FIG##2##Fig. 3B##–##FIG##2##D##), which arose after the Delta VOC. Third, DH1333 exhibited highly potent neutralization for all VOCs observed prior to the BA.1 VOC (##FIG##2##Fig. 3B##–##FIG##2##D##). Although, DH1333 did not neutralize BA.1, it neutralized BA.4/5 pseudovirus with a 30 ng/mL IC50 titer (##FIG##2##Fig. 3B##–##FIG##2##D##). Thus, the vaccine induced a polyclonal RBD neutralizing antibody response had multiple neutralization patterns against VOCs.</p>", "<title>Structural analysis of inner RBD human and macaque broad Sarbecovirus neutralizing antibodies</title>", "<p id=\"P17\">Next, to visualize the DH1338 epitope, we used cryo-EM to determine a structure of the DH1338 antigen-binding fragment (Fab) bound to the SARS-CoV-2 S to an overall resolution of 3.1 Å and performed local refinement to further resolve the Fab-RBD interface at 3.4 Å (##FIG##4##Fig. 5A##–##FIG##4##E##, ##SUPPL##0##S9##, ##SUPPL##0##table S1##–##SUPPL##0##2##). Like DH1047, the epitope of DH1338 is on the RBD inner face and overlaps with the ACE2 binding site on the RBD (##FIG##4##Fig. 5E##). The RBD-epitope of DH1338 resembled that of S2X259, and overlapped with the DH1047 epitope, although DH1338 had a smaller binding footprint compared to DH1047 (##FIG##4##Fig. 5B##–##FIG##4##E##, ##SUPPL##0##S10##). Like S2X259 and DH1047, DH1338 utilized its HCDR3 loop to contact the RBD β-2 strand (##FIG##4##Fig. 5C##). The DH1338 HCDR3 residue Tyr100D makes extensive H-bonds with residues Ser371, Thr376, Phe377, and Tyr369 in the RBD ß-2 strand. The light chain buried surface area (BSA) at the RBD interface is dominated by LCDR1 interactions (##SUPPL##0##Table S1##–##SUPPL##0##2##). Four residues in the LCDR1 Ser28, Ser30, Ser31, and Tyr32, as well as residue Ser67 in the framework region contact the RBD. The LCDR1 residues Ser30 and Ser 31 H-bond via their side chain hydroxyls with the side chain of residue Asp405, and Tyr32 H-bonds via its side chain hydroxyl with the carbonyl oxygen of RBD residue Gly404 and the side chain of residue Asp405, respectively. Another H-bond was observed between the main chain carbonyl oxygen of the LCDR3 residue Ser92 and main chain nitrogen of RBD residue Val503. Hence, the non-stabilized S mRNA-LNP-vaccinated macaques elicited cross-nAbs that used different molecular interactions to bind to the same RBD epitope as DH1047.</p>", "<title>Vaccine induction of protective antibodies against a pre-emergent BatCoV</title>", "<p id=\"P18\">DH1338 exhibited broad neutralization of Sarbecoviruses (##FIG##2##Fig. 3##), thus we investigated its ability to protect against a mouse-adapted bat Sarbecovirus, RsSHC014- MA15. RsSHC014 is a SARS-like virus from Chinese horseshoe bats with potential for human infection since it can infect human primary airway cells and binds human ACE2 (##REF##26552008##29##). We challenged mice with 1×10<sup>4</sup> PFU of pathogenic RsSHC014 MA15 virus (##FIG##5##Fig. 6A##). Twelve-month-old BALB/c mice were passively administered 300 μg of DH1338 12 hours prior to infection as prophylaxis or 12 hours post-infection as a therapy (##FIG##5##Fig. 6A##). Negative control mice received anti-influenza antibody CH65 12 hours prior to infection. Prophylactic DH1338 treatment protected mice from weight loss through 4 dpi and therapeutic treatment halted weight loss at day 2 post infection (##FIG##5##Fig. 6B##). Prophylactic DH1338 administration suppressed infectious virus in the lungs to undetectable levels in all but one mouse (##FIG##5##Fig. 6B##). Therapeutic administration of DH1338 suppressed infectious virus in the lungs to undetectable levels in four of ten mice and lowered infectious virus in the remaining six mice compared to the negative control group (##FIG##5##Fig. 6C##). Additionally, prophylactic administration of DH1338 completely protected all mice from macroscopic lung damage, as determined by the lung discoloration score (##FIG##5##Fig. 6D##). Finally, there was no mortality observed in any of the antibody groups (##FIG##5##Fig. 6E##). These results indicated mRNA vaccination with spike lacking 2P substitutions induced nAbs that provide prophylactic and therapeutic benefits against pre-emergent zoonotic Sarbecovirus infection in an aged mouse model.</p>" ]	[ "<title>DISCUSSION</title>", "<p id=\"P19\">Here, we show that the Wuhan-Hu-1 spike delivered as an mRNA can induce broadly reactive antibodies that either bind to the RBD outer face and neutralize multiple late Omicron variants or bind to the RBD inner face and neutralize SARS-CoV-1 and preemergent Sarbecoviruses. The 2P substitutions were not required for induction of such neutralizing antibodies. Moreover, we demonstrate different neutralization patterns by the Wuhan-Hu-1 RBD-induced antibodies. A subset of antibodies were capable of neutralizing XBB.1.5 despite being elicited by the Wuhan-Hu-1 ancestral isolate of SARS-CoV-2. Thus, these results show antibodies induced by ancestral versions of SARS-CoV-2 Spike have the potential to contribute to neutralization of current SARS-CoV-2 isolates. These results also show that there is a neutralizing antibody epitope that remains conserved between XBB.1.5 and the ancestral isolates of SARS-CoV-2. Our structural studies identified the DH1193 epitope as one of these conserved epitopes on SARS-CoV-2 S variants targeted by macaque antibodies. Thus, both human infection-induced and macaque vaccine-induced antibodies can target either the outer or the inner faces of the RBD to broadly neutralize CoVs (##REF##34726473##30##–##REF##35732171##32##, ##REF##37749254##36##).</p>", "<p id=\"P20\">The neutralization patterns of the broadly neutralizing Sarbecovirus antibodies showed that Omicron sublineages have mutated the inner face epitope that is conserved on SARS-CoV-1 and animal Sarbecoviruses. Hence, vaccines aiming to elicit the broadest response against both SARS-CoV-2 VOCs and SARS-like Sarbecoviruses should aim to elicit antibodies to both RBD inner and outer face epitopes. Wuhan-Hu-1 S-tm mRNA-LNP vaccines here and S nanoparticle vaccines in previous studies (##UREF##5##46##, ##REF##36274085##47##) elicited both responses in nonhuman primates, suggesting next-generation vaccines may only need to selectively boost antibodies targeting the most conserved epitopes on each face of the RBD. Designing resurfaced receptor binding domains that present only the conserved epitopes in the outer and inner faces would be one immunogen approach to directing antibodies to these conserved epitopes. Such vaccine approaches may be necessary since we observed only four omicron sublineage nAbs out of 88 total antibodies.</p>", "<p id=\"P21\">In summary, pan-coronavirus vaccines may benefit from the contributions of distinct broadly neutralizing antibodies that cooperate to provide immunity against SARS-CoV-2 VOCs and other Sarbecoviruses. Our findings show that conserved neutralizing epitopes present on ancestral SARS-CoV-2 RBD are present on the outer face of SARS-CoV-2 VOCs including XBB.1.5 RBD, as well as the inner face of pre-emergent Sarbecovirus RBDs. Boosting regimens will need to target these two epitopes to increase their immunogenicity and to convert such antibody responses to dominance. Immunogen designs such as non-stabilized spikes or engineered RBD nanoparticles (##REF##33971664##48##) may be strategies that can convert subdominant antibody responses to dominant responses. Finally, strategies of full-length S should consider non-stabilized S-tm as vaccine candidates.</p>" ]	[]	[ "<p id=\"P1\">Contributed equally</p>", "<p id=\"P2\">Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.</p>", "<title>One Sentence Summary:</title>", "<p id=\"P3\">Non-stabilized SARS-CoV-2 Spike mRNA vaccination activated B cells that target either conserved epitopes on SARS-CoV-2 Omicron variants of concern, or cross-neutralizing epitopes on pre-emergent Sarbecoviruses.</p>" ]	[ "<title>Supplementary Material</title>" ]	[ "<title>Acknowledgments:</title>", "<p id=\"P44\">We thank Margaret Deyton, Victoria Gee-Lai, Aja Sanzone, Nolan Jamieson, Lena Smith, Nicole De Naeyer and Conor Anderson for technical assistance. We thank Elizabeth Donahue, Cynthia Nagle and Kelly Soderberg for program management. We thank John Harrison, Alex Granados, Adrienne Goode, Anthony Cook, Alan Dodson, Katelyn Steingrebe, Bridget Bart, Laurent Pessaint, Alex VanRy, Daniel Valentin, Amanda Strasbaugh, and Mehtap Cabus for assistance with macaque studies. PCR purification for sequencing was performed by the DHVI Viral Genetics Analysis Core Facility. Single B cell sorting was performed in the DHVI Flow Cytometry Facility.</p>", "<title>Funding:</title>", "<p id=\"P45\">This work was supported by funds from:</p>", "<p id=\"P46\">The State of North Carolina with funds from the federal CARES Act (to B.F.H.)</p>", "<p id=\"P47\">NIH, NIAID, DAIDS grant AI142596 (to B.F.H.)</p>", "<p id=\"P48\">NIH, NIAID, DAIDS grant AI158571 (to B.F.H.)</p>", "<p id=\"P49\">UC6-AI058607 (to G.D.S.)</p>", "<p id=\"P50\">NIH, NIAID, grants R01AI146101 and R01AI153064 (to N.P.)</p>", "<p id=\"P51\">The Ting Tsung & Wei Fong Chao Foundation (to B.F.H.)</p>", "<p id=\"P52\">Hanna H Gray Fellowship from the Howard Hughes Medical Institute (to D.R.M.)</p>", "<p id=\"P53\">Postdoctoral Enrichment Award from the Burroughs Wellcome Fund (to D.R.M.).</p>", "<title>Data and materials availability:</title>", "<p id=\"P43\">All data are available in the main text or the ##SUPPL##0##supplementary materials##. Electron microscopy data has been deposited under accession numbers in PDB: 8DPZ, 8DTK,7RAL. Materials are available with a Materials transfer agreement.</p>" ]	[ "<fig position=\"float\" id=\"F1\"><label>Figure 1.</label><caption><title>SARS-CoV-2 mRNA-lipid nanoparticle (LNP) vaccines elicited neutralizing antibodies in rhesus macaques.</title><p id=\"P56\">(A) Schematic diagram of the mRNA-LNP vaccines. mRNA-LNP vaccines that encode monomeric receptor-binding domain (RBD), K986P/V987P mutations stabilized full-length spike (Spike 2P), S483C/D985C/K986P/V987P mutations stabilized full-length spike (Spike 2C 2P), or transmembrane spike (S-tm) were compared. A luciferase expressing mRNA-LNP vaccine was made as a control. (B) Rhesus macaque vaccination and challenge regimen. Rhesus macaque (n=8 per group) were immunized intramuscularly by mRNA-LNP vaccine two times in weeks 0 and 4, followed by 10<sup>5</sup> PFU of SARS-CoV-2 challenge at week 10. Nasal swab and Bronchoalveolar lavage (BAL) samples were collected on post-challenge days 0, 2, 4, and 7. (C) Vaccine-induced SARS-CoV-2 specific IgG binding titers. Serum IgG binding to Spike 2P (S-2P) and RBD was tested by ELISA and shown as log area under the curve (AUC). Symbols indicate the group mean value ± SEM of three replicates. Arrows indicate timing of immunization. (D) SARS-CoV-2 mRNA-lipid nanoparticle (LNP) vaccines elicited neutralizing antibodies against SARS-CoV-2 viruses in rhesus macaques. ID<sub>50</sub> titers of serum micro- and pseudovirus neutralization of SARS-CoV-2 D614G infection of ACE2-expressing 293T cells. Serum was examined after two immunizations. Each symbol indicates one animal. (E) Sera blocking of ACE-2, RBD neutralizing antibodies DH1041 and DH1047, NTD neutralizing antibodies DH1050.1, and NTD non-neutralizing antibody DH1052 binding to spike. The group mean percentage ± SEM of blocking is shown. Arrows indicate timing of immunization. (F) Reduced SARS-CoV-2 viral replication in the lower respiratory tract of vaccinated macaques. SARS-CoV-2 nucleocapsid gene (N gene) sgRNA was quantified in bronchoalveolar lavage (BAL) and nasal swab samples on Day 2. (G) Quantification of lung inflammation and lung viral nucleocapsid positivity determined by immunohistochemistry of lung tissue sections seven days after challenge. In each panel, symbols represent individual macaques.</p></caption></fig>", "<fig position=\"float\" id=\"F2\"><label>Figure 2.</label><caption><title>Monoclonal antibodies isolated from wild-type mRNA-LNP immunized macaques cross-react with SARS-CoV-2 variants and SARS-related betacoronaviruses.</title><p id=\"P57\">(A) Summary table of specificities of isolated macaque monoclonal antibodies. (B) Monoclonal antibodies isolated from S-tm mRNA-LNP vaccinated rhesus macaques bind to ectodomain, RBD, NTD from SARS-CoV-2, SARS-CoV-1, SARS-related animal betacoronaviruses, MERS-CoV, and endemic human coronaviruses. The mean log AUC values are shown in the heatmap. (C) Proportion of BA.5 spike reactive, SARS-CoV-1 cross reactive, and human and animal Sarbecovirus-reactive monoclonal antibodies isolated from wild-type mRNA-LNP immunized macaques.</p></caption></fig>", "<fig position=\"float\" id=\"F3\"><label>Figure 3.</label><caption><title>Distinct antibody clones confer pan-SARS-CoV-2 variants of concern neutralization or Sarbecovirus cross-neutralization.</title><p id=\"P58\">(A) The IC50 titer for vaccine-induced rhesus macaque cross-neutralizing RBD antibodies blocking potent vaccine-induced or infection-induced human RBD-reactive monoclonal antibodies. (B) Monoclonal antibodies isolated from S-tm mRNA-LNP vaccinated rhesus macaques neutralize replicating SARS-CoV-2, SARS-CoV, RsSCHC014 viruses, and SARS-CoV-2 pseudovirus variants of concern. (C) Monoclonal antibody neutralization against pseudoviruses of SARS-CoV-2 Omicron sublineages (BA.4/BA.5, BA.4.6, BA2.75.2, BF.7, BQ.1.1, XBB.1 AND XBB1.5) variants in 293T-ACE2 cells. (D) Summary of monoclonal nAb activity against various SARS-CoV-2 VOCs. Rows show neutralization of sequential SARS-CoV-2 VOCs by four individual clones. Columns represent neutralization against the virus listed at the top of the column. Lack of neutralization is shown as a break in the gray arrow and outlining the virus in salmon.</p></caption></fig>", "<fig position=\"float\" id=\"F4\"><label>Figure 4.</label><caption><title>Structural similarities of vaccine-induced neutralizing macaque antibodies and infection-induced human neutralizing antibodies.</title><p id=\"P59\">Structure of antibody bound to spike was determined by negative stain electron microscopy. 3D reconstruction of vaccine-induced and infection-induced cross-neutralizing antibodies (various colors) bound to SARS-CoV-2 Spike (gray). (A) The epitopes of broad SARS-CoV-2-neutralizing RBD antibodies that target outer RBD face. (B-C) Superimposition of Fab regions to compare binding angles of approach for vaccine-induced antibodies (B) DH1329 and DH1333 or (C) DH1345 with infection induced human outer face antibodies DH1044 or DH1193. (D) The epitopes of cross-neutralizing RBD antibodies that target inner RBD face. (E) Superimposition of Fab regions to compare human infection-induced cross-Sarbecovirus neutralizing antibody DH1047 with vaccine-induced antibodies (DH1328, DH1337, DH1338). Fab regions are depicted in different colors and SARS-CoV-2 S-2P spike protein is shown in gray.</p></caption></fig>", "<fig position=\"float\" id=\"F5\"><label>Figure 5.</label><caption><title>Cryo-EM reconstruction of DH1338 Fab bound to SARS-CoV-2 S protein.</title><p id=\"P60\">(A) 3-Fab bound complex of DH1338 to SARS-CoV-2 S HexaPro Protein reconstruction (EMD-27606). Colored by region. (B) Antibody binding interface. RBD shown in surface representation and colored red, with DH1338 shown in blues, DH1047 shown in yellows, and S2X259 shown in teals. (C) Top, DH1338 HCDR3 loop shown in brown, polar contacts with RBD, shown in black dashed lines. Middle, DH1047 HC polar contacts with RBD. Bottom, S2X259 HC polar contact with RBD. (D) Light chain polar contacts of DH1338 (top), DH1047 (middle), and S2X259 (bottom). (E) RBD is shown in black and ACE2 binding footprint is colored yellow. Binding footprints of antibodies DH1338 (PDB: 8DPZ), DH1047 (PDB: 8DTK), CR3022 (PDB: 6YLA), and S2X259 (PDB: 7RAL) are shown in purple. All RBDs were aligned to PDB: 6M0J, for RBD representation.</p></caption></fig>", "<fig position=\"float\" id=\"F6\"><label>Figure 6.</label><caption><title>Macaque antibody DH1338 confers prophylactic and therapeutic protection against batCoV RsSHC014 replication in aged mice.</title><p id=\"P61\">(A) Scheme of prophylactic and therapeutic administration of DH1338 in mice. DH1338 or control antibody, CH65, were administered either prophylactically 12 hours before infection, or therapeutically 12 hours after infection. Disease-susceptible aged mice (n=10) were challenged with a mouse-adapted bat coronavirus, SHC014-MA15. (B) The percent weight loss is shown for mice treated prophylactically or therapeutically. Values shown are group mean ± SEM. (C) Lung viral replication of SHC014-MA15 is shown for mice treated prophylactically or therapeutically with DH1338 and CH65 at 4 days post-infection (dpi). (D) Lung discoloration scores are shown for mice treated with DH1338 or CH65 prophylactically and therapeutically. (E) Percent survival is shown for all three groups challenged with SHC014-MA15. Horizontal bars are mean± SEM. *, Exact Wilcoxon <italic toggle=\"yes\">P</italic><0.05 n = 8–10 mice.</p></caption></fig>" ]	[]	[]	[]	[]	[]	[]	[ "<supplementary-material id=\"SD1\" position=\"float\" content-type=\"local-data\"><label>Supplement 1</label></supplementary-material>" ]	[ "<fn-group><fn fn-type=\"COI-statement\" id=\"FN2\"><p id=\"P54\">Competing interests:</p><p id=\"P55\">DW and NP are inventors on patents regarding nucleoside modified mRNA. Ying Tam and Christopher Barbosa are employees of Acuitas Therapeutics. Rory Henderson has patents regarding engineered forms of Spike proteins. Barton Haynes, Kevin Saunders, Dapeng Li, Priyamvada Acharya, and Xiaozhi Lu have patents regarding human antibodies and their uses. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022. N.P. is a member of the Scientific Advisory Board of AldexChem.</p></fn></fn-group>" ]	[ "<graphic xlink:href=\"nihpp-2023.12.18.572191v1-f0001\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.18.572191v1-f0002\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.18.572191v1-f0003\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.18.572191v1-f0004\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.18.572191v1-f0005\" position=\"float\"/>", "<graphic xlink:href=\"nihpp-2023.12.18.572191v1-f0006\" position=\"float\"/>" ]	[ "<media xlink:href=\"media-1.pdf\" id=\"d64e1185\" position=\"anchor\"/>" ]	[{"label": ["1."], "mixed-citation": [".("], "source": ["Johns Hopkins University"]}, {"label": ["8."], "surname": ["Premkumar"], "given-names": ["L."], "article-title": ["The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients"], "source": ["Sci Immunol"], "volume": ["5"], "year": ["2020"]}, {"label": ["15."], "surname": ["Xu"], "given-names": ["C."], "article-title": ["Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM"], "source": ["Sci Adv"], "volume": ["7"], "year": ["2021"]}, {"label": ["16."], "surname": ["Diaz-Salinas"], "given-names": ["M. A."], "article-title": ["Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike"], "source": ["Elife"], "volume": ["11"], "year": ["2022"]}, {"label": ["18."], "mixed-citation": [".("], "source": ["Centers for Disease Control and Prevention (CDC)"]}, {"label": ["46."], "surname": ["Saunders"], "given-names": ["K. O."], "article-title": ["Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses"], "source": ["Nature"], "year": ["2021"]}, {"label": ["57."], "surname": ["L"], "given-names": ["S."], "source": ["The PyMOL Molecular Graphics System."], "year": ["2015"]}]	{ "acronym": [], "definition": [] }	60	CC BY	no	2024-01-13 00:14:50	bioRxiv. 2023 Dec 19;:2023.12.18.572191	oa_package/61/6c/PMC10769253.tar.gz

Subsets and Splits

No community queries yet

The top public SQL queries from the community will appear here once available.